Comparative pharmacology of dothiepin,its metabolites,and other antidepressant drugs

The pharmacology of dothiepin and its human metabolites, northiaden, dothiepin sulfoxide, and northiaden sulfoxide, has been studied to determine whether the latter contribute to the therapeutic or side effects profile of the parent tricyclic antidepressant. In vitro, dothiepin was a potent noradrenaline and 5-hydroxytryptamine (5-HT) uptake inhibitor, while its secondary amine metabolite, northiaden, was selective for noradrenaline. However, the sulfoxide metabolites were almost inactive as uptake inhibitors. Dothiepin and northiaden prevented the ptosis produced by tetrabenazine in mice and reserpine in rats and increased the mobility of mice in the Porsolt test. After repeated administration, both drugs decreased β-adrenoceptor number and stimulation of the receptor-linked adenylate cyclase by noradrenaline. Dothiepin had a higher affinity than northiaden for histamine H₁, muscarinic and various adrenergic and 5-HT receptors in vitro, whereas the sulfoxide metabolites were inactive. Overall, the data indicate northiaden almost certainly contributes to the therapeutic actions of dothiepin, but the sulfoxide metabolites do not. However, the latter are also unlikely to produce any side effects. A comparison of dothiepin with other tricyclics revealed important divergences in the profiles of uptake inhibition and receptor affinity. Thus, dothiepin is generally similar to imipramine in its pharmacology, but it differs considerably from amitriptyline and doxepin. © 1992 Wiley-Liss, Inc.     

Novel CHST6 nonsense and missense mutations responsible for macular corneal dystrophy

PURPOSE: To identify the underlying mutations in two unrelated British families with macular corneal dystrophy (MCD) by screening the carbohydrate sulfotransferase (CHST6) gene. DESIGN: Case reports and results of DNA analysis. METHODS: Two subjects from two British families with MCD were studied. The genetic status of CHST6 was determined for all members of these MCD families. In addition, sulfated keratan sulfate (KS) assay from the probands was also undertaken. CHST6 gene was amplified by polymerase chain reaction (PCR). The PCR products were analyzed by sequencing and restriction digestion. Enzyme-linked immunosorbent assay (ELISA) was performed to assess KS presence in serum. RESULTS: Four compound heterozygous mutations were identified, three of which are novel. The ELISA showed that the probands were of MCD type I. CONCLUSIONS: These novel mutations are expected to result in loss of CHST6 function, which would account for the MCD phenotype.     

Gleason score concordance on biopsy‐confirmed prostate cancer: is pathological re‐evaluation necessary prior to radical prostatectomy?

Study Type – Diagnosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Following the updated Gleason grading system in 2005 by the International Society of Urological Pathologists (ISUP), studies demonstrated improved prediction of biochemical (PSA) progression‐free outcome by needle core biopsy specimens. To our knowledge, no studies have investigated the impact of the modified grading system on inter‐laboratory agreement of biopsy Gleason score (bGS) and the effect of re‐evaluation on accuracy in predicting the true underlying histopathology. We report that when biopsy re‐evaluation resulted in a change in bGS, there was a marked improvement in the prediction of underlying pathology as determined by prostatectomy Gleason score suggesting that when outside referral of bGS results in an equivocal clinical decision, biopsy re‐evaluation can provide clarity on the true underlying tumour architecture.

OBJECTIVES

? Gleason sum from prostate biopsy (bGS) is an important tool in classifying severity of disease, ultimately influencing clinical management. ? Commonly, pathology specimens are re‐evaluated internally prior to surgery. ? We evaluate agreement of bGS with prostatectomy Gleason sum (pGS) and the impact of re‐grading on prediction of true underlying tumor architecture.

MATERIALS AND METHODS

? Retrospective analysis of men who underwent robotic‐assisted radical prostatectomy (RARP) by two surgeons from 2005–2009. Initial transrectal ultrasound (TRUS) biopsy demonstrated carcinoma at an outside lab. Specimens were re‐evaluated by our GU pathologists prior to surgery. Biopsy data were correlated with pGS. ? Kappa (κ) statistics for agreement and linear regression analyses were used for categorical variables. Coefficient of concordance was used for continuous variables.

RESULTS

? 100 patients had 331 positive biopsies. Agreement (κ) for bGS between outside labs and our pathologists was 0.55 (p < 0.001). ? Internal read was twice as likely to upgrade vs. downgrade outside bGS (23% vs. 11%). ? When re‐evaluation resulted in a change in bGS, agreement with pGS was κ= 0.29, vs. κ=?0.04 for agreement of initial (outside) bGS with pGS. ? When no change was made to bGS, agreement with pGS was κ= 0.40 (p < 0.001).

CONCLUSION

? Good reproducibility seen between outside labs and our institution on bGS. Internal pathology re‐reads correlated better with pGS than original community bGS. When re‐reads result in a change in bGS, there is a marked improvement in prediction of underlying tumor architecture confirming the value of re‐evaluating all external biopsies prior to definitive surgery.     

Distinct melanocortin 2 receptor accessory protein domains are required for melanocortin 2 receptor interaction and promotion of receptor trafficking

Melanocortin 2 receptor (MC2R) is the receptor for the pituitary hormone ACTH. When activated, MC2R stimulates cAMP production and adrenal steroidogenesis. The functional expression of the receptor requires melanocortin 2 receptor accessory protein (MRAP), a single-transmembrane domain protein involved in the trafficking of MC2R from the endoplasmic reticulum to the cell surface. Mutations in both MC2R and MRAP cause the inherited disease familial glucocorticoid deficiency. At present, little is known regarding the mechanism of MRAP in MC2R functional expression. Here we report the characterization of MRAP in the trafficking of MC2R to the cell surface and the formation of a functional receptor. We identify the transmembrane domain of MRAP as the MC2R interaction domain and a conserved N-terminal tyrosine-rich domain of MRAP that is required for trafficking MC2R to the cell surface.     

Heart rate reduces when stroke patients are touched . . . And??

McFadden KL, Hernández TD. Cardiovascular benefits of acupressure (Jin Shin) following stroke. Complement Ther Med 2010; 18: 42–8.