Temporal trends in the impact factor of European versus USA biomedical journals

Background

The impact factors of biomedical journals tend to rise over time. We sought to assess the trend in the impact factor, during the past decade, of journals published on behalf of United States (US) and European scientific societies, in four select biomedical subject categories (Biology, Cell Biology, Critical Care Medicine, and Infectious Diseases).

Methods

We identified all journals included in the above-mentioned subject categories of Thomson Reuters Journal Citation Reports® for the years 1999, 2002, 2005, and 2008. We selected those that were published on behalf of US or European scientific societies, as documented in journal websites.

Results

We included 167 journals (35 in the subject category of Biology, 79 in Cell Biology, 27 in Critical Care Medicine, and 26 in Infectious Diseases). Between 1999 and 2008, the percentage increase in the impact factor of the European journals was higher than for the US journals (73.7±110.0% compared with 39.7±70.0%, p = 0.049). Regarding specific subject categories, the percentage change in the factor of the European journals tended to be higher than the respective US journals for Cell Biology (61.7% versus 16.3%), Critical Care Medicine (212.4% versus 65.4%), Infectious Diseases (88.3% versus 48.7%), whereas the opposite was observed for journals in Biology (41.0% versus 62.5%).

Conclusion

Journals published on behalf of European scientific societies, in select biomedical fields, may tend to close the “gap” in impact factor compared with those of US societies.

What''s Already Known About This Topic?

The impact factors of biomedical journals tend to rise through years. The leading positions in productivity in biomedical research are held by developed countries, including those from North America and Western Europe.

What Does This Article Add?

The journals from European biomedical scientific societies tended, over the past decade, to increase their impact factor more than the respective US journals.     

Pandemics in the age of Twitter: content analysis of Tweets during the 2009 H1N1 outbreak

Background

Surveys are popular methods to measure public perceptions in emergencies but can be costly and time consuming. We suggest and evaluate a complementary “infoveillance” approach using Twitter during the 2009 H1N1 pandemic. Our study aimed to: 1) monitor the use of the terms “H1N1” versus “swine flu” over time; 2) conduct a content analysis of “tweets”; and 3) validate Twitter as a real-time content, sentiment, and public attention trend-tracking tool.

Methodology/Principal Findings

Between May 1 and December 31, 2009, we archived over 2 million Twitter posts containing keywords “swine flu,” “swineflu,” and/or “H1N1.” using Infovigil, an infoveillance system. Tweets using “H1N1” increased from 8.8% to 40.5% (R ² = .788; p<.001), indicating a gradual adoption of World Health Organization-recommended terminology. 5,395 tweets were randomly selected from 9 days, 4 weeks apart and coded using a tri-axial coding scheme. To track tweet content and to test the feasibility of automated coding, we created database queries for keywords and correlated these results with manual coding. Content analysis indicated resource-related posts were most commonly shared (52.6%). 4.5% of cases were identified as misinformation. News websites were the most popular sources (23.2%), while government and health agencies were linked only 1.5% of the time. 7/10 automated queries correlated with manual coding. Several Twitter activity peaks coincided with major news stories. Our results correlated well with H1N1 incidence data.

Conclusions

This study illustrates the potential of using social media to conduct “infodemiology” studies for public health. 2009 H1N1-related tweets were primarily used to disseminate information from credible sources, but were also a source of opinions and experiences. Tweets can be used for real-time content analysis and knowledge translation research, allowing health authorities to respond to public concerns.     

Cloning and characterization of a putative TAC1 ortholog associated with leaf angle in maize (Zea mays L.)

Background

Modifying plant architecture to increase photosynthesis efficiency and reduce shade avoidance response is very important for further yield improvement when crops are grown in high density. Identification of alleles controlling leaf angle in maize is needed to provide insight into molecular mechanism of leaf development and achieving ideal plant architecture to improve grain yield.

Methodology/Principal Findings

The gene cloning was done by using comparative genomics, and then performing real-time polymerase chain reaction (RT-PCR) analysis to assay gene expression. The gene function was validated by sequence dissimilarity analysis and QTL mapping using a functional cleaved amplified polymorphism (CAP).

Conclusions

The leaf angle is controlled by a major quantitative trait locus, ZmTAC1 (Zea mays L. Leaf Angle Control 1). ZmTAC1 has 4 exons encoding a protein with 263 amino acids, and its domains are the same as those of the rice OsTAC1 protein. ZmTAC1 was found to be located in the region of qLA2 by using the CAP marker and the F_2:3 families from the cross between Yu82 and Shen137. Real-time PCR analysis revealed ZmTAC1 expression was the highest in the leaf-sheath pulvinus, less in the leaf and shoot apical meristem, and the lowest in the root. A nucleotide difference in the 5′-untranslated region (UTR) between the compact inbred line Yu82 (“CTCC”) and the expanded inbred line Shen137 (“CCCC”) influences the expression level of ZmTAC1, further controlling the size of the leaf angle. Sequence verification of the change in the 5′-UTR revealed ZmTAC1 with “CTCC” was present in 13 compact inbred lines and ZmTAC1 with “CCCC” was present in 18 expanded inbred lines, indicating ZmTAC1 had been extensively utilized in breeding with regard to the improvement of the maize plant architecture.     

Pilot study of the association of the DDAH2 -449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis

Background

Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock.

Methodology/Principal Findings

In a prospective study, blood and buccal swabs were obtained from 82 patients ≤18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the −871 6g/7g insertion/deletion and −449G/C single nucleotide polymorphisms. Shock type (“warm” versus “cold”) was characterized by clinical assessment. The −871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between −871 6g/7g genotypes. While genotype frequencies also did not vary between groups for the −449G/C SNP (p = 0.75), septic patients with at least one −449G allele had lower ADMA (median, IQR 0.36, 0.30–0.41 µmol/L) than patients with the −449CC genotype (0.55, 0.49–0.64 µmol/L, p = 0.008) and exhibited a higher incidence of “cold” shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration.

Conclusions/Significance

The −449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with “cold” shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology.     

Distinct functional patterns of gene promoter hypomethylation and hypermethylation in cancer genomes

Background

Aberrant DNA methylation plays important roles in carcinogenesis. However, the functional significance of genome-wide hypermethylation and hypomethylation of gene promoters in carcinogenesis currently remain unclear.

Principal Findings

Based on genome-wide methylation data for five cancer types, we showed that genes with promoter hypermethylation were highly consistent in function across different cancer types, and so were genes with promoter hypomethylation. Functions related to “developmental processes” and “regulation of biology processes” were significantly enriched with hypermethylated genes but were depleted of hypomethylated genes. In contrast, functions related to “cell killing” and “response to stimulus”, including immune and inflammatory response, were associated with an enrichment of hypomethylated genes and depletion of hypermethylated genes. We also observed that some families of cytokines secreted by immune cells, such as IL10 family cytokines and chemokines, tended to be hypomethylated in various cancer types. These results provide new hints for understanding the distinct functional roles of genome-wide hypermethylation and hypomethylation of gene promoters in carcinogenesis.

Conclusions

Genes with promoter hypermethylation and hypomethylation are highly consistent in function across different cancer types, respectively, but these two groups of genes tend to be enriched in different functions associated with cancer. Especially, we speculate that hypomethylation of gene promoters may play roles in inducing immunity and inflammation disorders in precancerous conditions, which may provide hints for improving epigenetic therapy and immunotherapy of cancer.     

dATP/ATP, a multifunctional nucleotide, stimulates bacterial cell lysis, extracellular DNA release and biofilm development

Background

Signaling by extracellular adenosine 5′-triphosphase (eATP) is very common for cell-to-cell communication in many basic patho-physiological development processes. Rapid release of ATP into the extracellular environment from distressed or injured eukaryotic cells due to pathogens or other etiological factors can serve as a “danger signal”, activating host innate immunity. However, little is known about how or whether pathogenic bacteria respond to this “danger signal”.

Methods and Principal Findings

Here we report that extracellular dATP/ATP can stimulate bacterial adhesion and biofilm formation via increased cell lysis and extracellular DNA (eDNA) release. We demonstrate that extracellular dATP/ATP also stimulates bacterial adherence in vitro to human bronchial epithelial cells.

Conclusions and Significance

These data suggest that bacteria may sense extracellular dATP/ATP as a signal of “danger” and form biofilms to protect them from host innate immunity. This study reveals a very important and unrecognized phenomenon that both bacteria and host cells could respond to a common important signal molecule in a race to adapt to the presence of one another. We propose that extracellular dATP/ATP functions as an “inter-domain” warning signal that serves to induce protective measures in both Bacterial and Eukaryotic cells.     

Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment

Background

Onchocerca volvulus is the causative agent of onchocerciasis, or “river blindness”. Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug. Should ivermectin resistance be developing, it would have a genetic basis. We monitored genetic changes in parasites obtained from the same patients before use of ivermectin and following different levels of ivermectin exposure.

Methods and Findings

O. volvulus adult worms were obtained from 73 patients before exposure to ivermectin and in the same patients following three years of annual or three-monthly treatment at 150 µg/kg or 800 µg/kg. Genotype frequencies were determined in β-tubulin, a gene previously found to be linked to ivermectin selection and resistance in parasitic nematodes. Such frequencies were also determined in two other genes, heat shock protein 60 and acidic ribosomal protein, not known to be linked to ivermectin effects. In addition, we investigated the relationship between β-tubulin genotype and female parasite fertility. We found a significant selection for β-tubulin heterozygotes in female worms. There was no significant selection for the two other genes. Quarterly ivermectin treatment over three years reduced the frequency of the β-tubulin “aa” homozygotes from 68.6% to 25.6%, while the “ab” heterozygotes increased from 20.9% to 69.2% in the female parasites. The female worms that were homozygous at the β-tubulin locus were more fertile than the heterozygous female worms before treatment (67% versus 37%; p = 0.003) and twelve months after the last dose of ivermectin in the groups treated annually (60% versus 17%; p<0.001). Differences in fertility between heterozygous and homozygous worms were less apparent three months after the last treatment in the groups treated three-monthly.

Conclusions

The results indicate that ivermectin is causing genetic selection on O. volvulus. This genetic selection is associated with a lower reproductive rate in the female parasites. We hypothesize that this genetic selection indicates that a population of O. volvulus, which is more tolerant to ivermectin, is being selected. This selection could have implications for the development of ivermectin resistance in O. volvulus and for the ongoing onchocerciasis control programmes.     

Estimation of individual muscle force using elastography

Background

Estimation of an individual muscle force still remains one of the main challenges in biomechanics. In this way, the present study aimed: (1) to determine whether an elastography technique called Supersonic Shear Imaging (SSI) could be used to estimate muscle force, (2) to compare this estimation to that one provided by surface electromyography (EMG), and (3) to determine the effect of the pennation of muscle fibers on the accuracy of the estimation.

Methods and Results

Eleven subjects participated in two experimental sessions; one was devoted to the shear elastic modulus measurements and the other was devoted to the EMG recordings. Each session consisted in: (1) two smooth linear torque ramps from 0 to 60% and from 0 to 30% of maximal voluntary contraction, for the first dorsal interosseous and the abductor digiti minimi, respectively (referred to as “ramp contraction”); (2) two contractions done with the instruction to freely change the torque (referred to as “random changes contraction”). Multi-channel surface EMG recordings were obtained from a linear array of eight electrodes and the shear elastic modulus was measured using SSI. For ramp contractions, significant linear relationships were reported between EMG activity level and torque (R² = 0.949±0.036), and between shear elastic modulus and torque (R² = 0.982±0.013). SSI provided significant lower RMS_deviation between measured torque and estimated torque than EMG activity level for both types of contraction (1.4±0.7 vs. 2.8±1.4% of maximal voluntary contraction for “ramp contractions”, p<0.01; 4.5±2.3 vs. 7.9±5.9% of MVC for “random changes contractions”, p<0.05). No significant difference was reported between muscles.

Conclusion

The shear elastic modulus measured using SSI can provide a more accurate estimation of individual muscle force than surface EMG. In addition, pennation of muscle fibers does not influence the accuracy of the estimation.     

A gene optimization strategy that enhances production of fully functional P-glycoprotein in Pichia pastoris

Background

Structural and biochemical studies of mammalian membrane proteins remain hampered by inefficient production of pure protein. We explored codon optimization based on highly expressed Pichia pastoris genes to enhance co-translational folding and production of P-glycoprotein (Pgp), an ATP-dependent drug efflux pump involved in multidrug resistance of cancers.

Methodology/Principal Findings

Codon-optimized “Opti-Pgp” and wild-type Pgp, identical in primary protein sequence, were rigorously analyzed for differences in function or solution structure. Yeast expression levels and yield of purified protein from P. pastoris (∼130 mg per kg cells) were about three-fold higher for Opti-Pgp than for wild-type protein. Opti-Pgp conveyed full in vivo drug resistance against multiple anticancer and fungicidal drugs. ATP hydrolysis by purified Opti-Pgp was strongly stimulated ∼15-fold by verapamil and inhibited by cyclosporine A with binding constants of 4.2±2.2 µM and 1.1±0.26 µM, indistinguishable from wild-type Pgp. Maximum turnover number was 2.1±0.28 µmol/min/mg and was enhanced by 1.2-fold over wild-type Pgp, likely due to higher purity of Opti-Pgp preparations. Analysis of purified wild-type and Opti-Pgp by CD, DSC and limited proteolysis suggested similar secondary and ternary structure. Addition of lipid increased the thermal stability from T_m ∼40°C to 49°C, and the total unfolding enthalpy. The increase in folded state may account for the increase in drug-stimulated ATPase activity seen in presence of lipids.

Conclusion

The significantly higher yields of protein in the native folded state, higher purity and improved function establish the value of our gene optimization approach, and provide a basis to improve production of other membrane proteins.     

Health Risk or Resource? Gradual and Independent Association between Self-Rated Health and Mortality Persists Over 30 Years

Background

Poor self-rated health (SRH) is associated with increased mortality. However, most studies only adjust for few health risk factors and/or do not analyse whether this association is consistent also for intermediate categories of SRH and for follow-up periods exceeding 5–10 years. This study examined whether the SRH-mortality association remained significant 30 years after assessment when adjusting for a wide range of known clinical, behavioural and socio-demographic risk factors.

Methods

We followed-up 8,251 men and women aged ≥16 years who participated 1977–79 in a community based health study and were anonymously linked with the Swiss National Cohort (SNC) until the end of 2008. Covariates were measured at baseline and included education, marital status, smoking, medical history, medication, blood glucose and pressure.

Results

92.8% of the original study participants could be linked to a census, mortality or emigration record of the SNC. Loss to follow-up 1980–2000 was 5.8%. Even after 30 years of follow-up and after adjustment for all covariates, the association between SRH and all-cause mortality remained strong and estimates almost linearly increased from “excellent” (reference: hazard ratio, HR 1) to “good” (men: HR 1.07 95% confidence interval 0.92–1.24, women: 1.22, 1.01–1.46) to “fair” (1.41, 1.18–1.68; 1.39, 1.14–1.70) to “poor”(1.61, 1.15–2.25; 1.49, 1.07–2.06) to “very poor” (2.85, 1.25–6.51; 1.30, 0.18–9.35). Persons answering the SRH question with “don''t know” (1.87, 1.21–2.88; 1.26, 0.87–1.83) had also an increased mortality risk; this was pronounced in men and in the first years of follow-up.

Conclusions

SRH is a strong and “dose-dependent” predictor of mortality. The association was largely independent from covariates and remained significant after decades. This suggests that SRH provides relevant and sustained health information beyond classical risk factors or medical history and reflects salutogenetic rather than pathogenetic pathways.     

Efficient silencing of gene expression by an ASON-bulge-DNAzyme complex

Background

DNAzymes are DNA molecules that can directly cleave cognate mRNA, and have been developed to silence gene expression for research and clinical purposes. The advantage of DNAzymes over ribozymes is that they are inexpensive to produce and exhibit good stability. The “10-23 DNA enzyme” is composed of a catalytic domain of 15 deoxynucleotides, flanked by two substrate-recognition domains of approximately eight nucleotides in each direction, which provides the complementary sequence required for specific binding to RNA substrates. However, these eight nucleotides might not afford sufficient binding energy to hold the RNA substrate along with the DNAzyme, which would interfere with the efficiency of the DNAzyme or cause side effects, such as the cleavage of non-cognate mRNAs.

Methodology

In this study, we inserted a nonpairing bulge at the 5′ end of the “10–23 DNA enzyme” to enhance its efficiency and specificity. Different sizes of bulges were inserted at different positions in the 5′ end of the DNAzyme. The non-matching bulge will avoid strong binding between the DNAzyme and target mRNA, which may interfere with the efficiency of the DNAzyme.

Conclusions

Our novel DNAzyme constructs could efficiently silence the expression of target genes, proving a powerful tool for gene silencing. The results showed that the six oligo bulge was the most effective when the six oligo bulge was 12–15 bp away from the core catalytic domain.     

Mirroring intentional forgetting in a shared-goal learning situation

Background

Intentional forgetting refers to the surprising phenomenon that we can forget previously successfully encoded memories if we are instructed to do so. Here, we show that participants cannot only intentionally forget episodic memories but they can also mirror the “forgetting performance” of an observed model.

Methodology/Principal Findings

In four experiments a participant observed a model who took part in a memory experiment. In Experiment 1 and 2 observers saw a movie about the experiment, whereas in Experiment 3 and 4 the observers and the models took part together in a real laboratory experiment. The observed memory experiment was a directed forgetting experiment where the models learned two lists of items and were instructed either to forget or to remember the first list. In Experiment 1 and 3 observers were instructed to simply observe the experiment (“simple observation” instruction). In Experiment 2 and 4, observers received instructions aimed to induce the same learning goal for the observers and the models (“observation with goal-sharing” instruction). A directed forgetting effect (the reliably lower recall of to-be-forgotten items) emerged only when models received the “observation with goal-sharing” instruction (P<.001 in Experiment 2, and P<.05 in Experiment 4), and it was absent when observers received the “simple observation” instruction (P>.1 in Experiment 1 and 3).

Conclusion

If people observe another person with the same intention to learn, and see that this person is instructed to forget previously studied information, then they will produce the same intentional forgetting effect as the person they observed. This seems to be a an important aspect of human learning: if we can understand the goal of an observed person and this is in line with our behavioural goals then our learning performance will mirror the learning performance of the model.     

Molecular typing of Treponema pallidum: a systematic review and meta-analysis

Background

Syphilis is resurgent in many regions of the world. Molecular typing is a robust tool for investigating strain diversity and epidemiology. This study aimed to review original research on molecular typing of Treponema pallidum (T. pallidum) with three objectives: (1) to determine specimen types most suitable for molecular typing; (2) to determine T. pallidum subtype distribution across geographic areas; and (3) to summarize available information on subtypes associated with neurosyphilis and macrolide resistance.

Methodology/Principal Findings

Two researchers independently searched five databases from 1998 through 2010, assessed for eligibility and study quality, and extracted data. Search terms included “Treponema pallidum,” or “syphilis,” combined with the subject headings “molecular,” “subtyping,” “typing,” “genotype,” and “epidemiology.” Sixteen eligible studies were included. Publication bias was not statistically significant by the Begg rank correlation test. Medians, inter-quartile ranges, and 95% confidence intervals were determined for DNA extraction and full typing efficiency. A random-effects model was used to perform subgroup analyses to reduce obvious between-study heterogeneity. Primary and secondary lesions and ear lobe blood specimens had an average higher yield of T. pallidum DNA (83.0% vs. 28.2%, χ² = 247.6, p<0.001) and an average higher efficiency of full molecular typing (80.9% vs. 43.1%, χ² = 102.3, p<0.001) compared to plasma, whole blood, and cerebrospinal fluid. A pooled analysis of subtype distribution based on country location showed that 14d was the most common subtype, and subtype distribution varied across geographic areas. Subtype data associated with macrolide resistance and neurosyphilis were limited.

Conclusions/Significance

Primary lesion was a better specimen for obtaining T. pallidum DNA than blood. There was wide geographic variation in T. pallidum subtypes. More research is needed on the relationship between clinical presentation and subtype, and further validation of ear lobe blood for obtaining T. pallidum DNA would be useful for future molecular studies of syphilis.     

Viral and Atypical Bacterial Etiology of Acute Respiratory Infections in Children under 5 Years Old Living in a Rural Tropical Area of Madagascar

Background

In Madagascar, very little is known about the etiology and prevalence of acute respiratory infections (ARIs) in a rural tropical area. Recent data are needed to determine the viral and atypical bacterial etiologies in children with defined clinical manifestations of ARIs.

Methods

During one year, we conducted a prospective study on ARIs in children between 2 to 59 months in the community hospital of Ampasimanjeva, located in the south-east of Madagascar. Respiratory samples were analyzed by multiplex real-time RT-PCR, including 18 viruses and 2 atypical bacteria. The various episodes of ARI were grouped into four clinical manifestations with well-documented diagnosis: “Community Acquired Pneumonia”(CAP, group I), “Other acute lower respiratory infections (Other ALRIs, group II)”, “Upper respiratory tract infections with cough (URTIs with cough, group III)”and “Upper respiratory tract infections without cough (URTIs without cough, group IV)”.

Results

295 children were included in the study between February 2010 and February 2011. Viruses and/or atypical bacteria respiratory pathogens were detected in 74.6% of samples, the rate of co-infection was 27.3%. Human rhinovirus (HRV; 20.5%), metapneumovirus (HMPV A/B, 13.8%), coronaviruses (HCoV, 12.5%), parainfluenza virus (HPIV, 11.8%) and respiratory syncytial virus A and B (RSV A/B, 11.8%) were the most detected. HRV was predominantly single detected (23.8%) in all the clinical groups while HMPV A/B (23.9%) was mainly related to CAP (group I), HPIV (17.3%) to the “Other ALRIs” (group II), RSV A/B (19.5%) predominated in the group “URTIs with cough” (group III) and Adenovirus (HAdV, 17.8%) was mainly detected in the “without cough” (group IV).

Interpretation

This study describes for the first time the etiology of respiratory infections in febrile children under 5 years in a malaria rural area of Madagascar and highlights the role of respiratory viruses in a well clinically defined population of ARIs.     

Non-Listening and Self Centered Leadership – Relationships to Socioeconomic Conditions and Employee Mental Health

Background

The way in which leadership is experienced in different socioeconomic strata is of interest per se, as well as how it relates to employee mental health.

Methods

Three waves of SLOSH (Swedish Longitudinal Occupational Survey of Health, a questionnaire survey on a sample of the Swedish working population) were used, 2006, 2008 and 2010 (n = 5141). The leadership variables were: “Non-listening leadership” (one question: “Does your manager listen to you?” - four response categories), “Self centered leadership” (sum of three five-graded questions – “non-participating”, “asocial” and “loner”). The socioeconomic factors were education and income. Emotional exhaustion and depressive symptoms were used as indicators of mental health.

Results

Non-listening leadership was associated with low income and low education whereas self-centered leadership showed a weaker relationship with education and no association at all with income. Both leadership variables were significantly associated with emotional exhaustion and depressive symptoms. “Self centered” as well as “non-listening” leadership in 2006 significantly predicted employee depressive symptoms in 2008 after adjustment for demographic variables. These predictions became non-significant when adjustment was made for job conditions (demands and decision latitude) in the “non-listening” leadership analyses, whereas predictions of depressive symptoms remained significant after these adjustments in the “self-centered leadership” analyses.

Conclusions

Our results show that the leadership variables are associated with socioeconomic status and employee mental health. “Non-listening” scores were more sensitive to societal change and more strongly related to socioeconomic factors and job conditions than “self-centered” scores.     

Noradrenergic α₁ receptor antagonist treatment attenuates positive subjective effects of cocaine in humans: a randomized trial

Background

Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α₁ receptor antagonist doxazosin on the positive subjective effects of cocaine.

Methods

Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind.

Results

Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of “high”, “stimulated”, “like cocaine”, “desire cocaine”, “any drug effect”, and “likely to use cocaine if had access” (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of “stimulated”, “like cocaine”, and “likely to use cocaine if had access” (p<.05). There were trends for doxazosin to reduce ratings of “stimulated”, “desire cocaine”, and “likely to use cocaine if had access” (p<.10).

Conclusions

Medications that block noradrenergic α₁ receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.

Trial Registration

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