Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8

Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥ 7.5 μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥ 10 μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material.     

Deep neural network for automatic characterization of lesions on 68Ga-PSMA-11 PET/CT

European Journal of Nuclear Medicine and Molecular Imaging - This study proposes an automated prostate cancer (PC) lesion characterization method based on the deep neural network to determine tumor...     

Microembolization and myonecrosis during elective percutaneous coronary interventions in diabetic patients: an intracoronary Doppler ultrasound study with 2-year clinical follow-up

Elevation of cardiac troponin I (cTnI) is a well-known complication after percutaneous coronary interventions (PCI). The aims of this study were to quantify the extent of coronary microembolization during elective PCI, to identify predisposing anatomical and procedural factors, and to evaluate its impact on long-term outcome in diabetic patients with a high cardiovascular risk. 48 patients (pts, median 66.7?years) with type 2 diabetes and coronary artery disease underwent elective PCI with stenting to treat single-vessel lesions. Real-time microembolization during PCI ("HITS") was detected by an intracoronary Doppler guide wire. Peak levels of cTnI were measured within 24?h after PCI. Pts were followed for 2?years to record major cardiac events (MACE: death, myocardial infarction, revascularization of target and non-target vessels). In 47 patients microemboli were detected during PCI. Nineteen patients showed pathologic cTnI elevation (0.13-28.9, median 0.39?μg/l). The amount of HITS correlated with cTnI levels (r?=?0.43, p?=?0.003), but not with other clinical or angiographic data. Within 2?years MACE were detected in 9 patients, who had significantly more microemboli (15.4?±?11.8 vs. 28.2?±?16.0 HITS; p?=?0.009, OR 1.07; 95?% CI 1.011-1.13) during PCI. HITS >23, but not cTnI elevation, predicted later MACE (ROC analysis, p?=?0.025). A high amount of microembolization during elective PCI in diabetic patients appears to be an indicator of greater atherosclerotic burden and accelerated coronary artery disease progression, associated with acute biomarker elevation and adverse long-term outcomes.     

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

PATIENTS AND METHODS

We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium‐lined space.

RESULTS

LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft‐tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer‐specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer‐specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer‐specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node‐positive patients, LVI only marginally improved the prediction of cancer‐specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%).

CONCLUSIONS

LVI is strongly associated with clinical outcome in node‐negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.     

Biomechanical comparison of four double-row speed-bridging rotator cuff repair techniques with or without medial or lateral row enhancement

Background  

Biomechanical comparison of four different Speed-Bridge configurations with or without medial or lateral row reinforcement. Reinforcement of the knotless Speed-Bridge double-row repair technique with additional medial mattress- or lateral single-stitches was hypothesized to improve biomechanical repair stability at time zero.     

Late neonatal hypocalcemia. Apropos of 33 cases treated with 1 alpha-hydroxycholecalciferol

Thirty-three observations of late-onset neonatal hypocalcemia were reviewed retrospectively. Their etiological, clinical and biological features were consistent with a transient congenital hypoparathyroidism, associated with a materno-foetal vitamin D deficiency. 1 alpha-hydroxycholecalciferol was used for rapid correction of calcemia and proved to be satisfactorily metabolized after its oral administration.     

Causes and consequences of elderly's agitated and aggressive behavior

Agitation and aggressiveness are frequent in the elderly and often related to dementia. As a result of the ageing of the general population this is becoming a major public health concern. No or little epidemiological data, during primary health care, about symptoms, co-morbidity, nor medical and social consequences of elderlys' disruptive behavior have been gathered or published in the French literature. Thus, in order to describe these disorders, a survey in cooperation with general practitioners (GP) was conducted. A representative sample of 212 French GP's, all with preferential geriatric activity were asked to conduct a study by including retrospectively their two most recent patients older than 65, who had exhibited agitation and/or aggressiveness. From this cross sectional study, 410 patients (female: 61%, male: 39%) were included. The mean age was 81 years (sd: 7.65). The patients suffered from change in verbal behavior (80%), verbal aggressiveness (71%), physical agitation (60%), wandering (48%), and/or physical aggressiveness (31%). The average of disruptive behavior symptoms per patient was 2.9. The symptoms appeared progressively in 81% of patients, the mean duration was two years and it was the first episode in 40% of patients. Disruptive behaviors may be explained in view of organic illness in 62% of patients (cardiovascular disease: 37%, neurologic: 12%, diabetes: 7%, dehydratation: 5%), dementia (Alzheimer disease: 20%, vascular dementia: 18%, mixed dementia: 14%). In 54% of patients disruptive behavior may be explained in view of depression: 34%, and anxiety disorder: 31%. A triggering factor was observed in 57% of cases (psychosocial stress: 39%). Somatic consequences of the symptoms were frequently identified: decrease of alimentary intake: 39%, weight loss: 27%, dehydratation: 11%, falls: 32%, and irregular medication intake: 31%. Limitation of daily life activities: 85%, and family life: 97% were also noted. Acceptability of patient's symptoms by the family was good (no discomfort or transitory and mild irritability) in 61% of cases, and very bad (reactions of exhaustion, hospitalization requirement) in 13%. This study carried out during primary care, showed that the elderly's disruptive behaviors cause severe medical consequences and familial and social distress.     

Conditioning stimulus can influence an external urethral sphincter contraction evoked by a magnetic stimulation

AIMS: To study the effect of a conditioning stimulus on an external urethral sphincter (EUS)contraction evoked by a magnetic stimulation at different time intervals. METHODS: Seven healthy male volunteers underwent EUS pressure measurement. At baseline, magnetic stimulation of the lumbosacral spinal cord above the motor threshold was performed and evoked EUS pressure responses were recorded. The lumbosacral magnetic stimulation was repeated with same intensity, while a selective electrical dorsal penile nerve stimulation below the bulbocavernosus reflex (BCR) threshold was preceding at five different intervals (10, 20, 30, 50, 100 msec). The protocol was performed with empty and full bladder (BLA), and baseline responses were statistically compared to those with combined stimulation. RESULTS: When the dorsal penile nerve electrical stimulation preceded the lumbosacral magnetic stimulation by 20 msec (P=0.0048), 50 msec (P=0.0039), or 100 msec (P=0.0002), the amplitudes of the EUS pressure response with empty BLA were significantly reduced compared to lumbosacral magnetic stimulation alone. With a filled BLA, the amplitudes of the EUS were significantly reduced only at an interval of 50 msec (P<0.0001). CONCLUSIONS: A conditional sensory pudendal stimulation seems to have the capacity to inhibit the external urethral sphincter contraction induced by a magnetic stimulation. The inhibitory effect seems to depend on the latency between the peripheral and lumbosacral stimulation as well as on the degree of BLA filling. It remains to be proved if the neuromodulative effect of the conditional stimulus occurs at a spinal or supraspinal level.     

Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study

The relationship among insulin resistance, adiponectin, and cardiovascular (CV) morbidity in patients with mild and moderate kidney disease was investigated. Insulin sensitivity (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]) and adiponectin plasma levels were assessed in 227 nondiabetic renal patients at different degrees of renal dysfunction and in 76 healthy subjects of similar age and gender distribution and body mass index. In renal patients, association with prevalent CV events was evaluated, and incident CV events were evaluated in a prospective study. HOMA-IR was markedly higher in patients than in healthy subjects (3.59 +/- 3.55 versus 1.39 +/- 0.51; P < 0.01). In renal patients, HOMA-IR was significantly correlated with body mass index (r = 0.477; P < 0.01), triglycerides (r = 0.384; P < 0.01), adiponectin plasma levels (r = -0.253; P < 0.01), and age (r = 0.164; P < 0.05), but not with renal function (GFR by iod-thalamate clearance). Patients with previous CV events were significantly older, had higher HOMA-IR and serum triglycerides, and had lower adiponectin plasma levels (all P < 0.05). Logistic regression analysis revealed age (P < 0.001) and adiponectin (P < 0.002) as independent variables related to prevalent CV events. In the prospective study, median follow-up was 54 mo. Patients who experienced CV events had significantly higher serum glucose and lower adiponectin plasma levels (both P < 0.05). In patients with chronic kidney diseases, a syndrome of insulin resistance is present even in the earliest stage of renal dysfunction, and several components of this syndrome are associated with CV events. Moreover, hypoadiponectinemia is a novel putative CV risk factor in patients with mild and moderate renal failure.