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According to Bauguil, the monohull market in the United States remains stagnant but stable, and the around 350 sailing monohulls above 30 feet sold annually is much less than in Europe. At the same time, the number of catamarans sold in the United States has been steadily growing, at around 220 boats per year, which represents a much larger portion of the total sailing market in the United States than in Europe. "The US sailing market is built around cruising and lifestyle, favoring the catamarans, especially with older mariners using their boats for part- or full-time living aboard", Bauguil said. [Extracted from the article]

I also found my latest obsession - code zero performance sails, fitted out on traditional cruising sailboats. An even greater thing, and what I found to be true at the Miami show, is how the industry has made a real effort to deliver boats and products that largely appeal to that demographic. My old Hunter 31 might not be anything close to what my kids would think of as a modern-day cruising boat ("No USB ports?. [Extracted from the article]

Dactylitis, a hallmark clinical feature of psoriatic arthritis (PsA) and other spondyloarthropathies, may also be a severity marker for PsA and psoriasis. Traditionally, clinicians have used nonsteroidal antiinflammatory drugs and local corticosteroid injections to treat dactylitis, although conventional disease-modifying antirheumatic drugs are also used. We performed a systematic literature review to determine the most efficacious current treatment options for dactylitis in PsA. Effect sizes were greatest for the biologic agents ustekinumab, certolizumab, and infliximab, suggesting that therapy with one of these agents should be initiated in patients with dactylitis. However, the limited data highlight the need for randomized, placebo-controlled trials, with dactylitis as a primary outcome, to determine a valid, reliable, and responsive clinical outcome measure for PsA patients with dactylitis.

A cross my 40 or so years spent simply messing about in boats (as Scottish writer Kenneth Grahame put it), a few voyages perpetually rank in my top 10, such as the final cruise of the season back in '92. After a brilliant, fair-weather sail, and with the mercury hovering in the 40s, we had the cove all to ourselves - which, as anyone who's ever tried to locate an available mooring ball there on a holiday weekend can attest, is a rare delight. I'd been sailing with my mom and dad for a little over a year, and while I had earned my dad's trust at the helm, I would still get apprehensive whenever the wind gauge perked up, especially when our course involved the dreaded Race. [Extracted from the article]

The ability of a drug to cause clinically significant drug-drug interactions due to direct or metabolism-dependent inhibition of cytochrome P450 (CYP) can generally be predicted from in vitrostudies with human liver microsomes (HLM) or recombinant CYP enzymes, as recommended by the FDA and other regulatory agencies. This review highlights some examples of system-dependent inhibition of CYP and uridine diphosphate glucuronosyltransferase (UGT) enzymes. In the case of CYP enzymes, examples are presented where in vitrostudies with HLM under-predict or over-predict the degree of inhibition observed in the clinic and where the correct prediction comes from studies with human hepatocytes. Studies with HLM under-predict the ability of gemfibrozil and bupropion to cause clinically significant inhibition of CYP2C8 and CYP2D6, respectively, and over-predict the ability of ezetimibe to cause clinically significant inhibition of CYP3A4. Gemfibrozil and bupropion represent examples of glucuronidation-dependent and reduction-dependent activation to metabolites that inhibit CYP2C8 and CYP2D6, respectively, whereas ezetimibe represents an example of glucuronidation-dependent protection against metabolism-dependent inhibition of CYP3A4. This article illustrates why, when drug candidates are extensively metabolized by non-CYP enzymes, it would be prudent to use human hepatocytes in addition to HLM or recombinant enzymes to evaluate their ability to inhibit CYP enzymes.

The article presents questions and answers related to security of Wi-Fi network, operation of electronic viewfinder in Sony Cyber-Shot camera, and networking problems associated with Windows 10 operating systems.

Gemfibrozil more potently inhibits CYP2C9 than CYP2C8 in vitro, and yet the opposite inhibitory potency is observed in the clinic. To investigate this apparent paradox, we evaluated both gemfibrozil and its major metabolite, an acyl-glucuronide (gemfibrozil 1-O-{szligbeta}-glucuronide) as direct-acting and metabolism-dependent inhibitors of the major drug-metabolizing cytochrome P450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) in human liver microsomes. Gemfibrozil most potently inhibited CYP2C9 (IC50 of 30 µM), whereas gemfibrozil glucuronide most potently inhibited CYP2C8 (IC50 of 24 µM). Unexpectedly, gemfibrozil glucuronide, but not gemfibrozil, was found to be a metabolism-dependent inhibitor of CYP2C8 only. The IC50 for inhibition of CYP2C8 by gemfibrozil glucuronide decreased from 24 µM to 1.8 µM after a 30-min incubation with human liver microsomes and NADPH. Inactivation of CYP2C8 by gemfibrozil glucuronide required NADPH, and proceeded with a KI (inhibitor concentration that supports half the maximal rate of enzyme inactivation) of 20 to 52 µM and a kinact (maximal rate of inactivation) of 0.21 min–1. Potent inhibition of CYP2C8 was also achieved by first incubating gemfibrozil with alamethicin-activated human liver microsomes and UDP-glucuronic acid (to form gemfibrozil glucuronide), followed by a second incubation with NADPH. Liquid chromatography-tandem mass spectrometry analysis established that human liver microsomes and recombinant CYP2C8 both convert gemfibrozil glucuronide to a hydroxylated metabolite, with oxidative metabolism occurring on the dimethylphenoxy moiety (the group furthest from the glucuronide moiety). The results described have important implications for the mechanism of the clinical interaction reported between gemfibrozil and CYP2C8 substrates such as cerivastatin, repaglinide, rosiglitazone, and pioglitazone.

A photograph of a fulmar (Fulmarus glacialis) flying among the cliffs of the Shetland Islands near Scotland is presented, which includes information on the seabird's breeding behavior.

One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for the CYP2A64(whole deletion) and CYP2A69. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of the CYP2A6gene (CYP2A69), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction. The mean expression levels of CYP2A6 mRNA in individuals with CYP2A61/4, CYP2A61/9and CYP2A64/9were 58%, 71% and 21% of the individuals genotyped as CYP2A61/1, respectively. The mean in-vitro coumarin 7-hydroxylase activities in subjects carrying CYP2A61/4, CYP2A61/9and CYP2A64/9were 41%, 71% and 12%, respectively, compared to those of the subjects judged as wild-type. Vmaxvalues for coumarin 7-hydroxylation in the liver microsomes from human subjects with genotypes of CYP2A61/1, CYP2A61/4, CYP2A61/9and CYP2A64/9were 0.58, 0.26, 0.44 and 0.13 nmol/min/nmol total P450, respectively. CYP2A6 protein levels in human liver microsomes with the CYP2A64and the CYP2A69alleles were markedly decreased. These results suggest that the genetic polymorphism in the promoter region of the CYP2A6gene (CYP2A69) reduced the expression levels of CYP2A6 mRNA and protein in human livers, resulting in the decrease of coumarin 7-hydroxylase activities. Individuals judged as CYP2A64/9were expected to be poor metabolizers, having extremely low activity of CYP2A6.

The aim of this study was to test suitable culture conditions for maintaining normal cellular cytoarchitecture and inducibility of P450 enzymes in primary cultures of human hepatocytes by prototypical inducers. The selectivity and sensitivity of a sandwich culture system were determined by treating cultures with a number of clinically relevant drugs that are known to be inducers of either rodent and/or human P450 enzymes. The results showed that considerable induction of CYP3A4 activity is observed at DMSO concentrations greater than 0.1% (v/v). No differences in P450 induction response were observed between cultures maintained under different matrix conditions. However, the matrix condition considered to be optimal for maintaining cellular integrity, protein yields, and P450 enzyme induction was a sandwich configuration in combination with modified Chee’s medium containing insulin (6.25 μg/mL) and dexamethasone (≤0.1 μM). Under these conditions, induction of CYP3A4 occurred at clinically relevant drug concentrations, and maximal activities were achieved after 3 days of exposure. Overall, the response of human hepatocyte cultures to treatment with both positive and negative modulators was found to reflect that observed in vivo with respect to both enzyme specificity and potency of enzyme induction, although considerable sample-to-sample variability was observed in the magnitude of induction. © 2000 John Wiley & Sons, Inc. J Biochem Toxicol 14:177–188, 2000

A well-characterized primary rat hepatocyte culture system was used to examine induction patterns of cytochrome 450 gene expression by a series of 4-n-alkyl-methylenedioxybenzene (MDBs) derivatives. Hepatocytes were treated for 24, 48, or 72 hours with 0–500 μM of the MDB compounds, and total cellular RNA and protein from each treatment was evaluated by hybridization and immunochemical techniques. Exposure to MDB congeners possessing increasing 4-n-alkyl side-chain length (C0–C8) resulted in dose- and structure-dependent activation of CYP2B1, 2B2, 3A1, 1A1, and 1A2 gene expression. At equivalent 100 μM concentrations, the C6 and C8 MDB congeners were more effective than the prototypical inducer phenobarbital (PB) with respect to induction potency of CYP2B1, CYP2B2, and CYP3A1 gene expression. In contrast to PB, longer side-chain–substituted MDBs effectively induced CYP1A1 and CYP1A2 gene expression, in addition to the CYP2B and CYP3A genes. At equivalent molar concentrations, the catechol derivative of C6-MDB was ineffective in its ability to induce CYP gene expression, indicating the importance of the intact methylenedioxy bridge in the induction mechanism. Levels of MDB-inducible CYP2B1 and CYP2B2 mRNA were highly correlated with CYP2B1/2 apoprotein levels, ascertained by immunoblot analysis of cultured hepatocyte S9 fractions. Compared with results from previous in vivo analysis (12), the current data indicate that pharmacodynamic factors may influence MDB induction profiles and that differences in MDB effects on CYP gene expression result depending on distinct structure-activity relationships. © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 12: 253–262, 1998

Two letters to the editor are presented in response to an article related to the android operating system KitKat and the article "Take One Tablet in the Morning" published in the previous issues.