Mesopontine rostromedial tegmental nucleus neurons projecting to the dorsal raphe and pedunculopontine tegmental nucleus: psychostimulant-elicited Fos expression and collateralization

The mesopontine rostromedial tegmental nucleus (RMTg) is a GABAergic structure in the ventral midbrain and rostral pons that, when activated, inhibits dopaminergic neurons in the ventral tegmental area and substantia nigra compacta. Additional strong outputs from the RMTg to the pedunculopontine tegmental nucleus pars dissipata, dorsal raphe nucleus, and the pontomedullary gigantocellular reticular formation were identified by anterograde tracing. RMTg neurons projecting to the ventral tegmental area express the immediate early gene Fos upon psychostimulant administration. The present study was undertaken to determine if neurons in the RMTg that project to the additional structures listed above also express Fos upon psychostimulant administration and, if so, whether single neurons in the RMTg project to more than one of these structures. We found that about 50% of RMTg neurons exhibiting retrograde labeling after injections of retrograde tracer in the dorsal raphe or pars dissipata of the pedunculopontine tegmental nucleus express Fos after acute methamphetamine exposure. Also, we observed that a significant number of RMTg neurons project both to the ventral tegmental area and one of these structures. In contrast, methamphetamine-elicited Fos expression was not observed in RMTg neurons labeled with retrograde tracer following injections into the pontomedullary reticular formation. The findings suggest that the RMTg is an integrative modulator of multiple rostrally projecting structures

Laminin γ2 fragments are increased in the circulation of patients with early phase acute lung injury

Katayama, M., Ishizaka, A., Sakamoto, M. et al. Intensive Care Med (2010) 36: 479. https://doi.org/10.1007/s00134-009-1719-

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

Nr4a1-eGFP Is a Marker of Striosome-Matrix Architecture, Development and Activity in the Extended Striatum

Transgenic mice expressing eGFP under population specific promoters are widely used in neuroscience to identify specific subsets of neurons in situ and as sensors of neuronal activity in vivo. Mice expressing eGFP from a bacterial artificial chromosome under the Nr4a1 promoter have high expression within the basal ganglia, particularly within the striosome compartments and striatal-like regions of the extended amygdala (bed nucleus of the stria terminalis, striatal fundus, central amygdaloid nucleus and intercalated cells). Grossly, eGFP expression is inverse to the matrix marker calbindin 28K and overlaps with mu-opioid receptor immunoreactivity in the striatum. This pattern of expression is similar to Drd1, but not Drd2, dopamine receptor driven eGFP expression in structures targeted by medium spiny neuron afferents. Striosomal expression is strong developmentally where Nr4a1-eGFP expression overlaps with Drd1, TrkB, tyrosine hydroxylase and phospho-ERK, but not phospho-CREB, immunoreactivity in “dopamine islands”. Exposure of adolescent mice to methylphenidate resulted in an increase in eGFP in both compartments in the dorsolateral striatum but eGFP expression remained brighter in the striosomes. To address the role of activity in Nr4a1-eGFP expression, primary striatal cultures were prepared from neonatal mice and treated with forskolin, BDNF, SKF-83822 or high extracellular potassium and eGFP was measured fluorometrically in lysates. eGFP was induced in both neurons and contaminating glia in response to forskolin but SKF-83822, brain derived neurotrophic factor and depolarization increased eGFP in neuronal-like cells selectively. High levels of eGFP were primarily associated with Drd1+ neurons in vitro detected by immunofluorescence; however ∼15% of the brightly expressing cells contained punctate met-enkephalin immunoreactivity. The Nr4a1-GFP mouse strain will be a useful model for examining the connectivity, physiology, activity and development of the striosome system

Meta-analysis of the relation between European and American smokeless tobacco and oral cancer

<p>Abstract</p> <p>Background</p> <p>Smokeless tobacco is often referred to as a major contributor to oral cancer. In some regions, especially Southeast Asia, the risk is difficult to quantify due to the variety of products, compositions (including non-tobacco ingredients) and usage practices involved. In Western populations, the evidence of an increased risk in smokeless tobacco users seems unclear, previous reviews having reached somewhat differing conclusions. We report a detailed quantitative review of the evidence in American and European smokeless tobacco users, and compare our findings with previous reviews and meta-analyses.</p> <p>Methods</p> <p>Following literature review a meta-analysis was conducted of 32 epidemiological studies published between 1920 and 2005 including tests for homogeneity and publication bias.</p> <p>Results</p> <p>Based on 38 heterogeneous study-specific estimates of the odds ratio or relative risk for smokeless tobacco use, the random-effects estimate was 1.87 (95% confidence interval 1.40–2.48). The increase was mainly evident in studies conducted before 1980. No increase was seen in studies in Scandinavia. Restricting attention to the seven estimates adjusted for smoking and alcohol eliminated both heterogeneity and excess risk (1.02; 0.82–1.28). Estimates also varied by sex (higher in females) and by study design (higher in case-control studies with hospital controls) but more clearly in studies where estimates were unadjusted, even for age. The pattern of estimates suggests some publication bias. Based on limited data specific to never smokers, the random-effects estimate was 1.94 (0.88–4.28), the eight individual estimates being heterogeneous and based on few exposed cases.</p> <p>Conclusion</p> <p>Smokeless tobacco, as used in America or Europe, carries at most a minor increased risk of oral cancer. However, elevated risks in specific populations or from specific products cannot definitely be excluded.</p

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038