A single institutional subset analysis of the WJLCG study comparing concurrent and sequential chemoradiotherapy for stage III non-small-cell lung cancer

PURPOSE: To supplement findings of the West Japan Lung Cancer Group (WJLCG) study, treatment outcomes in our institution were reviewed from the perspective of radiation oncology. MATERIALS AND METHODS: Chemotherapy consisted of cisplatin (80 mg/m2 on days 1 and 29), vindesine (3 mg/m2 on days 1, 8, 29, and 36), and mitomycin (8 mg/m2 on days 1 and 29). In the concurrent arm, radiation therapy began on day 2 with a dose of 56 Gy in 28 fractions over 6.8 weeks, with an interval of 10 days at 28 Gy. In the sequential arm, radiation therapy began on day 50 with a dose of 56 Gy in 28 fractions over 5.6 weeks, without an interval. RESULTS: Twenty-four patients in the concurrent arm and 25 patients in the sequential arm in our institution were eligible for the WJLCG study. In the concurrent arm, three patients could not receive the full dose of radiation therapy and 12 patients required interruption of radiation therapy for more than 4 days. The median survival time among per-protocol patients and in those with interruption or with incomplete radiation therapy was 28.9 months and 14.1 months, respectively (p = 0.02). In the sequential arm, one patient could not receive the full dose of radiation therapy and none of the patients required such interruption. Local relapse and distant metastases as the first site of relapse occurred in 12 (11 in-field, 1 marginal) and five patients, respectively, in the concurrent arm, and in eight (7 in-field, 1 marginal) and 11 patients, respectively, in the sequential arm. CONCLUSION: In the concurrent regimen, noncompletion or interruption of radiation therapy was frequent, and the prognosis of such patients was poor.     

Enhanced S-cone syndrome in a Japanese family with a nonsense NR2E3 mutation (Q350X)

PURPOSE: To describe the clinical characteristics of a Japanese male patient with enhanced S-cone syndrome (ESCS) and investigate the existence of mutations in the NR2E3 gene, which encodes a photoreceptor cell-specific nuclear receptor. METHODS: Fundus examinations, fluorescein angiography, colour vision tests, spectral sensitivity, and full-field and spectral electroretinography were performed. Mutation screening of the NR2E3 gene was performed with polymerase chain reaction (PCR) amplification and direct sequencing. RESULTS: We identified a novel homozygous mutation (c.1048C > T), that converts glutamine (CAA) to a termination codon (TAA) at amino acid position 350. The subject's unaffected parents were heterozygous for the mutation, consistent with autosomal recessive transmission. The electroretinographic findings revealed that the patient had neither rod nor 30-Hz flicker responses but did have cone responses with large a-wave and low b-wave amplitudes, similar to the rod-plus-cone responses, and also substantial short wavelength-sensitive (S) cone and extremely diminished long/middle wavelength-sensitive (L/M) cone responses. In the right eye, spectral sensitivity in the fovea revealed both functional S-cone and remarkably reduced L- and M-cone sensitivities, which was compatible with the decreased visual acuity (VA) and red/green colour vision defects noted in this eye. In contrast, the patient had good VA and normal red/green colour vision in the left eye. CONCLUSION: The nonsense mutation results in a truncated NR2E3 protein lacking 61 amino acids within the ligand-binding domain (LBD) that consists of 190 amino acids of the C-terminus end. Therefore, null function of the LBD is likely to cause ESCS in the patient. The clinical findings for this patient suggest that his left eye, with its functional L/M- and S-cones, was at an earlier stage of the syndrome than his right eye.     

Effects of 2-alkynyladenosine derivatives on intraocular pressure in rabbits

We evaluated the activities of 2-alkynyladenosine derivatives, relatively selective adenosine A2 receptor agonists, in the intraocular pressure regulation in rabbits. An adenosine A2 receptor agonist 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS-21680) decreased intraocular pressure, while another A2 receptor agonist 2-(phenylamino)adenosine transiently increased it. The first group of 2-alkynyladenosine derivatives (1-hexyn-1-yl derivatives) caused a transient increase followed by decrease in intraocular pressure, while the second group (1-octyn-1-yl and 6-cyano-1-hexyn-1-yl derivatives) only decreased it. The second group is also effective in the ocular hypertensive models induced by water-loading and alpha-chymotrypsin. The outflow facility was increased by a 1-octyn-1-yl derivative. Both increase and decrease in intraocular pressure induced by 2-alkynyladenosine derivatives were inhibited by an adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine, but not by an adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropyl xanthine. These findings suggest that 2-alkynyladenosine derivatives may affect intraocular pressure via adenosine A2 receptor, and 2-alkynyladenosine derivative-induced ocular hypotension is due to the increase of outflow facility.     

Time course of the change in optic nerve head circulation after an acute increase in intraocular pressure

PURPOSE: To investigate the time course of changes in optic nerve head (ONH) circulation after an acute increase in intraocular pressure (IOP), by using the laser speckle method, and to evaluate the effects of a calcium antagonist, the nitric oxide synthetase inhibitor, indomethacin, or sympathetic nerve amputation on the response in ONH circulation after an acute increase in IOP. METHODS: In rabbits, the normalized blur (NB) level, a quantitative index of tissue blood velocity in the ONH, was monitored for 60 minutes after an increase in IOP from 20 mm Hg to 40, 50, or 60 mm Hg and for 25 seconds after increase in IOP from 20 mm Hg to 50 or 60 mm Hg with high time resolution. The effects of systemic administration of 1 micro g/kg per hour nilvadipine (a calcium antagonist), 30 mg/kg N(omega)-nitro-L-arginine (L-NAME), or 5 mg/kg indomethacin, or those of sympathetic nerve amputation on the time course of the changes in NB were studied. RESULTS: NB showed a quick recovery within several seconds after increase in IOP to 40 or 50 mm Hg, whereas no or little recovery occurred after an increase to 60 mm Hg. The nilvadipine treatment significantly increased NB at IOP of 20 mm Hg (baseline NB, P = 0.045) and apparently impaired the recovery of NB after the increase in IOP. After L-NAME administration, baseline NB significantly decreased (P = 0.028), and the NB recovery time was slightly but significantly prolonged (P = 0.012). Indomethacin showed no effects on baseline NB or NB recovery. Sympathetic nerve amputation increased baseline NB (P = 0.027), but did not influence NB recovery. CONCLUSIONS: The current results showed a quick recovery response in the ONH circulation after an acute increase in IOP in rabbits. A calcium antagonist impaired the response. Production of nitric oxide or prostaglandins or the sympathetic nervous system is probably not mainly responsible for the reaction.     

Scintigraphic progress of the liver in a patient with Alagille syndrome (arteriohepatic dysplasia)

We encountered a 9-year-old Japanese girl with Alagille syndrome. Her scintigraphic examinations of the liver were performed at the ages of 16 months and 9 years. 99mTc-PMT, a hepatobiliary imaging agent, was distributed homogeneously in the liver at the younger age, but unevenly produced an area of focally increased uptake in the medial segment of the liver surrounded by peripheral atrophy at the older age. 99mTc-GSA, a hepatoreceptor binding agent, was highly accumulated in the area, corresponding to the focally increased uptake of 99mTc-PMT. These imaging findings suggest that the pathophysiological and morphological changes of the liver occurred in our patient during the clinical course.     

HIV-1 integrase inhibitory substances from Coleus parvifolius

For the purpose of discovering anti-HIV-1 agents from natural sources, water and EtOH extracts of 50 Thai plants were screened for their inhibitory activity against HIV-1 integrase (IN), an enzyme essential for viral replication. Of these plants, an EtOH extract of Coleus parvifolius Benth. (aerial parts) showed potent activity against HIV-1 IN with an IC50 value of 9.2 microg/mL. From this extract, 11 compounds were isolated and identified as luteolin 5-O-beta-d-glucopyranoside (1), luteolin (2), luteolin 7-methyl ether (3), luteolin 5-O-beta-d-glucuronide (4), 5-O-beta-d-glucopyranosyl-luteolin 7-methyl ether (5), rosmarinic acid (6), rosmarinic acid methyl ester (7), daucosterol (8), a mixture of alpha- and beta-amyrin (9, 10) and phytol (11). Of these compounds, rosmarinic acid methyl ester (7), rosmarinic acid (6), luteolin (2) and luteolin 7-methyl ether (3) exhibited inhibitory activities against HIV-1 IN with IC50 values of 3.1, 5.0, 11.0 and 11.0 microM, respectively. Among rosmarinic acid derivatives, the HIV-1 IN inhibitory activity increased in turn for a dimer (IC50 = 5.0 microM), a trimer (IC50 = 1.4 microM), and a tetramer (IC50 = 1.0 microM).     

The relationship between changes in normal-range systolic blood pressure and cognitive function in middle-aged healthy women.

Little is known about the effect of normal-range blood pressure (BP) on cognitive function. In previous studies investigating the relationship between BP and cognitive function in elderly subjects, underlying cerebrovascular damage has complicated the interpretation of results. To reveal the relationship between BP levels that were within an absolutely normal range and cognitive function, we examined cognitive function in normotensive, healthy middle-aged women. BP levels were measured on three separate occasions at 1-month intervals, and the subjects exhibiting normotension (< 140/90 mmHg) throughout the evaluation period were recruited as normotensive subjects. Cognitive function was assessed using subtests of the Wechsler Adult Intelligence Scale-Revised. The study demonstrated that, among the subtests examined, the scores on the Digit Symbol Test, an index of psychomotor performance, had a significant correlation with normotensive-range systolic blood pressure (SBP) (r=-0.51, p<0.05); this relation was negative-that is, higher but still normal-range SBP levels were associated with impaired Digit Symbol Test scores. In addition, the relationship adjusted by age and educational level was also significant (partial correlation = -0.56, p<0.05). In contrast, diastolic BP was not related to the Digit Symbol Test (r = -0.33, p = 0.13). Furthermore, the Digit Symbol Test was not influenced by blood glucose or serum cholesterol levels. These findings suggested that, even within the normotensive range, lower levels of SBP might be protective against impairment of psychomotor speed in middle-aged women.     

Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of the metabolic syndrome. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the efficacy of atorvastatin in the treatment of NASH associated with hyperlipidemia. This prospective study included 31 patients with biopsy-proven NASH with hyperlipidemia. Body mass index, serum lipids, liver function tests, fibrosis markers, and adipocytokines (adiponectin, leptin, tumor necrosis factor-α) were measured periodically during an open-label study of atorvastatin (10 mg daily) for 24 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance test and liver density assessed by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 17 patients. All 31 patients had high cholesterol levels at baseline, and 20 also presented high triglyceride levels. The body mass index and serum glucose levels did not change during the treatment. After treatment, 23 patients (74.2%) presented normal transaminase levels. Adiponectin levels were significantly increased, and the levels of tumor necrosis factor-α were significantly decreased. However, leptin levels were not changed significantly. The concentration of long-chain fatty acids was decreased; and significant decreases were observed in C18:2,n-6 (linoleic acid, −21%) and C20:4,n-6 (arachidonic acid, −22%). Liver steatosis and nonalcoholic fatty liver disease activity score were significantly improved, whereas 4 patients had increased fibrosis stage. The NASH-related metabolic parameters improved with therapy, including fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period, with 3 of them progressing to stage 3. It is unclear whether this divergent response represents sampling error, heterogeneity in the population, or untreated postprandial hyperglyceridemia. Controlled trials are needed to further investigate and resolve this.