Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Antenna-assisted picosecond control of nanoscale phase transition in vanadium dioxide

Nanoscale devices in which the interaction with light can be configured using external control signals hold great interest for next-generation optoelectronic circuits. Materials exhibiting a structural or electronic phase transition offer a large modulation contrast with multi-level optical switching and memory functionalities. In addition, plasmonic nanoantennas can provide an efficient enhancement mechanism for both the optically induced excitation and the readout of materials strategically positioned in their local environment. Here, we demonstrate picosecond all-optical switching of the local phase transition in plasmonic antenna-vanadium dioxide (VO2) hybrids, exploiting strong resonant field enhancement and selective optical pumping in plasmonic hotspots. Polarization- and wavelength-dependent pump-probe spectroscopy of multifrequency crossed antenna arrays shows that nanoscale optical switching in plasmonic hotspots does not affect neighboring antennas placed within 100 nm of the excited antennas. The antenna-assisted pumping mechanism is confirmed by numerical model calculations of the resonant, antenna-mediated local heating on a picosecond time scale. The hybrid, nanoscale excitation mechanism results in 20 times reduced switching energies and 5 times faster recovery times than a VO2 film without antennas, enabling fully reversible switching at over two million cycles per second and at local switching energies in the picojoule range. The hybrid solution of antennas and VO2 provides a conceptual framework to merge the field localization and phase-transition response, enabling precise, nanoscale optical memory functionalities

Speech therapy for compensatory articulations and velopharyngeal function: a case report

The objective of this study was to describe the process of intensive speech therapy for a 6-year-old child using compensatory articulations while presenting with velopharyngeal insufficiency (VPI) and a history of cleft lip and palate. The correction of VPI was temporarily done with a pharyngeal obturator since the child presented with very little movement of the pharyngeal walls during speech, compromising the outcome of a possible pharyngeal flap procedure (pharyngoplasty). The program of intensive speech therapy involved 3 phases, each for duration of 2 weeks incorporating 2 daily sessions of 50 minutes of therapy. A total of 60 sessions of intervention were done with the initial goal of eliminating the use of compensatory articulations. Evaluation before the program indicated the use of co-productions (coarticulations) of voiceless plosive and fricative sounds with glottal stops (simultaneous production of 2 places of productions), along with weak intraoral pressure and hypernasality, all compromising speech intelligibility. To address place of articulation, strategies to increase intraoral air pressure were used along with visual, auditory and tactile feedback, emphasizing the therapy target and the air pressure and airflow during plosive and fricative sound productions. After the first two phases of the program, oral place of articulation of the targets were achieved consistently. During the third phase, velopharyngeal closure during speech was systematically addressed using a bulb reduction program with the objective of achieving velopharyngeal closure during speech consistently. After the intensive speech therapy program involving the use of a pharyngeal obturator, we observed absence of hypernasality and compensatory articulation with improved speech intelligibility

Reproductive Schedules in Southern Bluefin Tuna: Are Current Assumptions Appropriate?

Southern bluefin tuna (SBT) appear to comprise a single stock that is assumed to be both mixed across its distribution and having reproductive adults that are obligate, annual spawners. The putative annual migration cycle of mature SBT consists of dispersed foraging at temperate latitudes with migration to a single spawning ground in the tropical eastern Indian Ocean. Spawning migrations have been assumed to target two peaks in spawning activity; one in September-October and a second in February-March. SBT of sizes comparable to that of individuals observed on the spawning ground were satellite tagged in the Tasman Sea region (2003–2008) and demonstrated both migrations to the spawning grounds and residency in the Tasman Sea region throughout the whole year. All individuals undertaking apparent spawning migrations timed their movements to coincide with the second recognised spawning peak or even later. These observations suggest that SBT may demonstrate substantial flexibility in the scheduling of reproductive events and may even not spawn annually as currently assumed. Further, the population on the spawning grounds may be temporally structured in association with foraging regions. These findings provide new perspectives on bluefin population and spatial dynamics and warrant further investigation and consideration of reproductive schedules in this species

Phoenix Is Required for Mechanosensory Hair Cell Regeneration in the Zebrafish Lateral Line

In humans, the absence or irreversible loss of hair cells, the sensory mechanoreceptors in the cochlea, accounts for a large majority of acquired and congenital hearing disorders. In the auditory and vestibular neuroepithelia of the inner ear, hair cells are accompanied by another cell type called supporting cells. This second cell population has been described as having stem cell-like properties, allowing efficient hair cell replacement during embryonic and larval/fetal development of all vertebrates. However, mammals lose their regenerative capacity in most inner ear neuroepithelia in postnatal life. Remarkably, reptiles, birds, amphibians, and fish are different in that they can regenerate hair cells throughout their lifespan. The lateral line in amphibians and in fish is an additional sensory organ, which is used to detect water movements and is comprised of neuroepithelial patches, called neuromasts. These are similar in ultra-structure to the inner ear's neuroepithelia and they share the expression of various molecular markers. We examined the regeneration process in hair cells of the lateral line of zebrafish larvae carrying a retroviral integration in a previously uncharacterized gene, phoenix (pho). Phoenix mutant larvae develop normally and display a morphologically intact lateral line. However, after ablation of hair cells with copper or neomycin, their regeneration in pho mutants is severely impaired. We show that proliferation in the supporting cells is strongly decreased after damage to hair cells and correlates with the reduction of newly formed hair cells in the regenerating phoenix mutant neuromasts. The retroviral integration linked to the phenotype is in a novel gene with no known homologs showing high expression in neuromast supporting cells. Whereas its role during early development of the lateral line remains to be addressed, in later larval stages phoenix defines a new class of proteins implicated in hair cell regeneration

Autism and Intellectual Disability Are Differentially Related to Sociodemographic Background at Birth

Background: Research findings investigating the sociodemographics of autism spectrum disorder (ASD) have been inconsistent and rarely considered the presence of intellectual disability (ID). Methods: We used population data on Western Australian singletons born from 1984 to 1999 (n = 398,353) to examine the sociodemographic characteristics of children diagnosed with ASD with or without ID, or ID without ASD compared with non-affected children. Results: The profiles for the four categories examined, mild-moderate ID, severe ID, ASD without ID and ASD with ID varied considerably and we often identified a gradient effect where the risk factors for mild-moderate ID and ASD without ID were at opposite extremes while those for ASD with ID were intermediary. This was demonstrated clearly with increased odds of ASD without ID amongst older mothers aged 35 years and over (odds ratio (OR) = 1.69 [CI: 1.18, 2.43]), first born infants (OR = 2.78; [CI: 1.67, 4.54]), male infants (OR = 6.57 [CI: 4.87, 8.87]) and increasing socioeconomic advantage. In contrast, mild-moderate ID was associated with younger mothers aged less than 20 years (OR = 1.88 [CI: 1.57, 2.25]), paternal age greater than 40 years (OR = 1.59 [CI: 1.36, 1.86]), Australian-born and Aboriginal mothers (OR = 1.60 [CI: 1.41, 1.82]), increasing birth order and increasing social disadvantage (OR = 2.56 [CI: 2.27, 2.97]). Mothers of infants residing in regional or remote areas had consistently lower risk of ASD or ID and may be linked to reduced access to services or underascertainment rather than a protective effect of location. Conclusions: The different risk profiles observed between groups may be related to aetiological differences or ascertainment factors or both. Untangling these pathways is challenging but an urgent public health priority in view of the supposed autism epidemic

Risk factors for complications after appendectomy in adults

OBJETIVO: Definir os fatores de risco para as complicações após as apendicectomias em adultos. INTRODUÇÃO: os fatores de risco que levam as complicações após as apendicectomias são ainda pouco conhecidos. Sua definição pré-operatória é importante na diminuição da morbi-mortalidade pós-operatória. MÉTODOS: Estudo retrospectivo de 500 pacientes submetidos à apendicectomia no Hospital Regional da Asa Norte entre os anos de 2003 e 2004. Estes foram avaliados quanto à idade, sexo, duração dos sintomas até a procura por assistência médica, presença de febre, características da dor abdominal, hemograma, tempo de admissão até a operação, co-morbidades, incisões utilizadas nas operações, achados operatórios, utilização de drenos, complicações pós-operatórias e dias de internação hospitalar. Foram utilizadas análises de regressões logísticas para predizer e quantificar os fatores de risco para as complicações após as operações. RESULTADOS: As chances de complicações foram maiores no gênero feminino (OR=1,97, 95%, IC-1,19-3,13), na apendicite perfurada (OR=4,67, 95%, IC-2,43-8,94), na apendicite sem perfuração (OR=3,32, 95%, IC-1,72-6,38), naqueles pacientes submetidos à drenagem abdominal (OR=17,54, 95%,IC-4,83-63,77) ou com ASA II (OR=1,53, 95%, IC 2,52-15,89). As infecções do sítio cirúrgico e os abscessos intra-abdominais foram os principais fatores de morbidade. A mortalidade foi nula. CONCLUSÕES: A análise de regressão logística multivariável demonstrou que o gênero, a necrose apendicular, a drenagem da cavidade abdominal e a classificação de ASA contribuíram para o aumento das complicações pós-operatórias dos pacientes submetidos às apendicectomias.BACKGROUND: Risk factors for adverse outcomes after the surgical treatment of appendicitis in adults are poorly defined. Accurate presurgical assessment of the risk of preoperative complications and mortality is important in planning surgical therapy. METHODS: All patients undergoing surgical intervention for appendicitis from January 2003 and January 2004 were selected for study. Independent variables examined included 11 putative preoperative risk factors and 4 intraoperative process measures. Dependents variables were complications. Stepwise logistic regression analysis was used for construct models predicting complications. RESULTS: There was a high risk in female (OR=1,97, 95%, IC-1,19-3,13), in appendix with perforation (OR=4,67 95%, IC-2,43-8,94), appendix without perforation (OR=3,32, 95%, IC-1,72-6,38), drainage (OR=17,54, 95%,IC-4,83-63,77) and ASA II (OR=1,53, 95%, IC 2,52-15,89). CONCLUSION: Four factors, in the logistic regression analysis, predicted a high risk of complications after the surgical treatment of appendicitis: female, necrosis with or without ruptured appendix, drainage and ASA Class II

Genomic Analysis of QTLs and Genes Altering Natural Variation in Stochastic Noise

Quantitative genetic analysis has long been used to study how natural variation of genotype can influence an organism's phenotype. While most studies have focused on genetic determinants of phenotypic average, it is rapidly becoming understood that stochastic noise is genetically determined. However, it is not known how many traits display genetic control of stochastic noise nor how broadly these stochastic loci are distributed within the genome. Understanding these questions is critical to our understanding of quantitative traits and how they relate to the underlying causal loci, especially since stochastic noise may be directly influenced by underlying changes in the wiring of regulatory networks. We identified QTLs controlling natural variation in stochastic noise of glucosinolates, plant defense metabolites, as well as QTLs for stochastic noise of related transcripts. These loci included stochastic noise QTLs unique for either transcript or metabolite variation. Validation of these loci showed that genetic polymorphism within the regulatory network alters stochastic noise independent of effects on corresponding average levels. We examined this phenomenon more globally, using transcriptomic datasets, and found that the Arabidopsis transcriptome exhibits significant, heritable differences in stochastic noise. Further analysis allowed us to identify QTLs that control genomic stochastic noise. Some genomic QTL were in common with those altering average transcript abundance, while others were unique to stochastic noise. Using a single isogenic population, we confirmed that natural variation at ELF3 alters stochastic noise in the circadian clock and metabolism. Since polymorphisms controlling stochastic noise in genomic phenotypes exist within wild germplasm for naturally selected phenotypes, this suggests that analysis of Arabidopsis evolution should account for genetic control of stochastic variance and average phenotypes. It remains to be determined if natural genetic variation controlling stochasticity is equally distributed across the genomes of other multi-cellular eukaryotes

Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

The endoneurial microenvironment, delimited by the endothelium of endoneurial vessels and a multi-layered ensheathing perineurium, is a specialized milieu intérieur within which axons, associated Schwann cells and other resident cells of peripheral nerves function. The endothelium and perineurium restricts as well as regulates exchange of material between the endoneurial microenvironment and the surrounding extracellular space and thus is more appropriately described as a blood–nerve interface (BNI) rather than a blood–nerve barrier (BNB). Input to and output from the endoneurial microenvironment occurs via blood–nerve exchange and convective endoneurial fluid flow driven by a proximo-distal hydrostatic pressure gradient. The independent regulation of the endothelial and perineurial components of the BNI during development, aging and in response to trauma is consistent with homeostatic regulation of the endoneurial microenvironment. Pathophysiological alterations of the endoneurium in experimental allergic neuritis (EAN), and diabetic and lead neuropathy are considered to be perturbations of endoneurial homeostasis. The interactions of Schwann cells, axons, macrophages, and mast cells via cell–cell and cell–matrix signaling regulate the permeability of this interface. A greater knowledge of the dynamic nature of tight junctions and the factors that induce and/or modulate these key elements of the BNI will increase our understanding of peripheral nerve disorders as well as stimulate the development of therapeutic strategies to treat these disorders