Cannabidivarin is anticonvulsant in mouse and rat

Background and Purpose

Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.

Experimental Approach

The effect of CBDV (1–100 μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg²⁺-free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50–200 mg·kg⁻¹) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays.

Key Results

CBDV significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP and Mg²⁺-free conditions. CBDV had significant anticonvulsant effects on the mES (≥100 mg·kg⁻¹), audiogenic (≥50 mg·kg⁻¹) and PTZ-induced seizures (≥100 mg·kg⁻¹). CBDV (200 mg·kg⁻¹) alone had no effect against pilocarpine-induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at this dose. CBDV had no effect on motor function.

Conclusions and Implications

These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti-epileptic in chronic epilepsy models.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8     

Targeting of ��v-Integrins in Stem/Progenitor Cells and Supportive Microenvironment Impairs Bone Metastasis in Human Prostate Cancer

Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide α_v-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that α_v-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking α_v-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms.     

Patient centredness and the outcome of primary care consultations with patients with depression in areas of high and low socioeconomic deprivation

Background

Most patients with depression are managed in general practice. In deprived areas, depression is more common and poorer outcomes have been reported.

Aim

To compare general practice consultations and early outcomes for patients with depression living in areas of high or low socioeconomic deprivation.

Design and setting

Secondary data analysis of a prospective observational study involving 25 GPs and 356 consultations in deprived areas, and 20 GPs and 303 consultations in more affluent areas, with follow-up at 1 month.

Method

Validated measures were used to (a) objectively assess the patient centredness of consultations, and (b) record patient perceptions of GP empathy.

Results

PHQ-9 scores >10 (suggestive of caseness for moderate to severe depression) were significantly more common in deprived than in affluent areas (30.1% versus 18.5%, P<0.001). Patients with depression in deprived areas had more multimorbidity (65.4% versus 48.2%, P<0.05). Perceived GP empathy and observer-rated patient-centred communication were significantly lower in consultations in deprived areas. Outcomes at 1 month were significantly worse (persistent caseness 71.4% deprived, 43.2% affluent, P = 0.01). After multilevel multiregression modelling, observer-rated patient centredness in the consultation was predictive of improvement in PHQ-9 score in both affluent and deprived areas.

Conclusion

In deprived areas, patients with depression are more common and early outcomes are poorer compared with affluent areas. Patient-centred consulting appears to improve early outcome but may be difficult to achieve in deprived areas because of the inverse care law and the burden of multimorbidity.     

New methods for using computer-aided detection information for the detection of lung nodules on chest radiographs

Objective:

To investigate two new methods of using computer-aided detection (CAD) system information for the detection of lung nodules on chest radiographs. We evaluated an interactive CAD application and an independent combination of radiologists and CAD scores.

Methods:

300 posteroanterior and lateral digital chest radiographs were selected, including 111 with a solitary pulmonary nodule (average diameter, 16 mm). Both nodule and control cases were verified by CT. Six radiologists and six residents reviewed the chest radiographs without CAD and with CAD (ClearRead +Detect™ 5.2; Riverain Technologies, Miamisburg, OH) in two reading sessions. The CAD system was used in an interactive manner; CAD marks, accompanied by a score of suspicion, remained hidden unless the location was queried by the radiologist. Jackknife alternative free response receiver operating characteristics multireader multicase analysis was used to measure detection performance. Area under the curve (AUC) and partial AUC (pAUC) between a specificity of 80% and 100% served as the measure for detection performance. We also evaluated the results of a weighted combination of CAD scores and reader scores, at the location of reader findings.

Results:

AUC for the observers without CAD was 0.824. No significant improvement was seen with interactive use of CAD (AUC = 0.834; p = 0.15). Independent combination significantly improved detection performance (AUC = 0.834; p = 0.006). pAUCs without and with interactive CAD were similar (0.128), but improved with independent combination (0.137).

Conclusion:

Interactive CAD did not improve reader performance for the detection of lung nodules on chest radiographs. Independent combination of reader and CAD scores improved the detection performance of lung nodules.

Advances in knowledge:

(1) Interactive use of currently available CAD software did not improve the radiologists'' detection performance of lung nodules on chest radiographs. (2) Independently combining the interpretations of the radiologist and the CAD system improved detection of lung nodules on chest radiographs.Chest radiography can be considered the workhorse of the radiology department. It is being used for the detection and diagnosis of multiple diseases, including lung nodules, which may represent early lung cancer. Since a chest radiograph is a two-dimensional image, overprojection of multiple anatomical structures is inevitable. This so-called anatomical noise substantially impedes interpretation of chest radiographs. Multiple studies have shown that a substantial amount of lung cancers are missed, ranging from 19% to 26%,^1,2 and even up to 90%.^3–5 More recent studies have shown that the problem of missing lung nodules is still present with the most modern digital radiographic technology.^6,7 Abnormalities can be missed as a result of inadequate search, perception errors or interpretation errors. It has been stated that interpretation by the radiologist is the most important factor for missing lung cancer on chest radiographs.^8,9To reduce miss rates, computer-aided detection (CAD) systems have been developed. Thus far, all studies dealing with chest radiography apply CAD as a second reader to the radiologist, meaning that the CAD marks are made available only after the radiologist has made a primary review. It remains the reader''s discretion to accept or disregard the CAD marks. Results of these studies were contradictory: some found an increased accuracy for the detection of lung nodules,^10–12 whereas other studies reported an increase in sensitivity only at the expense of loss in specificity.^13–16 One problem ameliorating the potential of CAD is the radiologist''s limited ability to reliably discriminate between true-positive (TP) and false-positive (FP) CAD marks.We therefore decided to explore alternative methods of using CAD information. First, we used CAD interactively. In the interactive mode, CAD marks remained hidden unless the radiologist queried a position in the image by clicking with the mouse on that location. If a CAD mark was present in this location, it was shown to the radiologist together with a score of suspicion. Such an interactive CAD system had been shown to be beneficial in chest radiography in an observer study that only used non-radiologists.¹⁷ Second, we computed a mathematical combination of reader and CAD scores. With this method, observers did not need to view the CAD marks at all during their reading of the images, but a mathematical combination of the reader and the CAD scores was computed afterwards. Both methods have been reported to outperform the use of CAD as a second reader for lesion detection in mammograms.^18–20The purpose of this observer study was to test the impact of these two alternative methods of using CAD information on nodule detection on chest radiographs. To optimize baseline performance without CAD, digitally bone-suppressed images (BSIs) were added to the original chest radiographs. BSIs have been shown to improve accuracy for the detection of focal lesions on chest radiographs;^21–24 a further increase in detection performance beyond that of BSIs by adding CAD has also been documented.²⁵     

Maternal and neonatal morbidity after elective repeat Cesarean delivery versus a trial of labor after previous Cesarean delivery in a community teaching hospital

Objective: To compare maternal and fetal outcomes after elective repeat Cesarean section versus a trial of labor in women after one prior uterine scar.

Study design: All women with a previous single low transverse Cesarean section delivered at term with no contraindications to vaginal delivery were retrospectively identified in our database from January 1995 to October 1998. Outcomes were first analyzed by comparing mother–neonate dyads delivered by elective repeat Cesarean section to those undergoing a trial of labor. Secondarily, outcomes of mother–neonatal dyads who achieved a vaginal delivery or failed a trial of labor were compared to those who had elective repeat Cesarean delivery.

Results: Of 1408 deliveries, 749/927 (81%) had a successful vaginal birth after a prior Cesarean delivery. There were no differences in the rates of transfusion, infection, uterine rupture and operative injury when comparing trial of labor versus elective repeat Cesarean delivery. Neonates delivered by elective repeat Cesarean delivery were of earlier gestation and had higher rates of respiratory complications (p?<?0.05). Mother–neonatal dyads with a failed trial of labor sustained the greatest risk of complications.

Conclusion: Overall, neonatal and maternal outcomes compared favorably among women undergoing a trial of labor versus elective repeat Cesarean delivery. The majority of morbidity was associated with a failed trial of labor. Better selection of women likely to have a successful vaginal birth after a prior Cesarean delivery would be expected to decrease the risks of trial of labor.     

Influence of gestational age and fetal heart rate on the fetal mechanical PR interval

Objective: The fetal mechanical PR interval obtained via pulsed Doppler has previously been demonstrated to correlate with electrocardiographic PR interval measured in the neonate. We sought to further analyze the influence of fetal heart rate and gestational age upon the fetal mechanical PR interval.

Methods: We searched our database for mechanical PR intervals, which were obtained during fetal echocardiography performed in our antenatal diagnostic unit. We included fetuses with a normal cardiac structural survey. The mechanical PR interval is measured from the A wave of the mitral valve to the beginning of ventricular systole corresponding to the opening of the aortic valve. Linear regression curves were generated to examine the correlation of mechanical PR interval with gestational age and fetal heart rate. Analysis of variance was used to compare the mean variation across three gestational age groups: 17–21.9 weeks (n?=?24), 22–25.9 weeks (n?=?52) and 26–38 weeks (n?=?20).

Results: Mechanical PR intervals were measured in 96 fetuses with normal fetal echocardiography. The mechanical PR interval was 123.9?±?10.3?ms (mean?±?SD), with a range of 90–150?ms. Linear regression curves correlating mechanical PR interval with fetal heart rate and gestational age demonstrated a flat slope with R²?=?0.016, p?=?0.22 and R²?=?0.0004, p?=?0.85, respectively. The mechanical PR interval measured over the three gestational ages was as follows (mean?±?SD): 122.3?±?10.5?ms for 17–21.9 weeks; 125.0?±?9.6?ms for 22–25.9 weeks; and 123.1?±?11.9?ms for 26–38 weeks. Analysis of variance revealed no difference among the mechanical PR interval means measured over the three gestational age groups (p?=?0.53).

Conclusions: Fetal mechanical PR interval ranges from 90 to 150?ms in fetuses with sonographically normal fetal cardiac structure and rate. The mechanical PR interval appears to be independent of gestational age and fetal heart rate.