Gabapentin increases the abuse liability of alcohol alone and in combination with oxycodone in participants with co-occurring opioid and alcohol use disorder.

BACKGROUND: People who have co-occurring Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) carry a higher risk of adverse outcomes, including drug overdose. Early clinical and preclinical studies suggested that gabapentin may be effective in treating both disorders. The present study was designed to assess the effects of gabapentin on the subjective and physiological effects of oxycodone (OXY) and alcohol (ALC), alone and in combination. METHODS: During an 8-week, inpatient, within-subject, randomized, double-blind, placebo-controlled crossover study, non-treatment seeking participants (N = 13; 12 M/1F; 44.1 ± 3 years of age) with OUD and AUD were maintained on oral morphine (120 mg daily). Under gabapentin (1800 mg/day) and placebo (0 mg/day) maintenance, participants completed nine separate test sessions (three sessions per week) during which they received an oral solution containing 0, 15, or 30 mg/70 kg OXY in combination with 0, 0.5, or 0.75 g/kg ALC. During test sessions, subjective effects and physiological responses were assessed repeatedly on 100-mm visual analog scales (VAS). The primary outcome variable was the VAS rating of drug liking after receiving the drug challenge. RESULTS: Alcohol alone (but not oxycodone alone) produced dose-related increases in several positive subjective responses, including drug liking. Gabapentin significantly increased drug liking when given in combination with ALC and OXY + ALC (p < 0.05). Gabapentin did not clinically compromise respiration or other vital functions. CONCLUSIONS: Gabapentin may increase the abuse liability of ALC and OXY + ALC in those with co-occurring OUD and AUD.

The potential of bacteriophage therapy in the treatment of paediatric respiratory infections.

The looming antibiotic resistance crisis is forcing clinicians to consider alternative approaches to treating bacterial infections. As the window of use for current antimicrobial agents becomes ever narrower, we consider if looking back will now be the way forward. Conceptually, phage therapy is simple and specific; a targeted treatment to control bacterial overgrowth. In this article we discuss bacteriophage and potential use in future therapy.

Minocycline attenuates oxycodone-induced positive subjective responses in non-dependent, recreational opioid users.

BACKGROUND: Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that mu-opioid-receptor-selective agonists, such as oxycodone, activate glia and increase the release of cytokines, causing a suppression of opioid-induced analgesic effects. Preclinical studies also show that certain medications, such as the broad-spectrum tetracycline antibiotic minocycline, inhibit opioid-induced glial activation and thereby enhance the analgesic effects of opioids. Importantly, minocycline reduces the rewarding effects of opioids at the same doses that it enhances opioid-induced analgesia. AIMS: The purpose of the present study was to assess the effects of acute administration of minocycline on the subjective, physiological, and analgesic effects of oxycodone in human research volunteers. DESIGN: This study was a within-subject, randomized, double-blind outpatient study. Participants completed five separate sessions in which they received 0, 100, or 200 mg minocycline (MINO) simultaneously with either 0 or 40 mg oxycodone (OXY). The subjective, physiological, and analgesic effects of OXY were measured before and repeatedly after drug administration. SETTINGS AND PARTICIPANTS: Participants were between 21 and 45 years of age, non-treatment seeking, non-dependent recreational opioid users (N = 12). This study was conducted between 2013 and 2014 at the New York State Psychiatric Institute in New York, NY. FINDINGS: MINO 100 and 200 mg were safe and well-tolerated in combination with OXY 40 mg. MINO 200 mg administered with OXY 40 mg attenuated OXY-induced positive subjective effects such as "Good Effect" and "Liking" compared to OXY alone. MINO did not alter the physiological or analgesic effects of OXY. CONCLUSIONS: MINO may attenuate the abuse liability of mu-opioid-receptor-selective agonists.

Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis.

Macrophages play a dual role in regulating tumor progression. They can either reduce tumor growth by secreting antitumorigenic factors or promote tumor progression by secreting a variety of soluble factors. The purpose of this study was to define the monocyte/macrophage population prevalent in skeletal tumors, explore a mechanism employed in supporting prostate cancer (PCa) skeletal metastasis, and examine a novel therapeutic target. Phagocytic CD68+ cells were found to correlate with Gleason score in human PCa samples, and M2-like macrophages (F4/80+CD206+) were identified in PCa bone resident tumors in mice. Induced M2-like macrophages in vitro were more proficient at phagocytosis (efferocytosis) of apoptotic tumor cells than M1-like macrophages. Moreover, soluble factors released from efferocytic versus nonefferocytic macrophages increased PC-3 prostate cancer cell numbers in vitro. Trabectedin exposure reduced M2-like (F4/80+CD206+) macrophages in vivo. Trabectedin administration after PC-3 cell intracardiac inoculation reduced skeletal metastatic tumor growth. Preventative pretreatment with trabectedin 7 days prior to PC-3 cell injection resulted in reduced M2-like macrophages in the marrow and reduced skeletal tumor size. Together, these findings suggest that M2-like monocytes and macrophages promote PCa skeletal metastasis and that trabectedin represents a candidate therapeutic target.

Two different R gene loci co-evolved with Avr2 of Phytophthora infestans and confer distinct resistance specificities in potato.

Late blight, caused by the oomycete pathogen Phytophthora infestans, is the most devastating disease in potato. For sustainable management of this economically important disease, resistance breeding relies on the availability of resistance (R) genes. Such R genes against P. infestans have evolved in wild tuber-bearing Solanum species from North, Central and South America, upon co-evolution with cognate avirulence (Avr) genes. Here, we report how effectoromics screens with Avr2 of P. infestans revealed defense responses in diverse Solanum species that are native to Mexico and Peru. We found that the response to AVR2 in the Mexican Solanum species is mediated by R genes of the R2 family that resides on a major late blight locus on chromosome IV. In contrast, the response to AVR2 in Peruvian Solanum species is mediated by Rpi-mcq1, which resides on chromosome IX and does not belong to the R2 family. The data indicate that AVR2 recognition has evolved independently on two genetic loci in Mexican and Peruvian Solanum species, respectively. Detached leaf tests on potato cultivar 'Désirée' transformed with R genes from either the R2 or the Rpi-mcq1 locus revealed an overlapping, but distinct resistance profile to a panel of 18 diverse P. infestans isolates. The achieved insights in the molecular R - Avr gene interaction can lead to more educated exploitation of R genes and maximize the potential of generating more broad-spectrum, and potentially more durable control of the late blight disease in potato.

Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.

Hepatitis C infection in non-treatment-seeking heroin users: the burden of cocaine injection.

BACKGROUND AND OBJECTIVES: In heroin dependent individuals, the HIV epidemic has been controlled in countries where access to opioid maintenance treatment (OMT) and needle exchange programs (NEP) have been implemented. However, despite similar routes of contamination for both viruses, the prevalence of hepatitis C (HCV) infection remains high in drug users. The objective of this analysis was to identify the prevalence of HCV and the correlates of being HCV-positive in a sample of out-of-treatment heroin-dependent individuals. METHODS: Data were collected from five inpatient studies (n = 120 participants) conducted at the New York State Psychiatric Institute. A logistic regression was used to identify correlates of being HCV-positive at baseline. RESULTS: Among the 120 heroin-dependent volunteers, 42 were HCV-positive. Participants who had heavier alcohol use, a longer duration of heroin use, or who reported using heroin by injection were more likely to be HCV-positive. Interestingly, participants who had injected cocaine during the previous month had a ninefold greater risk of being HCV-positive compared to non-cocaine users and those who used cocaine by a non-injecting route. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These findings confirm the risk of being HCV-infected through intravenous drug use, especially with cocaine use. These results underscore the importance of rethinking interventions to prevent HCV infection with combined strategies using pharmacological approaches for cocaine dependence and tailored prevention for cocaine users.

Mechanisms of nuclear suppression of host immunity by effectors from the Arabidopsis downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa).

Filamentous phytopathogens form sophisticated intracellular feeding structures called haustoria in plant cells. Pathogen effectors are likely to play a role in the establishment and maintenance of haustoria additional to their more characterized role of suppressing plant defense. Recent studies suggest that effectors may manipulate host transcription or other nuclear regulatory components for the benefit of pathogen development. However, the specific mechanisms by which these effectors promote susceptibility remain unclear. Of two recent screenings, we identified 15 nuclear-localized Hpa effectors (HaRxLs) that interact directly or indirectly with host nuclear components. When stably expressed in planta, nuclear HaRxLs cause diverse developmental phenotypes highlighting that nuclear effectors might interfere with fundamental plant regulatory mechanisms. Here, we report recent advances in understanding how a pathogen can manipulate nuclear processes in order to cause disease.

Health comorbidities and cognition in 1948 patients with idiopathic Parkinson's disease.

BACKGROUND: Health comorbidities, particularly cardiovascular factors, are well known to pose risks for cognitive decline in older adults. This study examined the prevalence and contribution of comorbidities on cognitive performance in a large cohort of Parkinson patients. METHODS: Data on 1948 PD patients were obtained from the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) registry, a multi-site initiative from NPF Centers of Excellence. Available comorbidity data included six common conditions (heart/circulation problems, diabetes, arthritis, cancer, respiratory disease, and other neurologic disease) that were clinician-rated for presence and severity. Available cognitive measures included semantic fluency and a 5-word recall memory task. The unique effects of comorbidities on cognition were analyzed (multiple hierarchical regression) controlling for demographic, PD disease severity (duration, Hoehn-Yahr), and medication status. RESULTS: The two most reported comorbidities were arthritis (46.6%) and heart/circulation problems (36.3%), with diabetes affecting 9% of the sample. Severity of heart/circulation problems independently contributed to worse delayed recall performance (p = 0.03). A trend emerged for more severe diabetes as contributing to worse semantic fluency scores (p = 0.06). CONCLUSIONS: This study with a large cohort of PD patients provides evidence for a small detrimental influence of specific health comorbidities, particularly heart/circulatory and diabetes, on general measures of cognition. This effect is present, above and beyond the influences of basic demographic information (age), duration and staging of PD, and medication status. Future studies involving more refined cognitive indices and direct assessment of comorbidities are warranted.

Effects of residual gas exposure on the field emission properties of ZnO nanorods.

We compare the effects of O2, CO2, N2, H2, and Ar residual gas exposure on the field emission (FE) properties of ZnO nanorods. In contrast to carbon nanotubes and Mo metal microtips, we find that O2 and CO2 exposures do not significantly degrade the FE properties of ZnO nanorods. However, N2 exposure significantly degrades the FE properties. We propose that this could be due to the dissociation of N2 into atomic nitrogen species and the reaction of such species with ZnO. H2 and Ar exposures are not observed to significantly degrade the FE properties.

A new species of Albugo parasitic to Arabidopsis thaliana reveals new evolutionary patterns in white blister rusts (Albuginaceae).

The obligate biotrophic lineages of the white blister rusts (Albuginales, Oomycota) are of ancient origin compared to the rather recently evolved downy mildews, and sophisticated mechanisms of biotrophy and a high degree of adaptation diversity are to be expected in these organisms. Speciation in the biotrophic Oomycetes is usually thought to be the consequence of host adaptation or geographic isolation. Here we report the presence of two distinct species of Albugo on the model plant Arabidopsis thaliana, Albugo candida and Albugo laibachii, the latter being formally described in this manuscript. Both species may occupy the same host within the same environment, but are nevertheless phylogenetically distinct, as inferred from analyses of both mitochondrial and nuclear DNA sequences. Different ways of adapting to their host physiology might constitute an important factor of their different niches. Evidence for this can be gained from the completely different host range of the two pathogens. While Albugo candida is a generalist species, consisting of several physiological varieties, which is able to parasitize a great variety of Brassicaceae, Albugo laibachii has not been found on any host other than Arabidopsis thaliana. Therefore, Albugo laibachii belongs to a group of highly specialised species, like the other known specialist species in Albugo s.s., Albugo koreana, Albugo lepidii and Albugo voglmayrii. The comparative investigation of the effector genes and host targets in the generalist and the specialist species may constitute a model system for elucidating the fundamental processes involved in plant pathogen co-adaptation and speciation.

Analysis of optical damage mechanisms in hollow-core waveguides delivering nanosecond pulses from a Q-switched Nd:YAG laser.

Hollow-core waveguides consisting of a glass capillary tube with an internal reflective coating are capable of delivering pulse energies of tens of millijoules with improved focusability compared to step index fibers of similar core diameter. We demonstrate the capability of these fibers to deliver high-power Q-switched pulses at the fundamental (1064 nm), second (532 nm), and third (355 nm) harmonics of a Nd:YAG laser, both in terms of peak power and beam quality delivered. In terms of peak power delivery, the primary limitation is the occurrence of bend-induced optical damage to the reflective coating. The damage mechanism and the influential factors are analyzed, in particular, the dependence upon the number of guided modes, core diameter, coating thicknesses, and input polarization alignment.

Solanum mochiquense chromosome IX carries a novel late blight resistance gene Rpi-moc1.

Screening of a large number of different diploid Solanum accessions with endosperm balance number (EBN) 1 revealed segregation for strong resistance and sensitivity to Phytophthora infestans in accessions of Solanum mochiquense. Genetic analysis showed that resistance in S. mochiquense accession CGN18263 resides at the distal end of the long arm of chromosome IX, is linked to restriction fragment length polymorphism marker TG328 and is in the neighbourhood of the quantitative trait locus (QTL) Ph-3 conferring resistance to P. infestans in tomato. This is the first genetic study of S. mochiquense, a wild diploid species originating from fog oases in the Peruvian coastal desert.

Two-axis bend measurement with Bragg gratings in multicore optical fiber.

We describe what is to our knowledge the first use of fiber Bragg gratings written into three separate cores of a multicore fiber for two-axis curvature measurement. The gratings act as independent, but isothermal, fiber strain gauges for which local curvature determines the difference in strain between cores, permitting temperature-independent bend measurement.

Multi-functional T-DNA/Ds tomato lines designed for gene cloning and molecular and physical dissection of the tomato genome.

In order to make the tomato genome more accessible for molecular analysis and gene cloning, we have produced 405 individual tomato (Lycopersicon esculentum) lines containing a characterized copy of pJasm13, a multifunctional T-DNA/modified Ds transposon element construct. Both the T-DNA and the Ds element in pJasm13 harbor a set of selectable marker genes to monitor excision and reintegration of Ds and additionally, target sequences for rare cutting restriction enzymes (I-PpoI, SfiI, NotI) and for site-specific recombinases (Cre, FLP, R). Blast analysis of flanking genomic sequences of 174 T-DNA inserts revealed homology to transcribed genes in 69 (40%), of which about half are known or putatively identified as genes and ESTs. The map position of 140 individual inserts was determined on the molecular genetic map of tomato. These inserts are distributed over the 12 chromosomes of tomato, allowing targeted and non-targeted transposon tagging, marking of closely linked genes of interest and induction of chromosomal rearrangements including translocations or creation of saturation-deletions or inversions within defined regions linked to the T-DNA insertion site. The different features of pJasm13 were successfully tested in tomato and Arabidopsis thaliana, thus providing a new tool for molecular/genetic dissection studies, including molecular and physical mapping, mutation analysis and cloning strategies in tomato and potentially, in other plants as well.

Developmental control of promoter activity is not responsible for mature onset of Cf-9B-mediated resistance to leaf mold in tomato.

Cf-9 confers resistance to tomato seedlings and mature plants against Cladosporium fulvum races expressing the Avr9 elicitor. It is the central member of a cluster of five paralogous genes in an introgressed segment of chromosome 1 derived from Lycopersicon pimpinellifolium. The other four genes have been named Hcr9-9A, Hcr9-9B, Hcr9-9D, and Hcr9-9E. Hcr9-9B, here designated Cf-9B, encodes weaker resistance than Cf-9, recognizes a different elicitor, and protects only mature plants from infection. The onset of Cf-9B-mediated resistance and the molecular basis for its developmental control were investigated in this study. Fungal inoculation of tomato plants containing reciprocal Cf-9/Cf-9B promoter-coding region swaps, analysis of tomato plants containing promoter-gusA fusions, and a reverse transcriptase-polymerase chain reaction study of Cf-9 and Cf-9B transcripts in tomato plants suggested that transcriptional control of Cf-9B did not account for the late onset of Cf-9B-mediated resistance. Alternative explanations for the onset of Cf-9B-mediated resistance in mature plants are discussed.

Predictors of bone mineral density in aging healthy men varies by skeletal site.

Factors contributing to the pathogenesis of osteoporosis in women are well defined. However, changes in bone mineral metabolism in aging men and the role of various factors in the pathogenesis of age-related bone loss in men are less well understood. To further clarify these changes, serum and urine biochemical parameters, and lumbar spine, hip, and total body bone mineral density (BMD) were evaluated in a small sample of 45 healthy men aged 20-80 years, and multiple regression models were developed to predict age-related bone loss. Serum calcium, phosphate, albumin, creatinine clearance, osteocalcin, C-terminal propeptide of type I procollagen, log-free androgen index, dehydroepiandrosterone sulfate (DHEA-S), and androstenedione decreased with age, and serum sex hormone binding globulin and urine total and free pyridinoline increased with age. Femoral neck BMD decreased with age, but remained stable at the other sites measured. Multiple regression analysis indicated that serum phosphate, DHEA-S, and intact parathyroid hormone (PTH) predicted lumbar spine BMD. Age, serum phosphate, and PTH predicted femoral neck BMD. Urine-free deoxypyridinoline alone predicted femoral greater trochanter BMD. Weight, serum creatinine, and urine-free deoxypyridinoline predicted total body BMD. We conclude that predictor variables of bone density vary by skeletal site in healthy men. Alterations in adrenal androgens, phosphate, and PTH may be important in the pathogenesis of bone loss with aging in men.

Transposition patterns of unlinked transposed Ds elements from two T-DNA loci on tomato chromosomes 7 and 8.

We have previously reported that unlinked transposed Ds elements originating from chromosome 4 of tomato preferentially inserted in chromosome 2. This observation, together with data from other studies, suggested that there may be absolute preferences for transposition, irrespective of the chromosomal location of the donor site. The aim of the present work was to verify whether the distribution of transposed Ds elements on chromosome 2 was non-random and thus whether, unlike the case in maize, unlinked transpositions in tomato are not distributed randomly. To do this, unlinked acceptor sites of Ds elements originating from two donor T-DNA loci lying on chromosomes 7 and 8 were mapped. Receptor sites for tr Ds elements transposed from the 1601D locus on chromosome 8 exhibited a non-random distribution (P<0.01). Eleven out of 46 independent transpositions mapped to chromosome 2 and, as this was statistically significant (P<0.01), proves that receptor sites for this element are not randomly distribution on the chromosomes. In addition, deviation of the observed number from the expected number of tr Dss was close to being significant for chromosome 4 (P=0.05-0.1). In contrast, the distribution of unlinked receptor sites for tr Dss derived from the 1481J locus on chromosome 7 was random. Chi(2)tests were performed for each chromosome, and for chromosome 4 the difference between the observed and the expected number of tr Dss was very high but statistically non-significant (P=0.05-0.1). For chromosome 2 the difference was statistically negligible. Therefore, we conclude that chromosome 2 does not serve as a preferential receptor for the transposition of Ds elements independently of the location of the donor site.