Behavioral Cross-Tolerance between Repeated Intracerebellar Nicotine and Acute ⌬ 9 -Tetrahydrocannabinol-Induced Cerebellar Ataxia: Role of Cerebellar Nitric Oxide

ABSTRACT We have previously demonstrated that acute intracerebellar nicotine or N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), a selective ␣ 4 ␤ 2 nicotinic acetylcholine receptor (nAChR) agonist, dose dependently attenuates ⌬ 9 -tetrahydrocannabinol (⌬ 9 THC)-induced ataxia. Presently, we have shown that intracerebellar nicotine (1.25, 2.5, and 5 ng; once daily for 5 days) and RJR-2403 (250, 500, and 750 ng; once daily for 5 days) significantly attenuate cerebellar ⌬ 9 -THC-induced ataxia dose dependently, suggesting the development of cross-tolerance between nicotine or RJR-2403 with ⌬ 9 -THC in male CD-1 mice. Intracerebellar RJR-2403 (750 ng) microinfused for 1, 2, 3, 5, and 7 days (once daily) significantly attenuated ⌬ 9 -THC-induced ataxia in the 3-, 5-, and 7-day treatment groups; optimal cross-tolerance was evident at day 5 and persisted till 36 h after the last RJR-2403 microinfusion. Intracerebellar microinfusion of hexamethonium (nAChR antagonist; 1 g) or dihydro-␤-erythroidine hydrobromide (␣ 4 ␤ 2 nAChR antagonist; 500 ng) for 5 days 10 min before daily intracerebellar nicotine or RJR-2403 microinfusion virtually abolished cross-tolerance between nicotine or RJR-2403 and ⌬ 9 -THC, indicating nAChR participation. In addition, microinfusion of antagonists 10 min after daily intracerebellar nicotine or RJR-2403 failed to alter the crosstolerance, suggesting possible involvement of downstream cerebellar second-messenger mechanisms. Finally, the cerebellar concentration of nitric oxide products [total sum of nitrite ϩ nitrate (NO x )] was increased after 5 days of intracerebellar nicotine or RJR-2403 treatment, which was decreased by acute intracerebellar ⌬ 9 -THC treatment. The "nicotine or RJR-2403 ϩ ⌬ 9 -THC" treatments significantly increased cerebellar NO x levels compared with treatment with ⌬ 9 -THC alone, supporting a functional correlation between cerebellar nitric oxide production and cerebellar ⌬ 9 -THC-induced ataxia and suggesting participation of nitric oxide in the observed cross-tolerance between nicotine/RJR-2403 and ⌬ 9 -THC. Several investigators have demonstrated a strong association between the abuse of nicotine and ⌬ 9 -THC together ABBREVIATIONS: ⌬ 9 THC, ⌬ 9 -tetrahydrocannabinol; nAChR, nicotinic acetylcholine receptor; AP, anteroposterior; ML, mediolateral; DV, dorsoventral; DH␤E, dihydro-␤-erythroidine hydrobromide; RJR-2403, N-methyl-4-(3-pyridinyl)-3-buten-1-amine; DMSO, dimethyl sulfoxide; aCSF, artificial cerebrospinal fluid; DAN, 2,3-diaminonaphthalene; G-6-P, glucose 6-phosphate; G-6-PDH, glucose-6-phosphate dehydrogenase; NO x , total sum of nitrite ϩ nitrate; NO, nitric oxide; ANOVA, analysis of variance; AUC, area under the curve; ICB, intracerebellar

Estrogen Modulation of Uterine Adrenergic-Cholinergic Interaction: Effects on Vasoactivity and Adrenergic Receptors in the Guinea Pig1

ABSTRACT ABBREVIATIONS: UBF, uterine blood flow; NE, norepinephrine; DHA, dihydroalprenolol; DHE, dihydroergocryptine; OVX, ovanectomized; ACh, acetylchohine; 5-HT, 5-hydroxytryptamine

Adding Psychotherapy to the Naltrexone Treatment of Alcohol Use Disorder: Metaanalytic Review

Background It remains unclear if naltrexone combined with psychotherapy is superior to naltrexone alone in treating alcohol use disorders (AUD). The current meta-analysis examined the hypothesis that psychotherapy is a significant moderator that influences AUD-related outcomes and that naltrexone combined with psychotherapy is associated with significantly better AUD-related outcomes than naltrexone alone. Methods A total of 30 studies (Nnaltrexone = 2317; Nplacebo = 2056) were included. Random effects model meta-analyses were carried out for each of the studied outcomes. Subsequently, the random effects model pooled estimates from studies with and without psychotherapy were compared using a Wald test. A mixed-effect model, incorporating psychotherapy as a moderator, was used to examine the impact of psychotherapy on treatment outcomes. Results Naltrexone had a significant treatment effect on abstinence relapse and Gamma-Glutamyl Transferase levels, but not cravings. The pooled estimates for studies with and without psychotherapy were not significantly different for any of the studied outcomes. Psychotherapy was not a significant moderator in the mixed effects models for any of the studied outcomes. Conclusions Naltrexone treatment is efficacious in reducing alcohol consumption, but not reducing cravings. Adding psychotherapy on top naltrexone did not result in any significant additional benefit for AUD patients

An empirical comparison of commercial and open‐source web vulnerability scanners

Web vulnerability scanners (WVSs) are tools that can detect security vulnerabilities in web services. Although both commercial and open-source WVSs exist, their vulnerability detection capability and performance vary. In this article, we report on a comparative study to determine the vulnerability detection capabilities of eight WVSs (both open and commercial) using two vulnerable web applications: WebGoat and Damn vulnerable web application. The eight WVSs studied were: Acunetix; HP WebInspect; IBM AppScan; OWASP ZAP; Skipfish; Arachni; Vega; and Iron WASP. The performance was evaluated using multiple evaluation metrics: precision; recall; Youden index; OWASP web benchmark evaluation; and the web application security scanner evaluation criteria. The experimental results show that, while the commercial scanners are effective in detecting security vulnerabilities, some open-source scanners (such as ZAP and Skipfish) can also be effective. In summary, this study recommends improving the vulnerability detection capabilities of both the open-source and commercial scanners to enhance code coverage and the detection rate, and to reduce the number of false-positives

Global Gene Expression Profiling Of Human Pleural Mesotheliomas: Identification of Matrix Metalloproteinase 14 (MMP-14) as Potential Tumour Target

BACKGROUND:The goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets. METHODOLOGY:We performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002). CONCLUSIONS:Based on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe