Analysis and clinical findings of cases positive for the novel synthetic cannabinoid receptor agonist MDMB-CHMICA

Context: MDMB-CHMICA is a synthetic cannabinoid receptor agonist which has caused concern due to its presence in cases of adverse reaction and death. Method: 43 cases of suspected synthetic cannabinoid ingestion were identified from patients presenting at an Emergency Department and from post-mortem casework. These were subjected to liquid-liquid extraction using tertiary-butyl methyl ether and quantitatively analysed by Electospray Ionisation Liquid Chromatography – tandem Mass Spectrometry. For positive samples, case and clinical details were sought and interrogated. Results: 11 samples were found positive for MDMB-CHMICA. Concentrations found ranged from <1 – 22 ng/mL (mean: 6 ng/mL, median: 3 ng/mL). The age range was 15 – 44 years (mean: 26 years, median: 21 years), with the majority (82%) of positive results found in males. Clinical presentations included hypothermia, hypoglycaemia, syncope, recurrent vomiting, altered mental state and serotonin toxicity, with corresponding concentrations of MDMB-CHMICA as low as <1 ng/mL. Duration of hospitalisation ranged from 3 – 24 hours (mean: 12 hours, median: 8 hours). Discussion: The concentration range presented in this case series is indicative of MDMB-CHMICA having a high potency, as is known to be the case for other synthetic cannabinoid receptor agonists. The age range and gender representation were consistent with that reported for users of other drugs of this type. The clinical presentations observed were typical of synthetic cannabinoid receptor agonists and show the difficulties in identifying reactions potentially associated with drugs of this type. Conclusion: The range of MDMB-CHMICA concentrations in Emergency Department presentations (n=9) and post-mortem cases (n=2) was reported. No correlation between the concentration of this drug and clinical presentation or cause of death was reported in this sample. However, the potential for harm associated with low concentrations of MDMB-CHMICA and the symptoms of toxicity being non-specific was highlighted

Synthetic Cannabinoid Receptor Agonists in Scottish sub-populations

The term Synthetic Cannabinoid Receptor Agonists (SCRAs) describes a group of hundreds of compounds which are not derived from the Cannabis plant but bind at the cannabinoid receptors. These compounds have been available for recreational use since the late 2000s and have been linked to a variety of adverse effects and death. Due to the number of compounds available, and their novel nature, controlling the manufacture, sale and possession of SCRAs has proved challenging under current legislative structure. The introduction of the Psychoactive Substances Act 2016 brought under control the manufacture, distribution and possession in a custodial facility of any SCRA which had not already been controlled by the Misuse of Drugs Act 1971. Whilst clarification has been brought to the legal status of these drugs, what remains largely unknown is the scale of use within Scotland, and different sub-populations. Simple and quick protocols were developed for the extraction of 40 SCRAs (comprising parent compounds and metabolites) from blood and urine. Sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) methods were developed to detect and quantify the most commonly encountered compounds at realistic blood and urine concentrations. Depending on the timing of cohort sample receipt, one of these methods was then applied to cohorts of individuals from various sub-populations within Scotland. Optimised methods for detection and quantitation in blood and urine then underwent validation. Overall, in 1177 cases tested, SCRA prevalence was found to be low, relative to the prevalence of more ‘traditional’ drugs of abuse such as opiates/opioids or benzodiazepines. The detection of SCRAs was highest in the cohort of individuals presenting at an Emergency Department (ED) with suspected drug toxicity, with 56% of cases tested positive. Second highest was the cohort of deceased individuals undergoing post-mortem (PM) examination, with SCRAs found in 11% of cases tested. It should be noted, though, that samples from both these cohorts were only tested if SCRA use had been suspected. Samples collected from individuals undergoing admission to or liberation from Scottish Prison Service (SPS) facilities were found to contain SCRAs at a rate of 3% for all samples. All of the positive samples in this cohort were admission samples (except one which was not labeled admission or liberation), thus 5% of admission samples were positive for SCRAs. Out of 73 samples collected from individuals under the jurisdiction of the Glasgow Drug Court (GDC), only 1 sample was positive (1.4%). All 95 samples collected from individuals being treated by the NHS Greater Glasgow and Clyde Forensic Directorate (FD) were negative for all SCRAs included in the panel. These results indicate that SCRAs are having negative effects on the health of users and that they are being used by the offending community, both of which have been reported in mainstream media. Another suspected aspect of SCRA use was the intention of avoiding detection by mandatory drug tests. Both the GDC and FD cohorts were aware of their required compliance with drug abstinence and mandatory drug testing regime, but the low findings of SCRAs in these groups suggest this is not the case. It is acknowledged that the numbers of individuals tested in the cohorts were relatively low, and that the studies were not a true calculation of prevalence. In addition to this, not all SCRAs were included in the analytical method, and those not included would not be identified in samples. Nonetheless, important information was gained about the scale and nature of SCRA use within Scotland

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PURPOSE: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information. MATERIALS AND METHODS: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997–2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade. RESULTS: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system. CONCLUSIONS: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival

Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients

<br>Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.</br> <br>Methods: Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.</br><br>Results:Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of ≤20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation.</br> <br>Conclusion: In prostate cancer patients with PSA at diagnosis of ≤20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.</br&gt

Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer

BACKGROUND: Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC. METHODS: Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway. RESULTS: Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours. CONCLUSION: We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer. British Journal of Cancer (2011) 104, 1920-1928. doi:10.1038/bjc.2011.163 www.bjcancer.com Published online 10 May 2011 (C) 2011 Cancer Research U

Procurement of construction projects in local government

This paper provides an evaluation of changes in procurement of capital projects in local government in recent years. These changes have been driven partly by changes in legislation regarding compulsory competitive tendering, best value and more lately prudential finance legislation. They have also been driven by developments in industry procurement practices, particularly following publication of the Latham and Egan reports. Results of research seeking to assess current practice regarding procurement of capital projects in local authorities following publication of the National Procurement Strategy in October 2003 are presented. The organisation of the procurement function, use of standard forms of contract, e-procurement, capability and arrangements for procurement-related training are discussed including use of external consultants. The overall conclusion is that local authorities are at various stages of development regarding implementation of the National Procurement Strategy. Although most of them have in place training arrangements to develop skills of technical and procurement staff, many local authorities will continue to use external consultants. Moreover, 75% of local authorities see use of external consultants to provide professional advice in various elements of project procurement as a long-term measure

Primary amyloidosis of the breast associated with invasive breast cancer

Amyloidosis is usually a systemic disorder. A localised form can involve the breast and may mimic breast cancer. We report a case of primary amyloid deposit confirmed by immunohistochemistry, occurring in a patient with early breast cancer and review other cases of breast involvement with various types of amyloid