Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity

Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob/ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity, and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility, we now show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypical cachectic cytokine, IL-1. Further analyses of hypothalamic signaling reveals that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain.

Quantification of the hydrophobic interaction by simulations of the aggregation of small hydrophobic solutes in water

The hydrophobic interaction, the tendency for nonpolar molecules to aggregate in solution, is a major driving force in biology. In a direct approach to the physical basis of the hydrophobic effect, nanosecond molecular dynamics simulations were performed on increasing numbers of hydrocarbon solute molecules in water-filled boxes of different sizes. The intermittent formation of solute clusters gives a free energy that is proportional to the loss in exposed molecular surface area with a constant of proportionality of 45 ± 6 cal/mol⋅Å2. The molecular surface area is the envelope of the solute cluster that is impenetrable by solvent and is somewhat smaller than the more traditional solvent-accessible surface area, which is the area transcribed by the radius of a solvent molecule rolled over the surface of the cluster. When we apply a factor relating molecular surface area to solvent-accessible surface area, we obtain 24 cal/mol⋅Å2. Ours is the first direct calculation, to our knowledge, of the hydrophobic interaction from molecular dynamics simulations; the excellent qualitative and quantitative agreement with experiment proves that simple van der Waals interactions and atomic point-charge electrostatics account for the most important driving force in biology.

Tobamovirus and Potyvirus Accumulation in Minor Veins of Inoculated Leaves from Representatives of the Solanaceae and Fabaceae1

Virus invasion of minor veins in inoculated leaves of a host is the likely prelude to systemic movement of the pathogen and to subsequent yield reduction and quality loss. In this study we have analyzed the cell number and arrangement in minor veins within mature leaves of various members of the Solanaceae and Fabaceae families. We then monitored the accumulation pattern of several tobamoviruses and potyviruses in these veins at the time of rapid, phloem-mediated movement of viruses. Vascular parenchyma cells were the predominant and sometimes only cells to become visibly infected among the cells surrounding the sieve elements in minor veins containing 9 to 12 cells. In no instance did we observe a companion cell infected without a vascular parenchyma cell also being infected in the same vein. This suggests that the viruses used in this study first enter the vascular parenchyma cells and then the companion cells during invasion. The lack of detectable infection of smooth-walled companion or transfer cells, respectively, from inoculated leaves of bean (Phaseolus vulgaris) and pea (Pisum sativum) during a period of known rapid, phloem-mediated movement suggests that some viruses may be able to circumvent these cells in establishing phloem-mediated infection. The cause of the barrier to virus accumulation in the companion or transfer cells, the relationship of this barrier to previously identified barriers for virus or photoassimilate transport, and the relevance of these findings to photoassimilate transport models are discussed.

Activation of NF-κB by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK–IKKα/β–IκBα and MKK3/6–p38 MAP kinase signaling pathways in epithelial cells

Nontypeable Hemophilus influenzae (NTHi) is an important human pathogen in both children and adults. In children, it causes otitis media, the most common childhood infection and the leading cause of conductive hearing loss in the United States. In adults, it causes lower respiratory tract infections in the setting of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. The molecular mechanisms underlying the pathogenesis of NTHi-induced infections remain undefined, but they may involve activation of NF-κB, a transcriptional activator of multiple host defense genes involved in immune and inflammatory responses. Here, we show that NTHi strongly activates NF-κB in human epithelial cells via two distinct signaling pathways, NF-κB translocation-dependent and -independent pathways. The NF-κB translocation-dependent pathway involves activation of NF-κB inducing kinase (NIK)–IKKα/β complex leading to IκBα phosphorylation and degradation, whereas the NF-κB translocation-independent pathway involves activation of MKK3/6–p38 mitogen-activated protein (MAP) kinase pathway. Bifurcation of NTHi-induced NIK–IKKα/β-IκBα and MKK3/6–p38 MAP kinase pathways may occur at transforming growth factor-β activated kinase 1 (TAK1). Furthermore, we show that toll-like receptor 2 (TLR2) is required for NTHi-induced NF-κB activation. In addition, several key inflammatory mediators including IL-1β, IL-8, and tumor necrosis factor-α are up-regulated by NTHi. Finally, P6, a 16-kDa lipoprotein highly conserved in the outer membrane of all NTHi and H. influenzae type b strains, appears to also activate NF-κB via similar signaling pathways. Taken together, our results demonstrate that NTHi activates NF-κB via TLR2–TAK1-dependent NIK–IKKα/β-IκBα and MKK3/6–p38 MAP kinase signaling pathways. These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases.

The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons.

The amino acid L-glutamate is a neurotransmitter that mediates fast neuronal excitation in a majority of synapses in the central nervous system. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stimulation (excitotoxicity) is thought to be primarily responsible for neuronal injury in a wide variety of acute neurological disorders including hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolamide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmitoylethanolamide, but not the cognate N-acylamide anandamide (the ethanolamide of arachidonic acid), protects cultured mouse cerebellar granule cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependent manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also prevented neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of the active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharmacological behaviors have been observed for palmitoylethanolamide (ALI-Amides) in downmodulating mast cell activation. Cerebellar granule cells expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon agonist binding, the downstream consequences of an excitotoxic stimulus; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for CB2-like receptors on granule cells; and (iii) activation of such receptors may serve to downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the nervous and immune systems.

Nonlinear control of heart rate variability in human infants.

Nonlinear analyses of infant heart rhythms reveal a marked rise in the complexity of the electrocardiogram with maturation. We find that normal mature infants (gestation greater than or equal to 35 weeks) have complex and distinctly nonlinear heart rhythms (consistent with recent reports for healthy adults) but that such nonlinearity is lacking in preterm infants (gestation > or = to 27 weeks) where parasympathetic-sympathetic interaction and function are presumed to be less well developed. Our study further shows that infants with clinical brain death and those treated with atropine exhibit a similar lack of nonlinear feedback control. These three lines of evidence support the hypothesis championed by Goldberger et al. [Goldberger, A.L., Rigney, D.R. & West, B.J. (1990) Sci. Am. 262, 43-49] that autonomic nervous system control underlies the nonlinearity and possible chaos of normal heart rhythms. This report demonstrates the acquisition of nonlinear heart rate dynamics and possible chaos in developing human infants and its loss in brain death and with the administration of atropine. It parallels earlier work documenting changes in the variability of heart rhythms in each of these cases and suggests that nonlinearity may provide additional power in characterizing physiological states.

Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.

The majority of severe visual loss in the United States results from complications associated with retinal neovascularization in patients with ischemic ocular diseases such as diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. Intraocular expression of the angiogenic protein vascular endothelial growth factor (VEGF) is closely correlated with neovascularization in these human disorders and with ischemia-induced retinal neovascularization in mice. In this study, we evaluated whether in vivo inhibition of VEGF action could suppress retinal neovascularization in a murine model of ischemic retinopathy. VEGF-neutralizing chimeric proteins were constructed by joining the extracellular domain of either human (Flt) or mouse (Flk) high-affinity VEGF receptors with IgG. Control chimeric proteins that did not bind VEGF were also used. VEGF-receptor chimeric proteins eliminated in vitro retinal endothelial cell growth stimulation by either VEGF (P < 0.006) or hypoxic conditioned medium (P < 0.005) without affecting growth under nonstimulated conditions. Control proteins had no effect. To assess in vivo response, animals with bilateral retinal ischemia received intravitreal injections of VEGF antagonist in one eye and control protein in the contralateral eye. Retinal neovascularization was quantitated histologically by a masked protocol. Retinal neovascularization in the eye injected with human Flt or murine Flk chimeric protein was reduced in 100% (25/25; P < 0.0001) and 95% (21/22; P < 0.0001) 0.0001) of animals, respectively, compared to the control treated eye. This response was evident after only a single intravitreal injection and was dose dependent with suppression of neovascularization noted after total delivery of 200 ng of protein (P < 0.002). Reduction of histologically evident neovascular nuclei per 6-microns section averaged 47% +/- 4% (P < 0.001) and 37% +/- 2% (P < 0.001) for Flt and Flk chimeric proteins with maximal inhibitory effects of 77% and 66%, respectively. No retinal toxicity was observed by light microscopy. These data demonstrate VEGF's causal role in retinal angiogenesis and prove the potential of VEGF inhibition as a specific therapy for ischemic retinal disease.

Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.

We have generated herpes simplex virus (HSV) vectors vIE1GT and v alpha 4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV alpha 4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypoglycemia. Microinfusion of GT vectors into the rat hippocampus also reduces kainic acid-induced seizure damage in the CA3 cell field. Furthermore, delivery of the vector even after onset of the seizure is protective, suggesting that HSV-mediated gene transfer for neuroprotection need not be carried out in anticipation of neurologic crises. Using the bicistronic vector v alpha 22 beta gal alpha 4GT, which coexpresses both GT and the Escherichia coli lacZ marker gene, we further demonstrate an inverse correlation between the extent of vector expression in the dentate and the amount of CA3 damage resulting from the simultaneous delivery of kainic acid.

Prenatal monocular enucleation induces a selective loss of low-spatial-frequency cortical responses to the remaining eye.

During early development, interactions between the two eyes are critical in the formation of eye-specific domains within the lateral geniculate nucleus and the visual cortex. When monocular enucleation is done early in prenatal life, it induces remarkable anatomical and functional reorganizations of the visual pathways. Behavioral data have shown a loss in sensitivity to low-spatial-frequency gratings in cats. To correlate the behavioral observations with a possible change in the analysis of contrast at the level of primary visual areas we recorded visual evoked potentials at the 17/18 border in two cats enucleated prenatally (gestational age at enucleation, 39-42 days), three neonatal, two control animals, and one animal with a surgical removal of Y-ganglion fibers. Our results show a strong attenuation in the amplitude of response at all contrast values for gratings of low spatial frequency in prenatally enucleated cats, whereas neonatally enucleated and control animals present responses of comparable amplitude. We conclude that the behavioral results reflect the reduced sensitivity for low frequencies of visual cortical neurons. In addition, we define a critical period for the development of the contrast-sensitivity function that seems to be limited to the prenatal gestation period. We suggest that the prenatal interruption of binocular interactions leads to a functional elimination of the Y-ganglion system.

Struggling, Coping, And Thriving: Sense-Making In Stepfamily Couples' Narratives About Coparenting

The term coparenting implies a bioparental dyad that often excludes the stepparent's role in sharing parenting across joint-custody households. Focusing solely on this dyad also precludes gaining an understanding of how stepfamily couples manage together the communication and sharing of parental responsibilities with the parent(s) in the shared children's other home. In a departure from this bioparental dyad-focused approach, this study locates the stepfamily couple at the center of an inquiry into managing coparenting across households. This mixed methods design study included in-depth interviews of 32 stepfamily couples whose narratives about coparenting were analyzed using grounded theory methods. Forty-one percent of stepparents engage in direct coparenting communication, sometimes manifested as the coactive approach identified in this study. Stepfamily couples also involve the stepparent indirectly in coparenting communication, through the conferred and consultative approaches. As well, the couples' narratives about coparenting identify them as either united, where they share the experience, or divided, where coparenting is reserved exclusively for the bioparent to manage. The stepfamily couples' narratives about significant coparenting experiences revealed that they experience and make sense of coparenting as 1) struggling, 2) coping, or 3) thriving. No significant relationship was found between marital satisfaction and experiencing coparenting as strugglers, copers or thrivers. Grounded theory analysis of these narratives also reflects the four dichotomous dimensions of 1) regard-disregard, 2) decency-duplicity, 3) facilitation-interference, and 4) accommodation-inflexibility. Significant incidents located along these dimensions contribute to the stepfamily couples' identification as struggling, coping, or thriving in coparenting. Experiences on the extreme ends of the dichotomous dimensions generate positive and negative turning points for the coparenting interactions and relationships. As well, experiences on the negative end of the dimensional poles can present challenges for the stepfamily couples. Finally, a synthesis of the findings related to the dichotomous dimensions generates a theory of shared parenting values expectancy.

Phototherapy as an Intervention in Identity Development with Adolescents.

Identity development in adolescence is a period of exploration and experimentation. During this stage of development, adolescents are defining their identity in terms of ethnicity, sexual orientation, and gender. It can be a confusing time and the lack of resources and support influence the ability of the adolescent to form a cohesive identity. This struggle to define an identity may lead to symptoms of depression and difficulties with interpersonal relationships. Identity interventions are limited and primarily involve the adolescent talking to a therapist and attempting to verbalize and define subjective distress. The use of a phototherapy intervention focuses on using an adolescent's subjective experiences. Phototherapy provides a way for the therapist and client to explore the photographs the client takes and opens different avenues in the areas of non-verbal and visual communication. Photographs can also promote increased communication about an adolescent's ethnic, sexual or gender identity. Interpretations made by the adolescent about images in the photographs will get in touch with emotional experiences that may be missed in traditional "talk therapy." This paper reviews literature on identity development, specifically in the areas of ethnicity, sexual orientation, and gender identity. Phototherapy, the use of photography to enhance traditional psychotherapy, is described and a rationale is provided for the utilization of phototherapy in adolescent identity development. Vignettes are provided illustrating how phototherapy can be used when working with adolescents who are questioning and exploring ethnic identity, sexual orientation, and gender identity.

Lessons of Loss

Lessons of Loss consists of four poems and four personal essays, each dealing with a profound loss in my life. I am forever in pursuit of the mastery of hope, and writing serves as a critical vehicle in moving me through grief towards that beacon of hope. In the most difficult times, I seek comfort from the writings of those who have endured loss with a sense of humility and grace. To express my gratitude to those who have provided me with comfort and direction, I strive to master Lessons of Loss so that someday I might provide some flicker of hope to those in search of solace.

Notificación de reacciones adversas a la vacuna frente al virus del papiloma humano en la Comunidad Valenciana (2007-2011)

Introducción: En 2009, 2 casos de convulsiones en adolescentes tras la administración de la vacuna tetravalente frente al virus del papiloma humano (VPH) generaron impacto mediático y afectaron negativamente la confianza del público en esta vacuna. Nuestros objetivos fueron describir las sospechas de reacciones adversas (SRA) notificadas al Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana (CAFCV) tras la administración de la vacuna frente al VPH y comparar la tasa de notificación de síncope y convulsiones de esta vacuna con la de otras vacunas administradas en adolescentes. Material y métodos: Estudio descriptivo de las notificaciones de SRA relacionadas con esta vacuna recibidas por el CAFCV entre 2007 y 2011. Resultados: Las manifestaciones clínicas más comunicadas fueron mareos, cefalea y síncope. Las tasas de notificación de síncope o pérdida de conciencia y convulsiones con la vacuna frente al VPH fueron de 17 y 3,2 por 100.000 dosis administradas, respectivamente, y de 15 y 1,6 para síncope o pérdida de conciencia y convulsiones sincopales ocurridas el día de la vacunación. Las tasas de notificación de síncope o pérdida de conciencia y convulsiones fueron de 6,4 y 0,4 para otras vacunas. Conclusiones: Las tasas de notificación de síncope o pérdida de conciencia y convulsiones fueron mayores para la vacuna frente al VPH que para otras vacunas administradas en adolescentes; esto es consistente con la atención mediática originada por la vacuna y con hallazgos de estudios previos. No obstante, la información obtenida sobre las SRA a la vacuna sugiere un buen perfil de seguridad.

Programas de intervención dietética para la pérdida de peso en edades de 2 a 17 años. Revisión sistemática

Introducción: Por la creciente prevalencia de la obesidad en la infancia y/o adolescencia, deben existir suficientes programas de intervención para combatirla. Objetivo: identificar y comparar los distintos tipos de programas de intervención en niños y adolescentes, para el tratamiento del sobrepeso y la obesidad en España y en otros países. Método: se realizó una búsqueda con las palabras clave “Obesity” AND “Diet” AND “intervention” en tres bases de datos documentales: Pubmed, EBSCO, Scielo. Criterios de inclusión: edad de la muestra (2-17 años, basado en el estudio Enkid), que el programa de intervención incluyera dieta, ensayos clínicos publicados entre el enero de 2.010 y abril de 2014, cuya fuente sean revistas científicas indexadas. Resultados: se han analizado 490 artículos, de los cuales sólo fueron seleccionados 13 artículos. El 85 % de los programas intervención son aplicados fuera de España; sólo el 23 % fueron realizadas en ambiente escolar; el 70% de las intervenciones fueron llevadas a cabo en niños menores de 12 años; el 62% de las investigaciones destacan el uso de la intervención multidisciplinar (dieta, ejercicio y en ocasiones, cambios de conducta); y se muestra una oscilación en la duración de estas intervenciones entre 3 y 24 meses. Discusión: se han encontrado pocas intervenciones a nivel nacional, en participantes obesos y se diferencia dos tipos de intervenciones, a corto y largo plazo. Conclusiones: se recomienda promover programas de intervención de pérdida de peso en España, sobre todo en centros docentes. El uso exclusivo de dieta, ha resultado efectiva a corto plazo. Y a largo plazo, la intervención multidisciplinar obtiene mejores resultados de pérdida, sobre todo de masa grasa.

Diferencias de género y edad en autoconcepto en estudiantes adolescentes chilenos

Investigaciones previas han puesto de manifiesto la importancia del estudio del autoconcepto durante la adolescencia. El objetivo de este estudio consistió en analizar las diferencias de género y edad en las distintas dimensiones del autoconcepto en una muestra de 1414 estudiantes chilenos de entre 13 y 18 años. El autoconcepto fue evaluado mediante la versión breve del SDQII. Los resultados evidenciaron diferencias de género para las dimensiones Autoconcepto Verbal, Apariencia Física, Sinceridad/Veracidad y Autoestima en favor de las jóvenes, así como diferencias en el Autoconcepto Matemático, Habilidades Físicas, Estabilidad Emocional y Relación con los Padres en favor de los varones. También se observó una tendencia en los alumnos de mayor edad a puntuar más alto en Autoconcepto Académico General, Habilidades Físicas, Apariencia Física, Relaciones con el Sexo Opuesto y Autoestima, que sus iguales de menor edad. Este mismo patrón, pero a la inversa, se obtuvo para las dimensiones de Autoconcepto Matemático, Verbal y Estabilidad Emocional. Los resultados no replicaron la tendencia de los varones, reportada en estudios previos, a valorar más positivamente su físico y a poseer una autoestima más elevada que las mujeres, así como a percibir más negativamente sus relaciones paterno-filiales.