Effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats

The purpose of this study was to examine the effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats. The "linked animals" experiments provided evidence that diflunisal exhibits an enterohepatic circulation. Within 26 hr after iv administration of diflunisal (10 mg/kg) to rats, excretion was as follows: 42.2% of the dose, bile; 2.3%, unchanged drug; 27.8%, ester glucuronide; and 12.1%, ether glucuronide. On the average, approximately 65% of the amount of the drug and its glucuronides excreted in bile was reabsorbed from the gut. Biliary excretion and plasma data showed that biotransformation of diflunisal to its glucuronides is the rate-limiting step in their elimination. A concentration-dependent decrease in the partial formation clearance to ester glucuronide was observed with decreased concentration of diflunisal. These concentration-dependent kinetics can be at least partly explained by the nonlinear protein binding of diflunisal.     

Viral transmission and evolution dynamics of SARS-CoV-2 in shipboard quarantine

ObjectiveTo examine transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in shipboard quarantine of the Diamond Princess cruise ship.MethodsWe obtained the full SARS-CoV-2 genome sequences of 28 samples from the Global Initiative on Sharing All Influenza Data database. The samples were collected between 10 and 25 February 2020 and came for individuals who had been tested for SARS-CoV-2 during the quarantine on the cruise ship. These samples were later sequenced in either Japan or the United States of America. We analysed evolution dynamics of SARS-CoV-2 using computational tools of phylogenetics, natural selection pressure and genetic linkage.FindingsThe SARS-CoV-2 outbreak in the cruise most likely originated from either a single person infected with a virus variant identical to the WIV04 isolates, or simultaneously with another primary case infected with a virus containing the 11083G > T mutation. We identified a total of 24 new viral mutations across 64.2% (18/28) of samples, and the virus evolved into at least five subgroups. Increased positive selection of SARS-CoV-2 were statistically significant during the quarantine (Tajima’s D: −2.03, P < 0.01; Fu and Li’s D: −2.66, P < 0.01; and Zeng’s E: −2.37, P < 0.01). Linkage disequilibrium analysis confirmed that ribonucleic acid (RNA) recombination with the11083G > T mutation also contributed to the increase of mutations among the viral progeny.ConclusionThe findings indicate that the 11083G > T mutation of SARS-CoV-2 spread during shipboard quarantine and arose through de novo RNA recombination under positive selection pressure.     

Distinguishing depression and negative symptoms in unmedicated patients with schizophrenia

Depression can occur in schizophrenia but can be difficult to distinguish from negative symptoms of the illness. To evaluate whether concurrent use of the Hamilton Rating Scale for Depression (HRSD) and the Brief Psychiatric Rating Scale (BPRS) could successfully separate depression and negative symptoms, we examined ratings on 69 unmedicated schizophrenic inpatients. A classical BPRS depression subscale score correlated highly (rho = 0.80) with the HRSD total score. The classical BPRS "negative symptom" subscale score was unrelated to both the BPRS and HRSD depression summary measures. Among individual HRSD items, negative symptoms correlated only with work/activities and retardation. The findings suggest that negative and depressive symptoms may be assessed independently.     

The expression of cytokeratin 18 in transitional cell carcinoma comparing with hepatoma

The epithelium in kidneys and urinary bladders contain CK18 as in liver cells. The modulation of cytokeratin 18 during tumor transformation in hepatoma had been previously recognized through a series of biochemical and immunological approaches. A 14 KD hepatoma related molecules was found in the previous studies. We would like to utilize the hepatoma transformation model to study the changes in CK18 in transitional cell carcinoma, using immunoblotting and western blotting techniques. The result is that transitional cell carcinoma retain their CK18 molecule. Furthermore, CK18 related molecules similar to those seen in hepatoma also present in transitional cell carcinoma. The conclusions are transitional cell carcinoma contains CK18 related proteins similar to those seen in hepatoma tissues. We suggest that this element would be responsible for the change during the malignant transformation processes.     

11C-acetate clearance in nasopharyngeal carcinoma

This study assessed 11C-acetate turnover (clearance) in nasopharyngeal carcinoma (NPC). Data were acquired by dynamic PET after the intravenous injection of 4.625 MBq.kg-1 body weight of 11C-acetate for 30 min. Tomograms were reconstructed and evaluated visually. A time-activity curve of the nasopharynx and neck was generated and the clearance rate of 11C-acetate from the nasopharynx in the slow phase and from NPC was calculated using 0.693/T1/2. Ten patients with nasopharyngeal carcinoma and nine normal subjects were studied. The clearance of 11C-acetate from the normal nasopharynx was rapid and biexponential, in contrast to the rapid uptake followed by extremely slow clearance in patients with NPC. The clearance rate (mean +/- S.D.) was 0.0074 +/- 0.0042 in NPC and 0.0263 +/- 0.0152 in controls in the slow phase, being significantly different between the two groups with no overlap. All nasopharyngeal carcinomas were clearly visualized, in contrast to no obvious retention in the normal nasopharynx. Our initial results indicate that 11C-acetate clearance can be used to differentiate nasopharyngeal carcinoma from a normal nasopharynx. This finding may lead to new applications of 11C-acetate in oncology.     

Telomerase activity is a useful marker to distinguish malignant pancreatic cystic tumors from benign neoplasms and pseudocysts

BACKGROUND: Pancreatic serous cystadenoma, mucinous cystic neoplasms, ductal adenocarcinoma with cystic change, and pseudocysts are a spectrum of pancreatic cystic lesions. Their management strategy and prognosis are extremely diverse. Imaging study, cytology, and analysis of the tumor markers of cyst fluid are not always reliable in differentiation of these disease entities. MATERIALS AND METHODS: Fifteen patients with pancreatic cystic neoplasms (including six mucinous cystadenocarcinomas, two mucinous cystic neoplasms with borderline malignancy, two mucinous cystadenomas, and five serous cystadenomas), 4 patients with pancreatic ductal adenocarcinomas with cystic change, and 10 patients with pseudocysts were studied. Echo-guided or computed tomography-guided biopsies of pancreatic cystic lesions and their normal counterparts were conducted on all patients prior to operation or other management. The specimens were assayed for telomerase activity by using TRAP (telomere repeat amplification protocol). The level of telomerase activity in each specimen was semiquantitated as strong, moderate, weak, and none. The final diagnoses were made from histopathological examination of surgically resected or biopsied specimens. The efficacy of telomerase activity as a tumor marker to predict malignancy of pancreatic cystic lesions was evaluated. RESULTS: Three of the four pancreatic ductal adenocarcinomas with cystic change had strong or moderate telomerase activity; four of the six mucinous cystadenocarcinomas had moderate or weak telomerase activity; one of the two mucinous cystadenomas with borderline malignancy had weak telomerase activity; and none of their normal counterparts had detectable telomerase activity. In contrast, none of the two mucinous cystadenomas, five serous cystadenomas, and 10 pseudocysts had detectable telomerase activity. Based on these results, the sensitivity of telomerase activity for prediction of malignancy or premalignancy of pancreatic cystic lesions was 67%, the specificity was 100%, and the positive and negative predictive values were 1.0 and 0.81, respectively. The overall accuracy was 86%. CONCLUSIONS: The differential expressions of telomerase activity have been detected specifically in malignant and premalignant pancreatic cystic tumors, but not in benign cystic neoplasms or pseudocysts. The implications of these results are that telomerase activation takes part in the malignant transformation of pancreatic cystic neoplasms and that telomerase activity is a useful marker to distinguish malignant pancreatic cystic tumors from benign neoplasms and pseudocysts.     

Origin of the "N10" stationary-field potential after median nerve stimulation.

The scalp far-field potentials after median nerve stimulation at the wrist consist of P9, P11, P13, and P14 positive components. Earlier, Emerson et al. (1984) identified the "N10" negative potential in-between the P9 and P11 and claimed that this was not merely a passive return to the baseline after the P9 positive deflection but a distinct component reflecting a proximal brachial plexus volley. They thought N10 was a far-field potential having widespread distribution with a fixed latency. In this study we found that N10 was of higher amplitude after median nerve stimulation at the elbow than after stimulation at the wrist. Indeed the N10 latency was fixed from the lower anterior neck to the scalp, and its amplitude was maximum at the anterior lower neck. The latency of N10 was about 0.3 milliseconds longer than the Erb's potential and 0.15 milliseconds longer than the potential recorded from the lateral neck on the side of stimulation. The N10 amplitude increased in parallel with increased stimulus intensity. In order to explore the origin of the N10 stationary field potential, we designed a paired stimuli paradigm applied to the wrist (S1) and to the elbow (S2). The interstimulus interval between S and S2 was adjusted so that the timing of S2 was immediately after the traveling impulse produced by the S1 stimulus as it passed through the S2 stimulus site. This technique allowed stimulation of the anterior interosseous nerve selectively at the elbow while the median nerve originating from the wrist was undergoing refractory period. The response of (S1 + S2) - S1 showed only the N10 with absence of cervical and cortical responses, implying that N10 was activated, predominantly by the interosseous nerve, i.e., an antidromic motor volley, when the median nerve was stimulated at the elbow.     

N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats

The present study examined the effect of N-tert-butyl-alpha-phenylnitrone (PBN) on 3,4-methylenedioxmathamphetamine (MDMA)-induced depletion of serotonin in the CNS. Rats were treated with two concurrent injections of MDMA (20 mg/kg, s.c.), PBN (50-400 mg/kg dissolved in ethanol, 50 mg/ml of 25% ethanol, i.p.), saline or 25% ethanol, alone or in combination, 6 h apart, and sacrificed 5 days later. Rectal temperature was measured prior to and hourly following the drug injection for 5 h. Monoamine levels in the tissue were measured by HPLC. Density of the 5-HT transporters was assayed by [3H]paroxetine binding. Rectal temperature of rats increased after MDMA, decreased after PBN, ethanol, PBN plus ethanol, and MDMA plus ethanol, and was not significantly altered after MDMA plus PBN. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, striatum, and brain stem of rats decreased significantly after MDMA or MDMA plus ethanol, but not after MDMA plus PBN, PBN plus ethanol (PBN dissolved in ethanol), or ethanol as compared to the saline controls. Levels of 5-HT and 5-HIAA in the brain tissues of rats treated with MDMA plus PBN were elevated as compared to those treated with MDMA plus saline. Similar results were observed in the density of 5-HT transporters in the frontal cortex and hippocampus. These results indicate that scavenging of free radicals of MDMA metabolites or reactive oxygen species by PBN and with lowering of body temperature protected against MDMA-induced depletion of serotonin transmitter.     

Liver resection for hepatocellular carcinoma in octogenarians

BACKGROUND: Liver resection is risky in patients aged > or = 80 years. Because of short life expectancies and improved nonoperative modalities, the role of liver resection in octogenarians with hepatocellular carcinoma (HCC) is unclear. METHODS: A retrospective review of the operative results of 260 patients with HCC between 1991 and 1997 was performed. According to the age at the time of operation, these patients were divided into 2 groups. Group 1 comprised 21 patients aged > or = 80 years, and group 2 comprised the other 239 younger patients. The backgrounds, pathologic features of the tumor, and operative results of the patients were compared. RESULTS: Octogenarians had a higher incidence of associated medical diseases, a higher incidence of negative serum hepatitis B surface antigen, a lower alpha-fetoprotein level, and a higher indocyanine green retention rate. Although octogenarians had a longer postoperative hospital stay, there were no significant differences between the 2 groups regarding operative morbidity and mortality. The 5-year disease-free and actuarial survival rates for octogenarians and younger patients were 50.6% and 35.3% (P = .15) and 40.9% and 59.3% (P = .46), respectively. CONCLUSION: Under meticulous preoperative assessments and postoperative care, liver resection for HCC is justified in selected octogenarians, with short- and long-term results comparable to those of younger patients.