Effects of surgical side and site on mood and behavior outcome in children with pharmacoresistant epilepsy

Children with epilepsy have a high rate of mood and behavior problems; yet few studies consider the emotional and behavioral impact of surgery. No study to date has been sufficiently powered to investigate effects of both side (left/right) and site (temporal/frontal) of surgery. One hundred patients (aged 6-16) and their families completed measures of depression, anxiety, and behavioral function as part of neuropsychological evaluations before and after surgery for pharmacoresistant epilepsy. Among children who had left-sided surgeries (frontal = 16; temporal = 38), there were significant interactions between time (pre to post-operative neuropsychological assessment) and resection site (frontal/temporal) on anhedonia, social anxiety, and withdrawn/depressed scales. Patients with frontal lobe epilepsy (FLE) endorsed greater pre-surgical anhedonia and social anxiety than patients with temporal lobe epilepsy (TLE) with scores normalizing following surgery. While scores on the withdrawn/depressed scale were similar between groups before surgery, the FLE group showed greater symptom improvement after surgery. In children who underwent right-sided surgeries (FLE = 20; TLE = 26), main effects of time (patients in both groups improved) and resection site (caregivers of FLE patients endorsed greater symptoms than those with TLE) were observed primarily on behavior scales. Individual data revealed that a greater proportion of children with left FLE demonstrated clinically significant improvements in anhedonia, social anxiety, and aggressive behavior than children with TLE. This is the first study to demonstrate differential effects of both side and site of surgery in children with epilepsy at group and individual levels. Results suggest that children with FLE have greater emotional and behavioral dysfunction before surgery, but show marked improvement after surgery. Overall, most children had good emotional and behavioral outcomes, with most scores remaining stable or improving. © 2014 Andresen, Ramirez, Kim, Dorfman, Haut, Klaas, Jehi, Shea, Bingaman and Busch

The Malagarasi River Does Not Form an Absolute Barrier to Chimpanzee Movement in Western Tanzania

The Malagarasi River has long been thought to be a barrier to chimpanzee movements in western Tanzania. This potential geographic boundary could affect chimpanzee ranging behavior, population connectivity and pathogen transmission, and thus has implications for conservation strategies and government policy. Indeed, based on mitochondrial DNA sequence comparisons it was recently argued that chimpanzees from communities to the north and to the south of the Malagarasi are surprisingly distantly related, suggesting that the river prevents gene flow. To investigate this, we conducted a survey along the Malagarasi River. We found a ford comprised of rocks that researchers could cross on foot. On a trail leading to this ford, we collected 13 fresh fecal samples containing chimpanzee DNA, two of which tested positive for SIVcpz. We also found chimpanzee feces within the riverbed. Taken together, this evidence suggests that the Malagarasi River is not an absolute barrier to chimpanzee movements and communities from the areas to the north and south should be considered a single population. These results have important consequences for our understanding of gene flow, disease dynamics and conservation management

Doping a semiconductor to create an unconventional metal

Landau Fermi liquid theory, with its pivotal assertion that electrons in metals can be simply understood as independent particles with effective masses replacing the free electron mass, has been astonishingly successful. This is true despite the Coulomb interactions an electron experiences from the host crystal lattice, its defects, and the other ~1022/cm3 electrons. An important extension to the theory accounts for the behaviour of doped semiconductors1,2. Because little in the vast literature on materials contradicts Fermi liquid theory and its extensions, exceptions have attracted great attention, and they include the high temperature superconductors3, silicon-based field effect transistors which host two-dimensional metals4, and certain rare earth compounds at the threshold of magnetism5-8. The origin of the non-Fermi liquid behaviour in all of these systems remains controversial. Here we report that an entirely different and exceedingly simple class of materials - doped small gap semiconductors near a metal-insulator transition - can also display a non-Fermi liquid state. Remarkably, a modest magnetic field functions as a switch which restores the ordinary disordered Fermi liquid. Our data suggest that we have finally found a physical realization of the only mathematically rigourous route to a non-Fermi liquid, namely the 'undercompensated Kondo effect', where there are too few mobile electrons to compensate for the spins of unpaired electrons localized on impurity atoms9-12.Comment: 17 pages 4 figures supplemental information included with 2 figure

Influences on gum feeding in primates

This chapter reviews the factors that may affect patterns of gum feeding by primates. These are then examined for mixed-species troops of saddleback (S. fuscicollis) and mustached (S. mystax) tamarins. An important distinction is made between gums produced by tree trunks and branches as a result of damage and those produced by seed pods as part of a dispersal strategy as these may be expected to differ in their biochemistry. Feeding on fruit and Parkia seed pod exudates was more prevalent in the morning whereas other exudates were eaten in the afternoon. This itinerary may represent a deliberate strategy to retain trunk gums in the gut overnight, thus maximising the potential for microbial fermentation of their β-linked oligosaccharides. Both types of exudates were eaten more in the dry than the wet season. Consumption was linked to seasonal changes in resource availability and not the tamarins’ reproductive status pro-viding no support for the suggestion that gums are eaten as a pri-mary calcium source in the later stages of gestation and lactation. The role of availability in determining patterns of consumption is further supported by the finding that dietary overlap for the trunk gums eaten was greater between species within mixed-species troops within years than it was within species between years. These data and those for pygmy marmosets (Cebuella pygmaea) suggest that patterns of primate gummivory may reflect the interaction of prefer-ence and availability for both those able to stimulate gum production and those not

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

An optical supernova associated with the X-ray flash XRF 060218

Long-duration gamma-ray bursts (GRBs) are associated with type Ic supernovae that are more luminous than average and that eject material at very high velocities. Less-luminous supernovae were not hitherto known to be associated with GRBs, and therefore GRB-supernovae were thought to be rare events. Whether X-ray flashes - analogues of GRBs, but with lower luminosities and fewer gamma-rays - can also be associated with supernovae, and whether they are intrinsically 'weak' events or typical GRBs viewed off the axis of the burst, is unclear. Here we report the optical discovery and follow-up observations of the type Ic supernova SN 2006aj associated with X-ray flash XRF 060218. Supernova 2006aj is intrinsically less luminous than the GRB-supernovae, but more luminous than many supernovae not accompanied by a GRB. The ejecta velocities derived from our spectra are intermediate between these two groups, which is consistent with the weakness of both the GRB output and the supernova radio flux. Our data, combined with radio and X-ray observations, suggest that XRF 060218 is an intrinsically weak and soft event, rather than a classical GRB observed off-axis. This extends the GRB-supernova connection to X-ray flashes and fainter supernovae, implying a common origin. Events such as XRF 060218 are probably more numerous than GRB-supernovae.Comment: Final published versio

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Sources of Community Health Worker Motivation: A Qualitative Study in Morogoro Region, Tanzania.

There is a renewed interest in community health workers (CHWs) in Tanzania, but also a concern that low motivation of CHWs may decrease the benefits of investments in CHW programs. This study aimed to explore sources of CHW motivation to inform programs in Tanzania and similar contexts. We conducted semi-structured interviews with 20 CHWs in Morogoro Region, Tanzania. Interviews were digitally recorded, transcribed, and coded prior to translation and thematic analysis. The authors then conducted a literature review on CHW motivation and a framework that aligned with our findings was modified to guide the presentation of results. Sources of CHW motivation were identified at the individual, family, community, and organizational levels. At the individual level, CHWs are predisposed to volunteer work and apply knowledge gained to their own problems and those of their families and communities. Families and communities supplement other sources of motivation by providing moral, financial, and material support, including service fees, supplies, money for transportation, and help with farm work and CHW tasks. Resistance to CHW work exhibited by families and community members is limited. The organizational level (the government and its development partners) provides motivation in the form of stipends, potential employment, materials, training, and supervision, but inadequate remuneration and supplies discourage CHWs. Supervision can also be dis-incentivizing if perceived as a sign of poor performance. Tanzanian CHWs who work despite not receiving a salary have an intrinsic desire to volunteer, and their motivation often derives from support received from their families when other sources of motivation are insufficient. Policy-makers and program managers should consider the burden that a lack of remuneration imposes on the families of CHWs. In addition, CHWs' intrinsic desire to volunteer does not preclude a desire for external rewards. Rather, adequate and formal financial incentives and in-kind alternatives would allow already-motivated CHWs to increase their commitment to their work

Therapeutic lung lavages in children and adults

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare disease, characterized by excessive intra-alveolar accumulation of surfactant lipids and proteins. Therapeutic whole lung lavages are currently the principle therapeutic option in adults. Not much is known on the kinetics of the wash out process, especially in children. METHODS: In 4 pediatric and 6 adult PAP patients 45 therapeutic half lung lavages were investigated retrospectively. Total protein, protein concentration and, in one child with a surfactant protein C mutation, aberrant pro-SP-C protein, were determined during wash out. RESULTS: The removal of protein from the lungs followed an exponential decline and averaged for adult patients 2 – 20 g and <0.5 to 6 g for pediatric patients. The average protein concentration of consecutive portions was the same in all patient groups, however was elevated in pediatric patients when expressed per body weight. The amount of an aberrant pro-SP-C protein, which was present in one patient with a SP-C mutation, constantly decreased with ongoing lavage. Measuring the optical density of the lavage fluid obtained allowed to monitor the wash out process during the lavages at the bedside and to determine the termination of the lavage procedure at normal protein concentration. CONCLUSION: Following therapeutic half lung lavages by biochemical variables may help to estimate the degree of alveolar filling with proteinaceous material and to improve the efficiency of the wash out, especially in children

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

BACKGROUND: Cross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; however, this antigen presentation pathway remains poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: In order to develop a comprehensive understanding of this process, we tested the hypothesis that the internalization of MHC class I molecules (MHC-I) from the cell surface is directly involved in cross-presentation pathway and the loading of antigenic peptides. Here we provide the first examination of the internalization of MHC-I in DCs and we demonstrate that the cytoplasmic domain of MHC-I appears to act as an addressin domain to route MHC-I to both endosomal and lysosomal compartments of DCs, where it is demonstrated that loading of peptides derived from exogenously-derived proteins occurs. Furthermore, by chasing MHC-I from the cell surface of normal and transgenic DCs expressing mutant forms of MHC-I, we observe that a tyrosine-based endocytic trafficking motif is required for the constitutive internalization of MHC-I molecules from the cell surface into early endosomes and subsequently deep into lysosomal peptide-loading compartments. Finally, our data support the concept that multiple pathways of peptide loading of cross-presented antigens may exist depending on the chemical nature and size of the antigen requiring processing. CONCLUSIONS/SIGNIFICANCE: We conclude that DCs have 'hijacked' and adapted a common vacuolar/endocytic intracellular trafficking pathway to facilitate MHC I access to the endosomal and lysosomal compartments where antigen processing and loading and antigen cross-presentation takes place