Flow of activation from V1 to frontal cortex in humans. A framework for defining "early" visual processing.
This study provides a time frame for the initial trajectory of activation flow along the dorsal and ventral visual processing streams and for the initial activation of prefrontal cortex in the human. We provide evidence that this widespread system of sensory, parietal, and prefrontal areas is activated in less than 30 ms, which is considerably shorter than typically assumed in the human event-related potential (ERP) literature and is consistent with recent intracranial data from macaques. We find a mean onset latency of activity over occipital cortex (C1(e)) at 56 ms, with dorsolateral frontal cortex subsequently active by just 80 ms. Given that activity in visual sensory areas typically continues for 100-400 ms prior to motor output, this rapid system-wide activation provides a time frame for the initiation of feedback processes onto sensory areas. There is clearly sufficient time for multiple iterations of interactive processing between sensory, parietal, and frontal areas during brief (e.g., 200 ms) periods of information processing preceding motor output. High-density electrical mapping also suggested activation in dorsal stream areas preceding ventral stream areas. Our data suggest that multiple visual generators are active in the latency range of the traditional C1 component of the ERP, which has often been taken to represent V1 activity alone. Based on the temporal pattern of activation shown in primate recordings and the evidence from these human recordings, we propose that only the initial portion of the C1 component (approximately the first 10-15 ms; C1(e)) is likely to represent a response that is predominated by V1 activity. These data strongly suggest that activity represented in the "early" ERP components such as P1 and N1 (and possibly even C1) is likely to reflect relatively late processing, after the initial volley of sensory afference through the visual system and involving top-down influences from parietal and frontal regions.


Advances in Crop Improvement and Delivery Research for Nutritional Quality and Health Benefits of Groundnut (Arachis hypogaea L.).
Groundnut is an important global food and oil crop that underpins agriculture-dependent livelihood strategies meeting food, nutrition, and income security. Aflatoxins, pose a major challenge to increased competitiveness of groundnut limiting access to lucrative markets and affecting populations that consume it. Other drivers of low competitiveness include allergens and limited shelf life occasioned by low oleic acid profile in the oil. Thus grain off-takers such as consumers, domestic, and export markets as well as processors need solutions to increase profitability of the grain. There are some technological solutions to these challenges and this review paper highlights advances in crop improvement to enhance groundnut grain quality and nutrient profile for food, nutrition, and economic benefits. Significant advances have been made in setting the stage for marker-assisted allele pyramiding for different aflatoxin resistance mechanisms-in vitro seed colonization, pre-harvest aflatoxin contamination, and aflatoxin production-which, together with pre- and post-harvest management practices, will go a long way in mitigating the aflatoxin menace. A breakthrough in aflatoxin control is in sight with overexpression of antifungal plant defensins, and through host-induced gene silencing in the aflatoxin biosynthetic pathway. Similarly, genomic and biochemical approaches to allergen control are in good progress, with the identification of homologs of the allergen encoding genes and development of monoclonal antibody based ELISA protocol to screen for and quantify major allergens. Double mutation of the allotetraploid homeologous genes, FAD2A and FAD2B, has shown potential for achieving >75% oleic acid as demonstrated among introgression lines. Significant advances have been made in seed systems research to bridge the gap between trait discovery, deployment, and delivery through innovative partnerships and action learning.


Splenectomy for people with thalassaemia major or intermedia.
Thalassaemia is a genetic disease of the haemoglobin protein in red blood cells. It is classified into thalassaemia minor, intermedia and major, depending on the severity of the disease and the genetic defect. Thalassaemia major and intermedia require frequent blood transfusions to compensate for the lack of well-functioning red blood cells, although this need is significantly less in thalassaemia intermedia.Damaged or defective red blood cells are normally eliminated in the spleen. In people with thalassaemia there is a large quantity of defective red blood cells which results in an enlarged hyperfunctioning spleen (splenomegaly). Removal of the spleen may thus prolong red blood cell survival by reducing the amount of red blood cells removed from circulation and may ultimately result in the reduced need for blood transfusions. To assess the efficacy and safety of splenectomy in people with beta-thalassaemia major or intermedia. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Review Group's Haemoglobinopathies Trials Register, compiled from searches of electronic databases and the handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of the most recent search: 25 April 2016. We included randomised controlled studies and quasi-randomised controlled studies of people of any age with thalassaemia major or intermedia, evaluating splenectomy in comparison to conservative treatment (transfusion therapy and iron chelation) or other forms of splenectomy compared to each other (laparoscopic, open, radio-frequency). Two authors independently selected and extracted data from the single included study using a customised data extraction form and assessed the risk of bias. One study, including 28 participants was included in the review; the results were described, primarily, in a narrative manner. The study assessed the feasibility of splenectomy using laparoscopy in comparison to open surgery. Given the lack of detail regarding the study methods beyond randomisation, the overall risk of bias for this study was unclear. The study was carried out over a period of 3.5 years, with each participant followed up only until discharge (less than one week after the intervention); it did not assess the majority of the outcomes outlined in this review (including two of the three primary outcomes, frequency of transfusion and quality of life). A total of three serious post-operative adverse events (the review's third primary outcome) were reported in the laparoscopic splenectomy group (one case of atelectasis and two cases of bleeding), compared to two events of atelectasis in the open surgery group; however, there were no significant differences between the groups for either atelectasis, risk ratio 0.50 (95% confidence interval 0.05 to 4.90) or for bleeding, risk ratio 5.00 (95% confidence interval 0.26 to 95.61). In addition, the study also reported three serious cases of intra-operative bleeding in the laparoscopic group which mandated conversion to open surgery, although the difference between groups was not statistically significant, risk ratio 7.00 (95% confidence interval 0.39 to 124.14). These effect estimates are based on very small numbers and hence are unreliable and imprecise. From this small study, there appeared to be an advantage for the laparoscopic approach, in terms of post-operative hospital stay, although the group difference was not large (median difference of 1.5 days, P = 0.03). The review was unable to find good quality evidence, in the form of randomised controlled studies, regarding the efficacy of splenectomy for treating thalassaemia major or intermedia. The single included study provided little information about the efficacy of splenectomy, and compared open surgery and laparoscopic methods. Further studies need to evaluate the long-term effectiveness of splenectomy and the comparative advantages of surgical methods. Due to a lack of high quality evidence from randomised controlled studies, well-conducted observational studies may be used to answer this question.


God, faith, and death: the impact of biological and religious correlates on mortality.
Marked denominational mortality differentials have been documented for various time periods and geographic locations. From a historical perspective, death rates among Catholics are often found to be higher than those among Protestants or Jews. Using a conceptual model based on the life history approach, biomedical and sociocultural factors of causation are extrapolated. In total, 5513 historical entries from family reconstitution were available. Selection of data was guided by the inclusion of information about religious affiliation. Only married couples with children as well as single mothers were considered. Of these, 1855 entries were of Roman Catholic (C), 1143 of Lutheran/Protestant (L/P), and 609 of Reformed Calvinist (R) denomination. With a focus on both adult and subadult mortality, this study attempted to document that the cultural patterns associated with religious behavior are merely proximate determinants, while the ultimate causes are biological in nature. Survival prospects depended on demographic and familial characteristics such as age-at-first-birth, spacing and stopping behavior, infant care, and targeted sibship size, rather than religiosity.


Tracking the recognition of static and dynamic facial expressions of emotion across the life span.
The effective transmission and decoding of dynamic facial expressions of emotion is omnipresent and critical for adapted social interactions in everyday life. Thus, common intuition would suggest an advantage for dynamic facial expression recognition (FER) over the static snapshots routinely used in most experiments. However, although many studies reported an advantage in the recognition of dynamic over static expressions in clinical populations, results obtained from healthy participants are contrasted. To clarify this issue, we conducted a large cross-sectional study to investigate FER across the life span in order to determine if age is a critical factor to account for such discrepancies. More than 400 observers (age range 5-96) performed recognition tasks of the six basic expressions in static, dynamic, and shuffled (temporally randomized frames) conditions, normalized for the amount of energy sampled over time. We applied a Bayesian hierarchical step-linear model to capture the nonlinear relationship between age and FER for the different viewing conditions. Although replicating the typical accuracy profiles of FER, we determined the age at which peak efficiency was reached for each expression and found greater accuracy for most dynamic expressions across the life span. This advantage in the elderly population was driven by a significant decrease in performance for static images, which was twice as large as for the young adults. Our data posit the use of dynamic stimuli as being critical in the assessment of FER in the elderly population, inviting caution when drawing conclusions from the sole use of static face images to this aim.


The crowded space of local accountability for maternal, newborn and child health: a case study of the South African health system.
Global and national accountability for maternal, newborn and child health (MNCH) is increasingly invoked as central to addressing preventable mortality and morbidity. Strategies of accountability for MNCH include policy and budget tracking, maternal and perinatal death surveillance, performance targets and various forms of social accountability. However, little is known about how the growing number of accountability strategies for MNCH is received by frontline actors, and how they are integrated into the overall functioning of local health systems. We conducted a case study of mechanisms of local accountability for MNCH in South Africa, involving a document review of national policies, programme reports, and other literature directly or indirectly related to MNCH, and in-depth research in one district. The latter included observations of accountability practices (e.g. through routine meetings) and in-depth interviews with 37 purposely selected health managers and frontline health workers involved in MNCH. Data collection and analysis were guided by a framework that defined accountability as answerability and action (both individual and collective), addressing performance, financial and public accountability, and involving both formal and informal processes. Nineteen individual accountability mechanisms were identified, 10 directly and 9 indirectly related to MNCH, most of which addressed performance accountability. Frontline managers and providers at local level are targeted by a web of multiple, formal accountability mechanisms, which are sometimes synergistic but often duplicative, together giving rise to local contexts of 'accountability overloads'. These result in a tendency towards bureaucratic compliance, demotivation, reduced efficiency and effectiveness, and limited space for innovation. The functioning of formal accountability mechanisms is shaped by local cultures and relationships, creating an accountability ecosystem involving multiple actors and roles. There is a need to streamline formal accountability mechanisms and consider the kinds of actions that build positive cultures of local accountability.


Peptidines: glycine-amidine-based oligomers for solution- and solid-phase synthesis.
Efforts to emulate biological oligomers have given rise to a host of useful technologies, ranging from solid-phase peptide and nucleic acid synthesis to various peptidomimetic platforms. Herein we introduce a novel class of peptide-like oligomers called "peptidines" wherein each carbonyl O-atom within poly-N-alkyl glycine oligomers is replaced with a functionalized N-atom. Compared to peptoids or peptides, the presence of this amidine N-substituent in peptidines effectively doubles the number of diversification sites per monomeric unit, and can decrease their overall conformational flexibility. We have developed iterative solution- and solid-phase protocols for the straightforward assembly of peptidines containing diverse backbone and amidine substituents, derived from readily available primary and secondary amines. We have also performed crystallographic and computational studies, which demonstrate a strong preference for the trans (E) amidine geometry. Given their straightforward synthetic preparation and high functional group density, peptidines have the potential to serve as useful tools for library generation, peptide mimicry, and the identification of biologically active small molecules.


Tracking the evolutionary history of Cortinarius species in section Calochroi, with transoceanic disjunct distributions.
Cortinarius species in section Calochroi display local, clinal and circumboreal patterns of distribution across the Northern Hemisphere where these ectomycorrhizal fungi occur with host trees throughout their geographical range within a continent, or have disjunct intercontinental distributions, the origins of which are not understood. We inferred evolutionary histories of four species, 1) C. arcuatorum, 2) C. aureofulvus, 3) C. elegantior and 4) C. napus, from populations distributed throughout the Old World, and portions of the New World (Central- and North America) based on genetic variation of 154 haplotype internal transcribed spacer (ITS) sequences from 83 population samples. By describing the population structure of these species across their geographical distribution, we attempt to identify their historical migration and patterns of diversification. Models of population structure from nested clade, demographic and coalescent-based analyses revealed genetically differentiated and geographically structured haplotypes in C. arcuatorum and C. elegantior, while C. aureofulvus showed considerably less population structure and C. napus lacked sufficient genetic differentiation to resolve any population structure. Disjunct populations within C. arcuatorum, C. aureofulvus and C. elegantior show little or no morphological differentiation, whereas in C. napus there is a high level of homoplasy and phenotypic plasticity for veil and lamellae colour. The ITS sequences of the type specimens of C. albobrunnoides and C. albobrunnoides var. violaceovelatus were identical to one another and are treated as one species with a wider range of geographic distribution under C. napus. Our results indicate that each of the Calochroi species has undergone a relatively independent evolutionary history, hypothesised as follows: 1) a widely distributed ancestral population of C. arcuatorum diverged into distinctive sympatric populations in the New World; 2) two divergent lineages in C. elegantior gave rise to the New World and Old World haplotypes, respectively; and 3) the low levels of genetic divergence within C. aureofulvus and C. napus may be the result of more recent demographic population expansions. The scenario of migration via the Bering Land Bridge provides the most probable explanation for contemporaneous disjunct geographic distributions of these species, but it does not offer an explanation for the low degree of genetic divergence between populations of C. aureofulvus and C. napus. Our findings are mostly consistent with the designation of New World allopatric populations as separate species from the European counterpart species C. arcuatorum and C. elegantior. We propose the synonymy of C. albobrunnoides, C. albobrunnoides var. violaceovelatus and C. subpurpureophyllus var. sulphureovelatus with C. napus. The results also reinforce previous observations that linked C. arcuatorum and C. aureofulvus displaying distributions in parts of North America and Europe. Interpretations of the population structure of these fungi suggest that host tree history has heavily influenced their modern distributions; however, the complex issues related to co-migration of these fungi with their tree hosts remain unclear at this time.


Preliminary outcomes of the SmartWheel Users' Group database: a proposed framework for clinicians to objectively evaluate manual wheelchair propulsion.
To describe a standard clinical protocol for the objective assessment of manual wheelchair propulsion; to establish preliminary values for temporal and kinetic parameters derived from the protocol; and to develop graphical references and a proposed application process for use by clinicians. Case series. Six research institutions that collect kinetic wheelchair propulsion data and contribute that data to an international data pool. Subjects with spinal cord injury (N=128). Subjects propelled a wheelchair from a stationary position to a self-selected velocity across a hard tile surface, a low pile carpet, and up an Americans with Disabilities Act-compliant ramp. Unilateral kinetic data were obtained from subjects using a force and moment sensing pushrim. Differences in self-selected velocity, peak resultant force, push frequency, and stroke length across all surfaces, relationship between (1) weight-normalized peak resultant force and self-selected velocity and (2) push frequency and self-selected velocity. Graphical references were generated for potential clinical use based on the relation between body weight-normalized peak resultant force, push frequency, and velocity. Self-selected velocity decreased (ramp < carpet < tile), peak resultant forces increased (ramp > carpet > tile), and push frequency and stroke length remained unchanged when compared across the different surfaces. Weight-normalized peak resultant force was a significant predictor of velocity on tile and ramp. Push frequency was a significant predictor of velocity on tile, carpet, and ramp. We present preliminary data generated from a clinically practical manual wheelchair propulsion evaluation protocol and we describe a proposed method for clinicians to objectively evaluate manual wheelchair propulsion.


The faintest speck of dirt: disgust enhances the detection of impurity.
Purity is commonly regarded as being physically embodied in the color white, with even trivial deviations from whiteness indicating a loss of purity. In three studies, we explored the implications of this "white = pure" association for disgust, an emotion that motivates the detection and avoidance of impurities that threaten purity and cleanliness. We hypothesized that disgust tunes perception to prioritize the light end of the light-dark spectrum, which results in a relative hypersensitivity to changes in lightness in this range. In studies 1 and 2, greater sensitivity to disgusting stimuli was associated with greater ability to make subtle gray-scale discriminations (e.g., detecting a faint gray stimulus against a white background) at the light end of the spectrum relative to ability to make subtle gray-scale discriminations at the dark end of the spectrum. In study 3, after viewing disgusting images, disgust-sensitive individuals demonstrated a heightened ability to detect deviations from white. These findings suggest that disgust not only motivates people to avoid impurities, but actually makes them better able to see them.


Decompressive craniectomy in the treatment of post-traumatic intracranial hypertension in children: our philosophy and indications.
Decompressive craniotomy (DC) in children is a life-saving procedure for the treatment of refractory intracranial hypertension related to traumatic, ischemic and infectious lesions. Different surgical procedures have been proposed including uni or bilateral hemicraniectomy, bi-frontal, bi-temporal, or bi-parietal craniotomies. DC can avoid the cascade of events related to tissue hypoxia, brain perfusion reduction, hypotension and the evolution of brain edema that can be responsible for brain herniation. The monitoring of intracranial pressure (ICP) is very important to take a decision as well as the value of Trans cranial Doppler (TCD). Repeated TCD in the intensive care unit give important information about the decrease of the cerebral perfusion pressure (CPP) and facilitates the decision making. The important question is about how long time we have to wait before to perform the DC. Three conditions can be distinguished: 1) ICP stable and TCD with good parameters: the decision can be postponed; 2) ICP>20 mmHg with good TCD and without clinical signs of deterioration: the decision can be postponed; 3) ICP>20 mmHg with altered CPP and degraded TCD value and clinical signs of brain herniation: the surgical procedure is indicated. The decision of a ventricular drainage can also be discussed but in cases of slit ventricles it is preferable to realize a DC to avoid the problems of multiple taps without finding the ventricular system. In some very specific situations, DC has to be contraindicated. The first one is a prolonged cardiopulmonary arrest with a no-flow longer than 15 minutes and irreversible lesions on the TCD or on the CT-scan. The second most common situation is a patient with GCS of 3 on admission associated with bilaterally fixed dilated pupils. In this case TCD is very useful to document the decrease or the absence of diastolic flux that indicates a very poor cerebral perfusion. In case of severe polytraumatism with multiorgan failure, especially in very severe hemorrhagic shock with incontrollable coagulopathy, the realization of DC is definitely hazardous with y a high risk of cardiac arrest during the surgical procedure. The decision to realize a hemicraniectomy or a bi-frontal craniotomy is related to the presence or not of associated traumatic lesions as hemorrhagic contusions or a sub-dural or extradural hematoma. In cases of diffuse cerebral edema the bi-frontal bone flap is indicated. In all cases a closure of the dura mater with a large dural patch has to be performed avoiding compression of the nervous system. Our results showed a mortality rate of 18%. Eighty percent of the survivors have a good quality of life but only 43% in a scholar age could attend a normal program. Patients treated with DC need a long follow-up and an important rehabilitation program to improve their quality of life. Our report shows that DC in children is effective to control the post-traumatic intracranial hypertension but a long follow-up is recommended to access the sequels and quality of life of these patients.


Absence seizures and their relationship to depression and anxiety: Evidence for bidirectionality.
Absence seizures (AS), presenting as short losses of consciousness with staring spells, are a common manifestation of childhood epilepsy that is associated with behavioral, emotional, and social impairments. It has also been suggested that patients with AS are more likely to suffer from mood disorders such as depression and anxiety. This systematic review and meta-analysis synthesizes human and animal models that investigated mood disorders and AS. Of the 1019 scientific publications identified, 35 articles met the inclusion criteria for this review. We found that patients with AS had greater odds of developing depression and anxiety when compared to controls (odds ratio = 4.93, 95% confidence interval = 2.91-8.35, p < .01). The included studies further suggest a strong correlation between AS and depression and anxiety in the form of a bidirectional relationship. The current literature emphasizes that these conditions likely share underlying mechanisms, such as genetic predisposition, neurophysiology, and anatomical pathways. Further research will clarify this relationship and ensure more effective treatment for AS and mood disorders.


Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice.
Oxidative stress plays an essential role in inflammation and fibrosis. Bach1 is an important transcriptional repressor that acts by modulating oxidative stress and represents a potential target in the treatment of pulmonary fibrosis (PF). In this study, we knocked down Bach1 using adenovirus-mediated small interfering RNA (siRNA) to determine whether the use of Bach1 siRNA is an effective therapeutic strategy in mice with bleomycin (BLM)‑induced PF. Mouse lung fibroblasts (MLFs) were incubated with transforming growth factor (TGF)-β1 (5 ng/ml) and subsequently infected with recombined adenovirus-like Bach1 siRNA1 and Bach1 siRNA2, while an empty adenovirus vector was used as the negative control. The selected Bach1 siRNA with higher interference efficiency was used for the animal experiments. A mouse model of BLM-induced PF was established, and Bach1 siRNA (1x109 pfu) was administered to the mice via the tail vein. The results revealed that the Bach1 mRNA and protein levels were significantly downregulated by Bach1 siRNA. Furthermore, the MLFs infected with Bach1 siRNA exhibited increased mRNA and protein expression levels of heme oxygenase-1 and glutathione peroxidase 1, but decreased levels of TGF-β1 and interleukin-6 in the cell supernatants compared with the cells exposed to TGF-β1 alone. Bach1 knockdown by siRNA also enhanced the expression of antioxidant factors, but suppressed that of fibrosis‑related cytokines in mice compared with the BLM group. Finally, the inflammatory infiltration of alveolar and interstitial cells and the destruction of lung structure were significantly attenuated in the mide administered Bach1 siRNA compared with those in the BLM group. On the whole, our findings demonstrate that Bach1 siRNA exerts protective effects against BLM-induced PF in mice. Our data may provide the basis for the development of novel targeted therapeutic strategies for PF.


Chronic central melanocortin-4 receptor antagonism and central neuropeptide-Y infusion in rats produce increased adiposity by divergent pathways.
Increased hypothalamic neuropeptide-Y (NPY) action and disruption of the melanocortin (MC)-4 receptor both result in hyperphagia and obesity. To determine whether similar hormonal and metabolic mechanisms are involved in these two obesity syndromes, we investigated the time course of effects induced by 6-day intracerebroventricular (ICV) infusion of NPY (3.5 nmol/day) or the MC4 receptor antagonist HS014 (4.8 nmol/day) in rats pair-fed with vehicle-infused controls. The weight of white adipose tissue (WAT) deposits was increased after 6-day NPY and HS014 infusion compared with controls, and the increase was significantly greater in HS014- than in NPY-infused rats (retroperitoneal WAT: NPY 0.57 +/- 0.05; HS014 0.80 +/- 0.05; control 0.43 +/- 0.03% body wt, n = 8-13, P < 0.05). Plasma leptin was also increased in both experimental groups (NPY 10.6 +/- 1.9; HS014 4.4 +/- 0.9; control 2.0 +/- 0.1 ng/ml, n = 8-13, P < 0.05 for all comparisons). Basal plasma corticosterone and insulin levels were increased by ICV NPY infusion, whereas HS014-infused rats showed no significant increase in these parameters on any of 1-6 days of infusion. Both NPY and HS014 infusion potentiated intravenous glucose-induced (300 mg/kg) plasma insulin levels, and there was no difference in glycemia among groups. In NPY-infused rats, the plasma free fatty acid levels were decreased and triglyceridemia was increased compared with controls, but these parameters were unchanged in HS014-infused rats. Hepatic triglyceride content was significantly increased by HS014 but not by NPY infusion. Levels of uncoupling protein-1 mRNA in brown adipose tissue were significantly decreased after 6 days of HS014 infusion, similar to the effect of central NPY. Because ICV HS014 induced at least as great an increase in fat mass as ICV NPY and yet had divergent hormonal and metabolic effects, we conclude that MC4 receptor antagonism does not induce obesity solely by regulation of the endogenous NPY-ergic system.


Independent vector analysis for source separation using a mixture of gaussians prior.
Convolutive mixtures of signals, which are common in acoustic environments, can be difficult to separate into their component sources. Here we present a uniform probabilistic framework to separate convolutive mixtures of acoustic signals using independent vector analysis (IVA), which is based on a joint distribution for the frequency components originating from the same source and is capable of preventing permutation disorder. Different gaussian mixture models (GMM) served as source priors, in contrast to the original IVA model, where all sources were modeled by identical multivariate Laplacian distributions. This flexible source prior enabled the IVA model to separate different type of signals. Three classes of models were derived and tested: noiseless IVA, online IVA, and noisy IVA. In the IVA model without sensor noise, the unmixing matrices were efficiently estimated by the expectation maximization (EM) algorithm. An online EM algorithm was derived for the online IVA algorithm to track the movement of the sources and separate them under nonstationary conditions. The noisy IVA model included the sensor noise and combined denoising with separation. An EM algorithm was developed that found the model parameters and separated the sources simultaneously. These algorithms were applied to separate mixtures of speech and music. Performance as measured by the signal-to-interference ratio (SIR) was substantial for all three models.


Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS.
The death of cranial and spinal motoneurons (MNs) is believed to be an essential component of the pathogenesis of amyotrophic lateral sclerosis (ALS). We tested this hypothesis by crossing Bax-deficient mice with mice expressing mutant superoxide dismutase 1 (SOD1), a transgenic model of familial ALS. Although Bax deletion failed to prevent neuromuscular denervation and mitochondrial vacuolization, MNs were completely rescued from mutant SOD1-mediated death. However, Bax deficiency extended lifespan and delayed the onset of motor dysfunction of SOD1 mutants, suggesting that Bax acts via a mechanism distinct from cell death activation. Consistent with this idea, Bax elimination delayed the onset of neuromuscular denervation, which began long before the activation of cell death proteins in SOD1 mutants. Additionally, we show that denervation preceded accumulation of mutant SOD1 within MNs and astrogliosis in the spinal cord, which are also both delayed in Bax-deficient SOD1 mutants. Interestingly, MNs exhibited mitochondrial abnormalities at the innervated neuromuscular junction at the onset of neuromuscular denervation. Additionally, both MN presynaptic terminals and terminal Schwann cells expressed high levels of mutant SOD1 before MNs withdrew their axons. Together, these data support the idea that clinical symptoms in the SOD1 G93A model of ALS result specifically from damage to the distal motor axon and not from activation of the death pathway, and cast doubt on the utility of anti-apoptotic therapies to combat ALS. Furthermore, they suggest a novel, cell death-independent role for Bax in facilitating mutant SOD1-mediated motor denervation.


Temporal loss of the activated L-selectin-low phenotype for virus-specific CD8+ memory T cells.
Whether the L-selectin-low (L-sel-lo) phenotype of acutely stimulated CD8+ T cells is a permanent characteristic of long-term memory CTL precursors (p) is addressed for mice primed with an influenza A virus or the murine parainfluenza type 1 virus, Sendai virus. In both cases, many of the splenic CD8+ CTLp gradually lose the predominantly L-sel-lo profile associated with recently generated CTLp populations. The influenza-specific CTLp also tend to revert from the activated alpha 4-integrin-high to the resting alpha 4-integrin-low form. The kinetics of the switch back to the "naive" L-sel-hi phenotype differs for the influenza and Sendai virus models, perhaps reflecting events occurring during the acute phases of these responses. The return to being L-sel-hi is not due to irreversible lymphocyte senescence, because restimulation of this set with the inducing virus in vitro causes most of the cells to become L-sel-lo. Also, despite the time-related drift of these particular memory CTLp to the L-sel-hi state, the size of the total pool of L-sel-lo CD8+ T cells increases with age.


Does providing nutrition information at vending machines reduce calories per item sold?
In 2010, the United States (US) enacted a restaurant menu labeling law. The law also applied to vending machine companies selling food. Research suggested that providing nutrition information on menus in restaurants might reduce the number of calories purchased. We tested the effect of providing nutrition information and 'healthy' designations to consumers where vending machines were located in college residence halls. We conducted our study at one university in Southeast US (October-November 2012). We randomly assigned 18 vending machines locations (residence halls) to an intervention or control group. For the intervention we posted nutrition information, interpretive signage, and sent a promotional email to residents of the hall. For the control group we did nothing. We tracked sales over 4 weeks before and 4 weeks after we introduced the intervention. Our intervention did not change what the residents bought. We recommend additional research about providing nutrition information where vending machines are located, including testing formats used to present information.


Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins.
Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte-melanoma cross-talk.Significance: We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target. Cancer Discov; 8(8); 1006-25. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.


Reverse engineering molecular hypergraphs.
Analysis of molecular interaction networks is pervasive in systems biology. This research relies almost entirely on graphs for modeling interactions. However, edges in graphs cannot represent multiway interactions among molecules, which occur very often within cells. Hypergraphs may be better representations for networks having such interactions, since hyperedges can naturally represent relationships among multiple molecules. Here, we propose using hypergraphs to capture the uncertainty inherent in reverse engineering gene-gene networks. Some subsets of nodes may induce highly varying subgraphs across an ensemble of networks inferred by a reverse engineering algorithm. We provide a novel formulation of hyperedges to capture this uncertainty in network topology. We propose a clustering-based approach to discover hyperedges. We show that our approach can recover hyperedges planted in synthetic data sets with high precision and recall, even for moderate amount of noise. We apply our techniques to a data set of pathways inferred from genetic interaction data in S. cerevisiae related to the unfolded protein response. Our approach discovers several hyperedges that capture the uncertain connectivity of genes in relevant protein complexes, suggesting that further experiments may be required to precisely discern their interaction patterns. We also show that these complexes are not discovered by an algorithm that computes frequent and dense subgraphs.


Spatial spread of the local field potential and its laminar variation in visual cortex.
We developed a new method to estimate the spatial extent of summation, the cortical spread, of the local field potential (LFP) throughout all layers of macaque primary visual cortex V1 by taking advantage of the V1 retinotopic map. We mapped multi-unit activity and LFP visual responses with sparse-noise at several cortical sites simultaneously. The cortical magnification factor near the recording sites was precisely estimated by track reconstruction. The new method combined experimental measurements together with a model of signal summation to obtain the cortical spread of the LFP. This new method could be extended to cortical areas that have topographic maps such as S1 or A1, and to cortical areas without functional columnar maps, such as rodent visual cortex. In macaque V1, the LFP was the sum of signals from a very local region, the radius of which was on average 250 microm. The LFP's cortical spread varied across cortical layers, reaching a minimum value of 120 microm in layer 4B. An important functional consequence of the small cortical spread of the LFP is that the visual field maps of LFP and MUA recorded at a single electrode site were very similar. The similar spatial scale of the visual responses, the restricted cortical spread, and their laminar variation led to new insights about the sources and possible applications of the LFP.


The Endocannabinoid System and its Modulation by Cannabidiol (CBD).
The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.


Reactivity of Uranium and Ferrous Iron with Natural Iron Oxyhydroxides.
Determining key reaction pathways involving uranium and iron oxyhydroxides under oxic and anoxic conditions is essential for understanding uranium mobility as well as other iron oxyhydroxide mediated processes, particularly near redox boundaries where redox conditions change rapidly in time and space. Here we examine the reactivity of a ferrihydrite-rich sediment from a surface seep adjacent to a redox boundary at the Rifle, Colorado field site. Iron(II)-sediment incubation experiments indicate that the natural ferrihydrite fraction of the sediment is not susceptible to reductive transformation under conditions that trigger significant mineralogical transformations of synthetic ferrihydrite. No measurable Fe(II)-promoted transformation was observed when the Rifle sediment was exposed to 30 mM Fe(II) for up to 2 weeks. Incubation of the Rifle sediment with 3 mM Fe(II) and 0.2 mM U(VI) for 15 days shows no measurable incorporation of U(VI) into the mineral structure or reduction of U(VI) to U(IV). Results indicate a significantly decreased reactivity of naturally occurring Fe oxyhydroxides as compared to synthetic minerals, likely due to the association of impurities (e.g., Si, organic matter), with implications for the mobility and bioavailability of uranium and other associated species in field environments.


The Clinical Performance of a New Chemiluminescent Immunoassay in Measuring Anti-β2 Glycoprotein 1 and Anti-Cardiolipin Antibodies.
BACKGROUND Laboratory criterion is needed for the classification of antiphospholipid syndrome (APS), which contain anticardiolipin antibodies (aCL) and anti-β2-glycoprotein 1 antibodies (aβ2GP1). They are commonly identified by enzyme-linked immunosorbent assay (ELISA), but lack standardized kits, resulting in substantial variations in the antibody positivity between different laboratories. The emergence of chemiluminescence automated -BIO-FLASH may improve the situation. MATERIAL AND METHODS We selected 185 patients with APS, systemic lupus erythematosus (SLE), infertility, connective tissue disease (CTD), and other conditions in Peking University Third Hospital. We tested the aCL and aβ2GP1 levels by EUROIMMUN ELISA and 105 patients had at least one positive result for aCL and aβ2GP1, while the others had negative results. We retested them by chemiluminescence assay (CIA) and analyzed the result and compared the coincidence rate. The IgM levels were retested by AESKU ELISA. Data were analyzed using SPSS. RESULTS Our result suggested that CIA had good performance for IgG isotype of aCL and aβ2GP1 in the coincidence rate. The positive coincidence rate of aCL IgM between CIA and EUROIMMUN ELISA was only 41.67%, but two ELISA kits showed good coincidence, CIA and AESKU ELISA had an obviously higher positive rate. CIA and AESKU had a higher coincidence than that of AESKU and EUROIMMUN in aβ2GP1-IgM. CONCLUSIONS The new automated CIA BIO-FLASH is suitable for detecting aCL and aβ2GP1 antibodies, especially IgG isotype, which may provide an alternative to time-consuming conventional ELISA method.


The Movember Prostate Cancer Landscape Analysis: an assessment of unmet research needs.
Prostate cancer is a heterogeneous cancer with widely varying levels of morbidity and mortality. Approaches to prostate cancer screening, diagnosis, surveillance, treatment and management differ around the world. To identify the highest priority research needs across the prostate cancer biomedical research domain, Movember conducted a landscape analysis with the aim of maximizing the effect of future research investment through global collaborative efforts and partnerships. A global Landscape Analysis Committee (LAC) was established to act as an independent group of experts across urology, medical oncology, radiation oncology, radiology, pathology, translational research, health economics and patient advocacy. Men with prostate cancer and thought leaders from a variety of disciplines provided a range of key insights through a range of interviews. Insights were prioritized against predetermined criteria to understand the areas of greatest unmet need. From these efforts, 17 research needs in prostate cancer were agreed on and prioritized, and 3 received the maximum prioritization score by the LAC: first, to establish more sensitive and specific tests to improve disease screening and diagnosis; second, to develop indicators to better stratify low-risk prostate cancer for determining which men should go on active surveillance; and third, to integrate companion diagnostics into randomized clinical trials to enable prediction of treatment response. On the basis of the findings from the landscape analysis, Movember will now have an increased focus on addressing the specific research needs that have been identified, with particular investment in research efforts that reduce disease progression and lead to improved therapies for advanced prostate cancer.


Effective Unconstrained Face Recognition by Combining Multiple Descriptors and Learned Background Statistics.
Computer vision systems have demonstrated considerable improvement in recognizing and verifying faces in digital images. Still, recognizing faces appearing in unconstrained, natural conditions remains a challenging task. In this paper, we present a face-image, pair-matching approach primarily developed and tested on the "Labeled Faces in the Wild" (LFW) benchmark that reflects the challenges of face recognition from unconstrained images. The approach we propose makes the following contributions. 1) We present a family of novel face-image descriptors designed to capture statistics of local patch similarities. 2) We demonstrate how unlabeled background samples may be used to better evaluate image similarities. To this end, we describe a number of novel, effective similarity measures. 3) We show how labeled background samples, when available, may further improve classification performance, by employing a unique pair-matching pipeline. We present state-of-the-art results on the LFW pair-matching benchmarks. In addition, we show our system to be well suited for multilabel face classification (recognition) problem, on both the LFW images and on images from the laboratory controlled multi-PIE database.


[Policy of using the right internal thoracic artery "in situ" for coronary artery bypass grafting].
The authors analysed the outcomes in a total of 73 patients subjected to coronary artery bypass grafting with the use of the "in situ" the right internal thoracic artery. Of these, 14 patients endured bypass grafting with assessment of the conformity of the length of the "in situ" right ITA as a conduit for the distal third of the right coronary artery (RCA). 16 patients underwent grafting of the RITA "in situ" with the RCA by passing through the pleural cavity. The remaining 43 patients were subjected to bilateral mammary composite bypass grafting using the radial artery (RA). A total of 22 segments of the RA were subjected to a comparative morphometric examination depending on the method of exposure. We additionally analysed 56 cases of utilizing the RA with the use of the pharmacological protocol of preventing spasm. The results were regarded statistically significant if p<0.05. We used the non-parametric criterion of Mann-Whitney. The obtained results showed that the right ITA "in situ" may be used for bypass grafting of the RCA system, excluding the risk of graft tension, if the perpendicular from the 6th intercostal space crosses the sharp edge of the heart 1.5-2 cm distal to the medial point, with the minimum number of complications after 1.5±0.3 years (7.1%). When the above-mentioned perpendicular is located proximal to the middle point of the sharp edge of the heart it is possible to use the right ITA "in situ" for the RCA system thanks to passing the conduit through the right pleural cavity under the anterior segment of the upper lobe and the medial segment of the middle lobe of the right lung with no complications after 1 year. The method of composite bypass grafting by means of the proximal segment of the right ITA "in situ" and the RA makes it possible to effectively revascularize any portions of the coronary bed (latency 94.7% after 3.0±0.8 years), to avoid manipulations on the aorta, and to save the bed of the right ITA in the middle and distal third of the sternum with no postoperative complications. It was revealed that in the conditions of decreased osmotic pressure the increase in the thickness of the vascular wall is more pronounced in the skeletonized segments of the RA (1.38±0.05 mm) as compared with the segments surrounded by connective and fatty tissue (1.09±0.04 mm). The pharmacological protocol for prevention of radial artery spasm used in 56 patients resulted in a small number of complications observed after 3.0±0.8 years (myocardial infarctions - 1.75%, angina pectoris relapse - 7%). Hence, the developed methods of using the right ITA "in situ" widen possibilities of bilateral mammary bypass grafting, excluding the existing problems of routine use of the both ITAs "in situ".


New polyaminocarboxylate macrocycles containing phenolate binding units: synthesis, luminescent and relaxometric properties of their lanthanide complexes.
The synthesis of two new polyaminocarboxylate macrocycles incorporating one or two intracyclic phenol units (H4L1 and H8L2, respectively) is described. The 12-membered H4L1 macrocycle leads to soluble and stable mononuclear LnIII complexes of [(L1)Ln(H2O)2]- composition (Ln = Eu, Tb and Gd) in aqueous solutions. In Tris buffer (pH 7.4), the [(L1)Tb(H2O)2]- complex displays a suitable efficiency for sensitized emission (ηsens = 48%) and a high luminescence quantum yield (Φ = 22%), which is worthy of note for a bis-hydrated terbium complex. Besides, luminescence experiments show that bidentate endogenous anions (citrate, carbonate, and phosphate) do not displace the two inner-sphere water molecules of this complex. In contrast, the possible presence of LMCT states causes the europium complex to be weakly luminescent. The [(L1)Gd(H2O)2]- complex is characterized by high relaxivity (r = 7.2 s-1 mM-1 at 20 MHz) and a very short water residence time of the coordinated water molecules (τ = 9 ns), promising values for the realisation of macromolecular systems with high relaxivities. Thus, the Tb and Gd complexes of the H4L1 macrocycle exhibit several improvements in terms of luminescent (lower excitation energy, higher brightness) and relaxometric (shorter τM) properties compared to the corresponding LnPCTA complexes, where a phenol moiety substitutes a pyridine ring. On the other hand, the 24-membered H8L2 macrocycle including two phenol units in its structure leads to dinuclear complexes of [(L2)Ln2]2- composition. Its terbium complex shows a long luminescence lifetime (2 ms) and a high quantum yield (43%) in aqueous solutions, making this compound a new promising candidate for time-resolved applications.


Optical properties of biaxial nanopatterned gold plasmonic nanowired grid polarizer.
Gold nanoparticles deposited on self-organized nano-ripple quartz substrates have been studied by spectroscopic Mueller matrix ellipsometry. The surface was found to have biaxial anisotropic optical properties. For electric field components normal to the ripples the periodic and disconnected nature of the in plane nanowires gives rise to an optical response dominated by the localized plasmon resonance. In the direction parallel to the ripples the gold nanoparticles are aligned closely leading to localized plasmon resonances in the infrared. As Au was deposited at an angle oblique to the surface normal, the gold nanoparticles were formed on the side of the ripples facing the incoming evaporation flux. This makes the gold particles slightly inclined, correspondingly the principal coordinate system of the biaxial dielectric tensor results tilted. The anisotropic plasmonic optical response results in a strong polarizing effect, making it suitable as a plasmonic nanowired grid polarizer.


Trefoil knotting revealed by molecular dynamics simulations of supercoiled DNA.
Computer simulations of the supercoiling of DNA, largely limited to stochastic search techniques, can offer important information to complement analytical models and experimental data. Through association of an energy function, minimum-energy supercoiled conformations, fluctuations about these states, and interconversions among forms may be sought. In theory, the observation of such large-scale conformational changes is possible, but modeling and numerical considerations limit the picture obtained in practice. A new computational approach is reported that combines an idealized elastic energy model, a compact B-spline representation of circular duplex DNA, and deterministic minimization and molecular dynamics algorithms. A trefoil knotting result, made possible by a large time-step dynamics scheme, is described. The simulated strand passage supports and details a supercoiled-directed knotting mechanism. This process may be associated with collective bending and twisting motions involved in supercoiling propagation and interwound branching. The results also demonstrate the potential effectiveness of the Langevin/implicit-Euler dynamics scheme for studying biomolecular folding and reactions over biologically interesting time scales.


Plug-and-play pairing via defined divalent streptavidins.
Streptavidin is one of the most important hubs for molecular biology, either multimerizing biomolecules, bridging one molecule to another, or anchoring to a biotinylated surface/nanoparticle. Streptavidin has the advantage of rapid ultra-stable binding to biotin. However, the ability of streptavidin to bind four biotinylated molecules in a heterogeneous manner is often limiting. Here, we present an efficient approach to isolate streptavidin tetramers with two biotin-binding sites in a precise arrangement, cis or trans. We genetically modified specific subunits with negatively charged tags, refolded a mixture of monomers, and used ion-exchange chromatography to resolve tetramers according to the number and orientation of tags. We solved the crystal structures of cis-divalent streptavidin to 1.4Å resolution and trans-divalent streptavidin to 1.6Å resolution, validating the isolation strategy and explaining the behavior of the Dead streptavidin variant. cis- and trans-divalent streptavidins retained tetravalent streptavidin's high thermostability and low off-rate. These defined divalent streptavidins enabled us to uncover how streptavidin binding depends on the nature of the biotin ligand. Biotinylated DNA showed strong negative cooperativity of binding to cis-divalent but not trans-divalent streptavidin. A small biotinylated protein bound readily to cis and trans binding sites. We also solved the structure of trans-divalent streptavidin bound to biotin-4-fluorescein, showing how one ligand obstructs binding to an adjacent biotin-binding site. Using a hexaglutamate tag proved a more powerful way to isolate monovalent streptavidin, for ultra-stable labeling without undesired clustering. These forms of streptavidin allow this key hub to be used with a new level of precision, for homogeneous molecular assembly.


Efficacy of cardiac rehabilitation 2: Smoking and behaviour modification.
The first part of this article (Vol 6(12): 697-702) critically reviewed the research on the acclaimed beneficial effects of a number of cardiac rehabilitation programmes including exercise, stress management and educational interventions. This article will examine empirical studies on the efficacy of smoking cessation and type A behavioural modification programmes. Lamentably, few studies have been conducted on the efficacy of smoking cessation. Caution is indicated when establishing conclusions from studies on type A behaviour given the conceptual problems of this construct, i.e. its inability to consistently predict coronary heart disease, evidence of confusion surrounding the improper use of the psychometric measures and the neglect of salient psychosocial baseline variables. A number of clinical implications and future directions for research are indicated.


Examining within-person and between-person effects of victimization and social risk on cannabis use among emerging adults in substance-use treatment.
The goals of this study were to examine associations between within- and between-person social risk and victimization and cannabis use among emerging adults in substance-use treatment. We also tested gender differences for both victimization and social risk. Participants consisted of 3,052 emerging adults (M(age) = 20.0 years; SD = 2.21) entering substance-use treatment in a wide range of treatment centers across the United States. Individuals were assessed on all measures at baseline 3, 6, and 12 months. We fitted a taxonomy of multilevel growth curve models to test main effects, and interactive relations between within- and between-person social risk, victimization, and gender on cannabis use. Several significant interactions were evident. Irrespective of gender, within-person increases in social risk were associated with contemporaneous increases in cannabis use; however, the magnitude of this relation was comparatively more pronounced for men. Similar gender differences emerged between individuals. Males experiencing heightened social risk over time tended to show high levels of early cannabis use. Simple slope analyses revealed that reporting more (+1 SD) social risk than one's own mean resulted in significant increases in cannabis use for both men and women. Cross-level simple slope analyses revealed no differences in cannabis use among individuals reporting low (-1 SD) social risk and victimization, but significant increases in cannabis use for individuals reporting high (+ 1 SD) victimization and social risk. Results demonstrate support for gender differences in social risk on cannabis use and the importance of considering within-person effects. (PsycINFO Database Record


Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine.
COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.


Progress in the Development and Challenges for the Use of Artificial Kidneys and Wearable Dialysis Devices.
Renal transplantation is the treatment of choice for chronic kidney disease (CKD) patients, but the shortage of kidneys and the disabling medical conditions these patients suffer from make dialysis essential for most of them. Since dialysis drastically affects the patients' lifestyle, there are great expectations for the development of wearable artificial kidneys, although their use is currently impeded by major concerns about safety. On the other hand, dialysis patients with hemodynamic instability do not usually tolerate intermittent dialysis therapy because of their inability to adapt to a changing scenario of unforeseen events. Thus, the development of novel wearable dialysis devices and the improvement of clinical tolerance will need contributions from new branches of engineering such as artificial intelligence (AI) and machine learning (ML) for the real-time analysis of equipment alarms, dialysis parameters, and patient-related data with a real-time feedback response. These technologies are endowed with abilities normally associated with human intelligence such as learning, problem solving, human speech understanding, or planning and decision-making. Examples of common applications of AI are visual perception (computer vision), speech recognition, and language translation. In this review, we discuss recent progresses in the area of dialysis and challenges for the use of AI in the development of artificial kidneys. Emerging technologies derived from AI, ML, electronics, and robotics will offer great opportunities for dialysis therapy, but much innovation is needed before we achieve a smart dialysis machine able to analyze and understand changes in patient homeostasis and to respond appropriately in real time. Great efforts are being made in the fields of tissue engineering and regenerative medicine to provide alternative cell-based approaches for the treatment of renal failure, including bioartificial renal systems and the implantation of bioengineered kidney constructs.


The influence of a visuospatial grounding task on intrusive images of a traumatic film.
Nonclinical participants watched a trauma film under two processing conditions. During part of the film participants carried out a concurrent visuospatial grounding task consisting of the construction of shapes out of plasticine (modelling clay), while the rest of the film constituted a control, no task condition. The visuospatial task was predicted to selectively compete for processing resources required for intrusive image formation. As predicted, spontaneous intrusive images during the succeeding week were significantly less common from those parts of the film that coincided with the concurrent task. The task had no effect on levels of distress or peritraumatic dissociation, consistent with the hypothesis that intrusions were reduced because the task competed for resources necessary for encoding into an image-based memory system.


CD28null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death.
An increased risk of cardiovascular death in Cytomegalovirus (CMV)-infected individuals remains unexplained, although it might partly result from the fact that CMV infection is closely associated with the accumulation of CD28null T-cells, in particular CD28null CD4 T-cells. These cells can directly damage endothelium and precipitate cardiovascular events. However, the current paradigm holds that the accumulation of CD28null T-cells is a normal consequence of aging, whereas the link between these T-cell populations and CMV infection is explained by the increased prevalence of this infection in older people. Resolving whether CMV infection or aging triggers CD28null T-cell expansions is of critical importance because, unlike aging, CMV infection can be treated. Methods: We used multi-color flow-cytometry, antigen-specific activation assays, and HLA-typing to dissect the contributions of CMV infection and aging to the accumulation of CD28null CD4 and CD8 T-cells in CMV+ and CMV- individuals aged 19 to 94 years. Linear/logistic regression was used to test the effect of sex, age, CMV infection, and HLA-type on CD28null T-cell frequencies. Results: The median frequencies of CD28null CD4 T-cells and CD28null CD8 T-cells were >12-fold (p=0.000) but only approximately 2-fold higher (p=0.000), respectively, in CMV+ (n=136) compared with CMV- individuals (n=106). The effect of CMV infection on these T-cell subsets was confirmed by linear regression. Unexpectedly, aging contributed only marginally to an increase in CD28null T-cell frequencies, and only in CMV+ individuals. Interestingly, the presence of HLA-DRB1*0301 led to an approximately 9-fold reduction of the risk of having CD28null CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28null. Conclusion: CMV infection and HLA type are major risk factors for CD28null CD4 T-cell-associated cardiovascular pathology. Increased numbers of CD28null CD8 T-cells are also associated with CMV infection, but to a lesser extent. Aging, however, makes only a negligible contribution to the expansion of these T-cell subsets, and only in the presence of CMV infection. Our results open up new avenues for risk assessment, prevention, and treatment.


Differential stability of PNS and CNS nodal complexes when neuronal neurofascin is lost.
Fast, saltatory conduction in myelinated nerves requires the clustering of voltage-gated sodium channels (Nav) at nodes of Ranvier in a nodal complex. The Neurofascin (Nfasc) gene encodes neuronal Neurofascin 186 (Nfasc186) at the node and glial Neurofascin 155 at the paranode, and these proteins play a key role in node assembly. However, their role in the maintenance and stability of the node is less well understood. Here we show that by inducible ablation of Nfasc in neurons in adult mice, Nfasc186 expression is reduced by >99% and 94% at PNS and CNS nodes, respectively. Gliomedin and NrCAM at PNS and brevican at CNS nodes are largely lost with neuronal neurofascin; however, Nav at nodes of Ranvier persist, albeit with ∼40% reduction in expression levels. βIV Spectrin, ankyrin G, and, to a lesser extent, the β1 subunit of the sodium channel, are less affected at the PNS node than in the CNS. Nevertheless, there is a 38% reduction in PNS conduction velocity. Loss of Nfasc186 provokes CNS paranodal disorganization, but this does not contribute to loss of Nav. These results show that Nav at PNS nodes are still maintained in a nodal complex when neuronal neurofascin is depleted, whereas the retention of nodal Nav in the CNS, despite more extensive dissolution of the complex, suggests a supportive role for the partially disrupted paranodal axoglial junction in selectively maintaining Nav at the CNS node.


Mechanisms of action of probiotics in intestinal diseases.
Intestinal microbiota is a positive health asset that exerts a conditioning effect on intestinal homeostasis. Resident bacteria deliver regulatory signals to the epithelium and instruct mucosal immune responses. Recent research has revealed a potential therapeutic role for the manipulation of the microbiota and exploitation of host-microbial signalling pathways in the maintenance of human health and treatment of various mucosal disorders. A variety of pharmabiotic strategies, such as the use of specific members of the microbiota, their surface components, or metabolites, as well as genetically modified commensal bacteria, are being investigated for their ability to enhance the beneficial components of the microbiota. It is clear that engagement with host cells is central to pharmabiotic action, and several strain-specific mechanisms of action have been elucidated. However, the molecular details underpinning these mechanisms remain almost entirely unknown. Understanding how pharmabiotics exert their beneficial effects is critical for the establishment of definitive selection criteria for certain pharmabiotic strategies for specific clinical conditions. Scientifically accredited evidence of efficacy and studies to elucidate the molecular mechanisms of host-microbiota interactions are needed to lend credence to the use of pharmabiotic strategies in clinical medicine.


Low effectiveness of syndromic treatment services for curable sexually transmitted infections in rural South Africa.
Syndromic sexually transmitted infection (STI) treatment remains a cost-saving HIV prevention intervention in many countries in Africa. We estimate the effectiveness of syndromic treatment for curable STIs in rural KwaZulu-Natal, South Africa, and the trend in STI prevalences before and after the introduction of syndromic treatment in 1995. Data were available from various clinical studies, surveys of public and private health providers, the general population and women attending antenatal, family planning and child immunisation clinics in rural northern KwaZulu-Natal between 1987 and 2004. Overall effectiveness was defined as the estimated proportion of the annual number of symptomatic curable STI episodes cured by syndromic treatment based on separate estimates for six curable STI aetiologies by gender. Median overall effectiveness was 13.1% (95% CI 8.9 to 17.8%) of symptomatic curable STI episodes cured. Effectiveness increased to 25.0% (95% CI 17.3 to 33.8%), 47.6% (95% CI 44.5 to 50.8%) or 14.3% (95% CI 9.9 to 19.4%) if 100% treatment seeking, 100% correct treatment provision or 100% cure were assumed, respectively. Time-trends were difficult to assess formally but there was little evidence of decreasing STI prevalences. Including incurable but treatable herpes simplex virus (HSV)-2 ulcers in the effectiveness calculation would halve the proportion of ulcers cured or correctly treated, but this reduction could be entirely countered by including episodic antiviral treatment in the national guidelines. Overall effectiveness of syndromic treatment for curable STIs in rural KwaZulu-Natal remains low and there is little evidence of reduced curable STI prevalences. As syndromic treatment is likely to be a cost-saving HIV prevention intervention in South Africa, innovative strategies are urgently needed to increase rates of treatment seeking and correct treatment provision.


Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats.
Human autosomal-dominant polycystic kidney disease (ADPKD) is variable in the rate of deterioration of renal function, with end-stage renal disease (ESRD) occurring in only approximately 50% of affected individuals. Evidence suggests that interstitial inflammation may be important in the development of ESRD in ADPKD. Han:SPRD rats manifest ADPKD that resembles the human disease. Homozygous cystic (Cy/Cy) rats develop rapidly progressive PKD and die near age 3 weeks. Heterozygous (Cy/+) females develop slowly progressive PKD without evidence of renal dysfunction until the second year of life, whereas heterozygous (Cy/+) males develop more aggressive PKD with renal failure beginning by 8 to 12 weeks of age. To examine the relationship between proinflammatory chemoattractants and the development of interstitial inflammation and ultimately renal failure in ADPKD, we evaluated monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNAs and proteins in kidneys from Han:SRPD rats. MCP-1 and osteopontin mRNAs, expressed at low levels in kidneys from normal (+/+) animals at all ages, were markedly elevated in kidneys from 3-week-old Cy/Cy animals. In kidneys from heterozygous (Cy/+) adults of either gender, MCP-1 and osteopontin mRNAs were more abundant than normal; MCP-1 mRNA was more abundant in Cy/+ males than in females. Thus, chemoattractant mRNA expression correlated with the development of renal failure in Cy/Cy and Cy/+ rats. Osteopontin mRNA, localized by in situ hybridization, was moderately expressed in the renal medulla of normal animals; however, this mRNA was expressed at very high levels in the cystic epithelia of Cy/+ and Cy/Cy animals. MCP-1 and osteopontin proteins, localized by immunohistochemistry, were weakly detected in +/+ kidneys but were densely expressed in Cy/Cy and in adult Cy/+ kidneys, primarily over cystic epithelium. Increased expression of chemoattractants was associated with the accumulation of ED-1 positive cells (macrophages) in the interstitium of cystic kidneys. We suggest that proinflammatory chemoattractants have a role in the development of interstitial inflammation and renal failure in ADPKD.


Visual field deficits in conventional anterior temporal lobectomy versus amygdalohippocampectomy.
To evaluate and identify the incidence of visual field defects (VFD) after anterior temporal lobectomy (ATL) versus amygdalohippocampectomy (AH). VFD occur frequently after ATL and are usually superotemporal quadrantanopias. Little is known about the incidence of VFD after AH and this surgical method offers the possibility of a seizure-free survival without visual loss. Patients with similar characteristics were examined. All patients had intractable seizures and mesial temporal sclerosis, small tumors localized to only the uncus, amygdala, or hippocampus, or no known pathology. Postoperative kinetic field testing using the I4e isopter on a Goldmann perimeter was performed 30 days or more after surgery. Of 29 patients examined, 14 underwent AH and 15 had ATL. Four of 14 AH patients (28%) had a VFD at 10 degrees from center and 11/14 (78%) had VFD at 40 degrees. One of 15 ATL patients (7%) had a VFD at 10 degrees from center and 11/15 (73%) had VFD at 40 degrees. There was no significant difference between surgery types. AH in this study was associated with a significant number of VFD. No significant difference was found between the frequency of VFD produced from AH and ATL. The mechanism of injury is due to direct trauma to the optic radiations while accessing the mesial temporal structures. Because all patients in the study were asymptomatic for VFD, it remains to be determined whether these VFD are clinically significant.


Analytical considerations and plans to standardize or harmonize assays for the reference bone turnover markers PINP and β-CTX in blood.
Procollagen type I N-propeptide (PINP) and the C-terminal telopeptide of type I collagen (β-CTX) in blood have been designated as reference bone turnover markers in osteoporosis by the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The IFCC Committee on Bone Metabolism (C-BM) has examined current commercial assays and performed a multicentre study to examine the agreement between assays for PINP and β-CTX in serum and plasma. The results of these studies will inform our work towards the harmonization of PINP assays and the standardization of β-CTX assays in blood, with the development of common calibrators and reference measurement procedures in collaboration with the reagent manufacturing industry. Successful achievement of these goals will help develop universally acceptable practice guidelines for the management of osteoporosis with the inclusion of common reference intervals and treatment targets for PINP and β-CTX.


Prenatal Alcohol Screening During Pregnancy by Midwives and Nurses.
Alcohol use during pregnancy can have a variety of harmful consequences on the fetus. Lifelong effects include growth restriction, characteristic facial anomalies, and neurobehavioral dysfunction. This range of effects is known as fetal alcohol spectrum disorders (FASD). There is no amount, pattern, or timing of alcohol use during pregnancy proven safe for a developing embryo or fetus. Therefore, it is important to screen patients for alcohol use, inform them about alcohol's potential effects during pregnancy, encourage abstinence, and refer for intervention if necessary. However, how and how often nurses and midwives inquire about alcohol drinking during pregnancy or use recommended screening tools and barriers they perceive to alcohol screening has not been well established. This survey was sent to about 6,000 American midwives, nurse practitioners, and nurses who provide prenatal care about their knowledge of the effects of prenatal alcohol exposure, the prevalence of alcohol use during pregnancy, and practices for screening patients' alcohol use. Participants were recruited by e-mail from the entire membership roster of the American College of Nurse-Midwives. There were 578 valid surveys returned (about 9.6%). Analyses showed that 37.7% of the respondents believe drinking alcohol is safe during at least one trimester of pregnancy. Only 35.2% of respondents reported screening to assess patient alcohol use. Only 23.3% reported using a specific screening tool, and few of those were validated screens recommended for use in pregnant women. Respondents who believe alcohol is safe at some point in pregnancy were significantly less likely to screen their patients. Respondents who reported that pregnancy alcohol use is unsafe felt more prepared to educate and intervene with patients regarding alcohol use during pregnancy and FASD than respondents who reported drinking in pregnancy was safe. Perceived alcohol safety and perceived barriers to screening appeared to influence screening practices. Improving prenatal care provider knowledge about the effects of prenatal alcohol exposure and the availability of valid alcohol screening tools will improve detection of drinking during pregnancy, provide more opportunities for meaningful intervention, and ultimately reduce the incidence of FASD.


Gene expression analyses of immune responses in Atlantic salmon during early stages of infection by salmon louse (Lepeophtheirus salmonis) revealed bi-phasic responses coinciding with the copepod-chalimus transition.
The salmon louse (Lepeophtheirus salmonis Krøyer), an ectoparasitic copepod with a complex life cycle causes significant losses in salmon aquaculture. Pesticide treatments against the parasite raise environmental concerns and their efficacy is gradually decreasing. Improvement of fish resistance to lice, through biological control methods, needs better understanding of the protective mechanisms. We used a 21 k oligonucleotide microarray and RT-qPCR to examine the time-course of immune gene expression changes in salmon skin, spleen, and head kidney during the first 15 days after challenge, which encompassed the copepod and chalimus stages of lice development. Large scale and highly complex transcriptome responses were found already one day after infection (dpi). Many genes showed bi-phasic expression profiles with abrupt changes between 5 and 10 dpi (the copepod-chalimus transitions); the greatest fluctuations (up- and down-regulation) were seen in a large group of secretory splenic proteases with unknown roles. Rapid sensing was witnessed with induction of genes involved in innate immunity including lectins and enzymes of eicosanoid metabolism in skin and acute phase proteins in spleen. Transient (1-5 dpi) increase of T-cell receptor alpha, CD4-1, and possible regulators of lymphocyte differentiation suggested recruitment of T-cells of unidentified lineage to the skin. After 5 dpi the magnitude of transcriptomic responses decreased markedly in skin. Up-regulation of matrix metalloproteinases in all studied organs suggested establishment of a chronic inflammatory status. Up-regulation of putative lymphocyte G0/G1 switch proteins in spleen at 5 dpi, immunoglobulins at 15 dpi; and increase of IgM and IgT transcripts in skin indicated an onset of adaptive humoral immune responses, whereas MHCI appeared to be down-regulated. Atlantic salmon develops rapid local and systemic reactions to L. salmonis, which, however, do not result in substantial level of protection. The dramatic changes observed after 5 dpi can be associated with metamorphosis of copepod, immune modulation by the parasite, or transition from innate to adaptive immune responses.


Keypoint-MoSeq: parsing behavior by linking point tracking to pose dynamics.
Keypoint tracking algorithms have revolutionized the analysis of animal behavior, enabling investigators to flexibly quantify behavioral dynamics from conventional video recordings obtained in a wide variety of settings. However, it remains unclear how to parse continuous keypoint data into the modules out of which behavior is organized. This challenge is particularly acute because keypoint data is susceptible to high frequency jitter that clustering algorithms can mistake for transitions between behavioral modules. Here we present keypoint-MoSeq, a machine learning-based platform for identifying behavioral modules ("syllables") from keypoint data without human supervision. Keypoint-MoSeq uses a generative model to distinguish keypoint noise from behavior, enabling it to effectively identify syllables whose boundaries correspond to natural sub-second discontinuities inherent to mouse behavior. Keypoint-MoSeq outperforms commonly used alternative clustering methods at identifying these transitions, at capturing correlations between neural activity and behavior, and at classifying either solitary or social behaviors in accordance with human annotations. Keypoint-MoSeq therefore renders behavioral syllables and grammar accessible to the many researchers who use standard video to capture animal behavior.


Umbilical cord-derived Wharton's jelly for regenerative medicine applications.
The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton's Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton's jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes. Human umbilical cords were obtained from consenting caesarian section donors. The Wharton's jelly was then isolated from the procured umbilical cord and formulated into an injectable form. Randomly selected samples from different batches were analyzed for sterility testing and to quantify the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles. All samples passed the sterility test. Growth factors including IGFBP 1, 2, 3, 4, and 6, TGF-α, and PDGF-AA were detected. Several immunomodulatory cytokines, such as RANTES, IL-6R, and IL-16, were also detected. Pro-inflammatory cytokines MCSFR, MIP-1a; anti-inflammatory cytokines TNF-RI, TNF-RII, and IL-1RA; and homeostatic cytokines TIMP-1 and TIMP-2 were observed. Cytokines associated with wound healing, ICAM-1, G-CSF, GDF-15, and regenerative properties, GH, were also expressed. High concentrations of hyaluronic acid were observed. Particles in the extracellular vesicle size range were also detected and were enclosed by the membrane, indicative of true extracellular vesicles. There are numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles present in the Wharton's jelly formulation analyzed. The amount of these factors in Wharton's jelly is higher compared with other biologics and may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries.


Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group.
To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc.


Peregrination of the selectivity filter delineates the pore of the human voltage-gated proton channel hHV1.
Extraordinary selectivity is crucial to all proton-conducting molecules, including the human voltage-gated proton channel (hHV1), because the proton concentration is >10(6) times lower than that of other cations. Here we use "selectivity filter scanning" to elucidate the molecular requirements for proton-specific conduction in hHV1. Asp(112), in the middle of the S1 transmembrane helix, is an essential part of the selectivity filter in wild-type (WT) channels. After neutralizing Asp(112) by mutating it to Ala (D112A), we introduced Asp at each position along S1 from 108 to 118, searching for "second site suppressor" activity. Surprisingly, most mutants lacked even the anion conduction exhibited by D112A. Proton-specific conduction was restored only with Asp or Glu at position 116. The D112V/V116D channel strikingly resembled WT in selectivity, kinetics, and ΔpH-dependent gating. The S4 segment of this mutant has similar accessibility to WT in open channels, because R211H/D112V/V116D was inhibited by internally applied Zn(2+). Asp at position 109 allowed anion permeation in combination with D112A but did not rescue function in the nonconducting D112V mutant, indicating that selectivity is established externally to the constriction at F150. The three positions that permitted conduction all line the pore in our homology model, clearly delineating the conduction pathway. Evidently, a carboxyl group must face the pore directly to enable conduction. Molecular dynamics simulations indicate reorganization of hydrogen bond networks in the external vestibule in D112V/V116D. At both positions where it produces proton selectivity, Asp frequently engages in salt linkage with one or more Arg residues from S4. Surprisingly, mean hydration profiles were similar in proton-selective, anion-permeable, and nonconducting constructs. That the selectivity filter functions in a new location helps to define local environmental features required to produce proton-selective conduction.


Borrelia burgdorferi sensu lato spirochetes in wild birds in northwestern California: associations with ecological factors, bird behavior and tick infestation.
Although Borrelia burgdorferi sensu lato (s.l.) are found in a great diversity of vertebrates, most studies in North America have focused on the role of mammals as spirochete reservoir hosts. We investigated the roles of birds as hosts for subadult Ixodes pacificus ticks and potential reservoirs of the Lyme disease spirochete B. burgdorferi sensu stricto (s.s.) in northwestern California. Overall, 623 birds representing 53 species yielded 284 I. pacificus larvae and nymphs. We used generalized linear models and zero-inflated negative binomial models to determine associations of bird behaviors, taxonomic relationships and infestation by I. pacificus with borrelial infection in the birds. Infection status in birds was best explained by taxonomic order, number of infesting nymphs, sampling year, and log-transformed average body weight. Presence and counts of larvae and nymphs could be predicted by ground- or bark-foraging behavior and contact with dense oak woodland. Molecular analysis yielded the first reported detection of Borrelia bissettii in birds. Moreover, our data suggest that the Golden-crowned Sparrow (Zonotrichia atricapilla), a non-resident species, could be an important reservoir for B. burgdorferi s.s. Of 12 individual birds (9 species) that carried B. burgdorferi s.l.-infected larvae, no birds carried the same genospecies of B. burgdorferi s.l. in their blood as were present in the infected larvae removed from them. Possible reasons for this discrepancy are discussed. Our study is the first to explicitly incorporate both taxonomic relationships and behaviors as predictor variables to identify putative avian reservoirs of B. burgdorferi s.l. Our findings underscore the importance of bird behavior to explain local tick infestation and Borrelia infection in these animals, and suggest the potential for bird-mediated geographic spread of vector ticks and spirochetes in the far-western United States.


Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.
Fludarabine is an effective treatment for chronic lymphocytic leukemia that does not respond to initial treatment with chlorambucil. We compared the efficacy of fludarabine with that of chlorambucil in the primary treatment of chronic lymphocytic leukemia. Between 1990 and 1994, we randomly assigned 509 previously untreated patients with chronic lymphocytic leukemia to one of the following treatments: fludarabine (25 mg per square meter of body-surface area, administered intravenously daily for 5 days every 28 days), chlorambucil (40 mg per square meter, given orally every 28 days), or fludarabine (20 mg per square meter per day for 5 days every 28 days) plus chlorambucil (20 mg per square meter every 28 days). Patients with an additional response at each monthly evaluation continued to receive the assigned treatment for a maximum of 12 cycles. Assignment of patients to the fludarabine-plus-chlorambucil group was stopped when a planned interim analysis revealed excessive toxicity and a response rate that was not better than the rate with fludarabine alone. Among the other two groups, the response rate was significantly higher for fludarabine alone than for chlorambucil alone. Among 170 patients treated with fludarabine, 20 percent had a complete remission, and 43 percent had a partial remission. The corresponding values for 181 patients treated with chlorambucil were 4 percent and 33 percent (P< 0.001 for both comparisons). The median duration of remission and the median progression-free survival in the fludarabine group were 25 months and 20 months, respectively, whereas both values were 14 months in the chlorambucil group (P<0.001 for both comparisons). The median overall survival among patients treated with fludarabine was 66 months, which was not significantly different from the overall survival in the other two groups (56 months with chlorambucil and 55 months with combined treatment). Severe infections and neutropenia were more frequent with fludarabine than with chlorambucil (P=0.08), although, overall, toxic effects were tolerable with the two single-drug regimens. When used as the initial treatment for chronic lymphocytic leukemia, fludarabine yields higher response rates and a longer duration of remission and progression-free survival than chlorambucil.


Semimicro Chemical and X-ray Fluorescence Analysis of Lunar Samples.
Major and selected minor elements were determined in seven whole rock fragments, five portions of pulverized lunar rock, and the lunar soil. Three different rock types were represented: vesicular, fine-grained basaltic rocks; medium to coarse-grained, vuggy gabbroic rocks; and breccia. The ranges (in percent) for the major constituents of the lunar samples are: SiO(2), 38 to 42; Al(2)O(3), 8 to 14; total iron as FeO, 15 to 20; MgO, 6 to 8; CaO, 10 to 12; Na(2)O, 0.5 to 1; K(2)0, 0.05 to 0.4; TiO(2), 8 to 13; MnO, 0.2 to 0.3; and Cr(2)O(3), 0.2 to 0.4. The high reducing capacity of the samples strongly suggests the presence of Ti(III).


Dried salted plum consumption ameliorates hyperbaric oxygen therapy-induced otalgia severity at the first chamber session: a prospective randomized controlled study.
One of the most common complications of hyperbaric oxygen (HBO₂) therapy is middle ear barotrauma (MEB), occasionally causing otalgia. The objective of this study was to evaluate the effect of dried salted plum consumption on MEB and otalgia associated with HBO₂ therapy. Patients undergoing the first chamber session of HBO₂ therapy were included in the present prospective randomized controlled trial. The Valsalva maneuver was administered to all patients before HBO₂. The patients were randomly divided into two groups: one that ate a dried salted plum during HBO₂ treatment and the other that did not. An otoscopic examination was performed after HBO₂ therapy. The MEB was graded according to Teed scores. The degree of otalgia was recorded using the Visual Analog Scale (VAS). Ninety patients were enrolled. The overall incidence of MEB (Teed score grade 1~4) was 39.6% (21 of 53) for patients administered a dried salted plum versus 37.8% (14 of 37) for the control group (P=1.000). The incidence of mild MEB (Teed score grade 1~2) and severe MEB (Teed score Grade 3~4) between the two groups was not significantly different. Otalgia was present in 5.7% (3 of 53) of patients administered a dried salted plum versus 18.9% (7 of 37) for the control group (P=.085). No patients administered a dried salted plum had a VAS score ≥4 for otalgia versus 10.8% (4 of 37) for the control group (P=.026). Dried salted plum consumption does not decrease the incidence of MEB, but may ameliorate the severity of first chamber session HBO₂-induced otalgia.


Motorcycle helmet effectiveness in reducing head, face and brain injuries by state and helmet law.
Despite evidence that motorcycle helmets reduce morbidity and mortality, helmet laws and rates of helmet use vary by state in the U.S. We pooled data from eleven states: five with universal laws requiring all motorcyclists to wear a helmet, and six with partial laws requiring only a subset of motorcyclists to wear a helmet. Data were combined in the Crash Outcome Data Evaluation System's General Use Model and included motorcycle crash records probabilistically linked to emergency department and inpatient discharges for years 2005-2008. Medical outcomes were compared between partial and universal helmet law settings. We estimated adjusted relative risks (RR) and 95 % confidence intervals (CIs) for head, facial, traumatic brain, and moderate to severe head/facial injuries associated with helmet use within each helmet law setting using generalized log-binomial regression. Reported helmet use was higher in universal law states (88 % vs. 42 %). Median charges, adjusted for inflation and differences in state-incomes, were higher in partial law states (emergency department $1987 vs. $1443; inpatient $31,506 vs. $25,949). Injuries to the head and face, including traumatic brain injuries, were more common in partial law states. Effectiveness estimates of helmet use were higher in partial law states (adjusted-RR (CI) of head injury: 2.1 (1.9-2.2) partial law single vehicle; 1.4 (1.2, 1.6) universal law single vehicle; 1.8 (1.6-2.0) partial law multi-vehicle; 1.2 (1.1-1.4) universal law multi-vehicle). Medical charges and rates of head, facial, and brain injuries among motorcyclists were lower in universal law states. Helmets were effective in reducing injury in both helmet law settings; lower effectiveness estimates were observed in universal law states.


Dopamine: stimulation-induced release from central neurons.
Dopamine, synthesized in rat brain slices from labeled L-tyrosine or L-dopa, can be released by electrical stimulation of a type known to induce neuronal depolarization. Pretreatment of the animals with 6-hydroxydopamine, which destroys central catecholamine-containing nerve terminals, substantially reduced the release of dopamine synthesized from [(14)C]tyrosine or from a low concentration of [(3)H]dopa, whereas the release of dopamine formed from a high concentration of [(3)H]dopa remained essentially unchanged. The observations that at high concentrations L-dopa may enter noncatecholaminergic cells, undergo decarboxylation to dopamine, and subsequently be liberated in response to depolarization suggest that dopamine may act as a substitute central transmitter, possibly in serotonergic neurons. This mechanism may contribute to L-dopa's clinical effects in parkinsonian patients.