New diagnostic and evaluative tests for rheumatoid arthritis

To prevent joint destruction, it is important to diagnose RA early and to consider the prognosis. For this purpose, several new laboratory tests, such as IgG-RF, anti-agalactosyl IgG antibodies (CARF), and matrix metalloproteinase-3 (MMP-3), have become available for diagnosing RA. RF has a tolerable sensitivity of 68.5% for RA, but low specificity of 77.1%, and also 76.0% for patients with other rheumatic diseases and chronic inflammatory disease, respectively. CARF showed slightly higher sensitivity but low specificity for other rheumatic diseases and chronic inflammatory patients. In contrast, anti-cyclic citrullinated peptide antibody (anti-CCP), a new diagnostic test for RA, demonstrated significantly high specificity for other rheumatic diseases, and also for chronic inflammatory disease patients. Anti-CCP was superior to other laboratory tests by ROC analysis. Moreover, both CARF and anti-CCP had higher sensitivity of 66.7%, 61.5%, respectively, for the diagnosis of early RA than RF. On the other hand, MMP-3 is thought to be not only an evaluative test for the activity of RA because of its significant correlation with CRP, but also has potential as a prognostic test to identify joint damage from RA. Anti-CCP was also reported to associate with the progression of joint damage and may be also used as a prognostic test. We next examined the efficiency of RA diagnosis made by combining these laboratory tests. The specificity of RF was not as high as anti-CCP but reached 92% when combined with MMP-3. Thus, it is concluded that anti-CCP is superior to other laboratory tests in sensitivity and specificity, and that these combination assays are useful in the early diagnosis of RA.     

In vitro metabolism of alectinib,a novel potent ALK inhibitor,in human: contribution of CYP3A enzymes

1.?The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated.

2.?The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b.

3.?M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major.

4.?In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug–drug interactions.     

Effects of Various Pharmaceutical Excipients on the Intestinal Transport and Absorption of Sulfasalazine,a Typical Substrate of Breast Cancer Resistance Protein Transporter

Breast cancer resistance protein (BCRP) transporter is an efflux transporter that utilizes energy from adenosine triphosphate hydrolysis to push its substrates, regardless of the concentration gradient. Its presence on the apical membrane of the intestinal mucosa is a major obstacle for the intestinal absorption of its substrates. In this study, we examined the effects of various pharmaceutical excipients on the intestinal transport and absorption of sulfasalazine, a BCRP substrate. Four excipients, including 0.05% and 0.075% BL-9EX, 0.01% and 0.05% Brij 97, 0.075% Labrasol, and 0.05% and 0.1% Tween 20 decreased the secretory transport of sulfasalazine in an in vitro diffusion chamber. Further investigation in an in situ closed loop experiment in rats showed that 0.05% and 0.1% BL-9EX and 0.1% Brij 97 effectively enhanced the intestinal absorption of sulfasalazine while maintaining minimal toxicity to the intestinal mucosa. However, 0.1% Brij 97 also increased the intestinal absorption of 5(6)-carboxyfluorescein, a paracellular marker compound. These findings suggest that BL-9EX might effectively inhibit the BCRP-mediated efflux of sulfasalazine in vivo, indicating that BL-9EX could improve the intestinal absorption of sulfasalazine and other BCRP substrates.     

Left ventricular apical pseudoaneurysm with aortic prosthetic valve endocarditis

We report an 83-year-old man with a mycotic left ventricular apical pseudoaneurysm and aortic prosthetic valve endocarditis caused by Enterococcus spp. Mycotic left ventricular pseudoaneurysm is very rare and is associated with a high risk of rupture. Here, we report the clinical presentation, diagnosis, prognosis, and treatment of a case of mycotic left ventricular pseudoaneurysm to raise awareness regarding this unusual and potentially fatal complication.     

Distinct intraspecific variations of garlic (Allium sativum L.) revealed by the exon–intron sequences of the alliinase gene

Garlic (Allium sativum L.) has been used worldwide as a food and for medicinal purposes since early times. Garlic cultivars exhibit considerable morphological diversity despite the fact that they are mostly sterile and are grown only by vegetative propagation of cloves. Considerable recombination occurs in garlic genomes, including the genes involved in secondary metabolites. We examined the genomic DNAs (gDNAs) from garlic, encoding alliinase, a key enzyme involved in organosulfur metabolism in Allium plants. The 1.7-kb gDNA fragments, covering three exons (2, 3, and 4) and all four introns, were amplified from total DNAs prepared from garlic samples produced in Asia and Europe, leading to 73 sequences in total: Japan (JPN), China (CHN), India (IND), Spain (ESP), and France (FRA). The exon sequences were highly conserved among all the sequences, probably reflecting the fully functional alliinase associated with the flavor quality. Distinct intraspecific variations were detected for all four intron sequences, leading to the haplotype classifications. A close relationship between JPN and CHN was observed for all four introns, whereas IND showed a more divergent distribution. ESP and FRA afforded clearly different variants compared with those from Asian sequences. The present study provides information that could be useful in the development of an additional molecular marker for garlic authentication and quality control.     

Impact of preoperative uncontrollable hepatic hydrothorax and massive ascites in adult liver transplantation

Purpose

Uncontrollable hepatic hydrothorax and massive ascites (H&MA) requiring preoperative drainage are sometimes encountered in liver transplantation (LT). We retrospectively analyzed the characteristics of such patients and the impact of H&MA on the postoperative course.

Methods

We evaluated 237 adult patients who underwent LT in our institute between April 2006 and October 2010.

Results

Recipients with uncontrollable H&MA (group HA: n = 36) had more intraoperative bleeding, higher Child–Pugh scores, lower serum albumin concentrations and higher blood urea nitrogen concentrations than those without uncontrollable H&MA (group C: n = 201). They were also more likely to have preoperative hepatorenal syndrome and infections. The incidence of postoperative bacteremia was higher (55.6 vs. 46.7 %, P = 0.008) and the 1- and 3-year survival rates were lower (1 year: 58.9 vs. 82.9 %; 3 years: 58.9 vs. 77.7 %; P = 0.003) in group HA than in group C. The multivariate proportional regression analyses revealed that uncontrollable H&MA and the Child–Pugh score were independent risk factors for the postoperative prognosis.

Conclusions

Postoperative infection control may be an important means of improving the outcome for patients with uncontrollable H&MA undergoing LT, and clinicians should strive to perform surgery before H&MA becomes uncontrollable.     

Endoscopic imaging modalities for diagnosing the invasion depth of superficial esophageal squamous cell carcinoma: a systematic review

Esophagus - Endoscopic diagnosis of the invasion depth of superficial esophageal squamous cell carcinoma (ESCC) is an important determinant of the treatment strategy. The three endoscopic imaging...     

Hepatoma development during long term follow-up period of liver cirrhosis.

An attempt was made to elucidate the pathogenesis of hepatoma. The material comprises 20 cases which were followed up more than 3 years after diagnosed liver cirrhosis and verified by autopsy. Hepatoma was found in 10 out of these 20 cases (50%). The follow-up period of these 10 cases with hepatoma was from 3 to 9.5 years (the mean value; 5.5 years). All 10 cases were not heavy drinkers, and showed liver cirrhosis of the mixed type by autopsy. HBsAG was positive in 6 out of 8 cases by RIA method (75%), and alpha-f was also detected in 5 of 7 cases by RIA method (70%). On the contrary, only 2 out of 10 cases without hepatoma were HBsAG positive (20%). The present results indicate that HBsAG positive liver cirrhosis of the mixed type is closely related to hepatoma in our country.