The protective effects of acute cardiovascular exercise on the interference of procedural memory.

Numerous studies have reported a positive impact of acute exercise for procedural skill memory. Previous work has revealed this effect, but these findings are confounded by a potential contribution of a night of sleep to the reported exercise-mediated reduction in interference. Thus, it remains unclear if exposure to a brief bout of exercise can provide protection to a newly acquired motor memory. The primary objective of the present study was to examine if a single bout of moderate-intensity cardiovascular exercise after practice of a novel motor sequence reduces the susceptibility to retroactive interference. To address this shortcoming, 17 individuals in a control condition practiced a novel motor sequence that was followed by test after a 6-h wake-filled interval. A separate group of 17 individuals experienced practice with an interfering motor sequence 45 min after practice with the original sequence and were then administered test trials 6 h later. One additional group of 12 participants was exposed to an acute bout of exercise immediately after practice with the original motor sequence but prior to practice with the interfering motor sequence and the subsequent test. In comparison with the control condition, increased response times were revealed during the 6-h test for the individuals that were exposed to interference. The introduction of an acute bout of exercise between the practice of the two motor sequences produced a reduction in interference from practice with the second task at the time of test, however, this effect was not statistically significant. These data reinforce the hypothesis that while there may be a contribution from exercise to post-practice consolidation of procedural skills which is independent of sleep, sleep may interact with exercise to strengthen the effects of the latter on procedural memory.

The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases.

BACKGROUND: Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. PATIENTS AND METHODS: To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. RESULTS: The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. CONCLUSION: DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.

Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited-disease small-cell lung cancer.

BACKGROUND: We compared late thoracic radiotherapy (TRT) with early TRT in the treatment of limited-disease small-cell lung cancer (LD-SCLC). PATIENTS AND METHODS: Patients with LD-SCLC received four cycles of etoposide plus cisplatin every 21 days. Patients were randomly assigned to receive either TRT administered concurrently with the first cycle (early TRT) or the third cycle (late TRT) of chemotherapy. The primary end point was complete response rate. RESULTS: Two hundred twenty-two patients were randomly assigned.Late TRT was not inferior to early TRT in terms of the complete response rate (early v late; 36.0% v 38.0%). Other efficacy measures including overall survival [median, 24.1 v 26.8 months;hazard ratio (HR) 0.93; 95% CI = 0.67­1.29] and progression free survival (median, 12.4 v 11.2 months; HR 1.09; 95%CI = 0.80­1.48) were not different between two arms. No statistical difference was noted in the pattern of treatment failures.However, neutropenic fever occurred more commonly in the early TRT arm than the late TRT arm (21.6% v 10.2%; P = 0.02) [corrected]. CONCLUSION: In LD-SCLC treatment, TRT starting in the third cycle of chemotherapy seemed to be noninferior to early TRT, and had a more favorable profile with regard to neutropenic fever.

Effects of oxygen on invertase expression in continuous culture of recombinant Saccharomyces cerevisiae containing the SUC2 gene.

The yeast SUC2 gene, cloned on a multicopy plasmid pRB58, was used to study the effect of oxygen on the invertase expression of the recombinant Saccharomyces cerevisiae. Glucose repression was not the only factor affecting the invertase expression. The results obtained from the single-stage continuous cultures under microaerobic conditions showed that invertase expression was also strongly dependent on oxygen availability, and moving from anaerobic to aerobic conditions led to a five-fold increase in specific invertase activity. However, the cell yields under anaerobic conditions were quite low compared to those under aerobic conditions. These opposite effects of oxygen on cell growth and gene expression offer a strategy for maximizing invertase productivity by a two-stage continuous culture. The first stage was operated at a low level of glucose, around 100 mg/l, under aerobic conditions in order to obtain a high yield of yeast biomass, and the second stage maintained anaerobic conditions with residual glucose levels of 50 mg/l to derepress and fully induce invertase expression. The two-stage continuous culture resulted in a 2.5-fold increase in invertase productivity over that of a single-stage continuous culture.

Pupil-plane filtering for improved signal detection in an optical data-storage system incorporating a solid immersion lens.

A pupil-plane filtering technique is applied to data-signal detection in an optical data-storage system that uses a solid immersion lens (SIL) and a four-layered phase-change recording medium. We have confirmed by numerical calculations and experiment that the technique improves signal contrast and makes the contrast less sensitive to the gap width between the bottom surface of the SIL and the top surface of the recording medium. Light that is incident upon the objective lens that is used with the SIL is linearly polarized, and the full vectorial feature of the light is considered in the calculations.

Roles of propagating and evanescent waves in solid immersion lens systems.

The electromagnetic field incident on the thin-film layers in a solid immersion lens (SIL) system is decomposed into contributions from homogeneous and inhomogeneous waves, which are commonly referred to as propagating and evanescent waves, respectively. The homogeneous and the inhomogeneous parts have different properties with respect to the field distribution in the gap and inside the recording layers. The homogeneous part is shown to diffract like a focused wave with a numerical aperture of 1, and the inhomogeneous part decays exponentially away from the bottom of the SIL. Two examples are discussed in detail, and the concept of a vector illumination system transfer function, which includes effects of the recording layers, is introduced.

Bisindolylmaleimide inhibits the PMA-induced down-regulation of collagen synthesis in fibroblasts.

We assessed the role of protein kinase C (PKC) in the regulation of collagen synthesis. Two PKC activators, Phorbol 12-myristate 13-acetate (PMA) and 1-oleyl 2-acetyl-sn-glycerol (OAG), decreased the relative rate of collagen synthesis in a dose- and time-dependent manner in fibroblasts, whereas an inactive phorbol ester, 4 alpha-phorbol didecanoate failed to affect the collagen synthesis. In PKC-depleted cells both PMA and OAG were unable to inhibit collagen synthesis. Bisindolylmaleimide, a specific inhibitor of PKC, completely abrogated PMA-induced inhibition of collagen synthesis in a dose-dependent fashion while two other PKC inhibitors with low specificity, H7 and staurosporin failed to block PMA effect on collagen synthesis. The results provide evidence that collagen synthesis is regulated through the signal pathway involving PKC activation.

Expression patterns of bone-related proteins during osteoblastic differentiation in MC3T3-E1 cells.

Bone formation involves several tightly regulated gene expression patterns of bone-related proteins. To determine the expression patterns of bone-related proteins during the MC3T3-E1 osteoblast-like cell differentiation, we used Northern blotting, enzymatic assay, and histochemistry. We found that the expression patterns of bone-related proteins were regulated in a temporal manner during the successive developmental stages including proliferation (days 4-10), bone matrix formation/maturation (days 10-16), and mineralization stages (days 16-30). During the proliferation period (days 4-10), the expression of cell-cycle related genes such as histone H3 and H4, and ribosomal protein S6 was high. During the bone matrix formation/maturation period (days 10-16), type I collagen expression and biosynthesis, fibronectin, TGF-beta 1 and osteonectin expressions were high and maximal around day 16. During this maturation period, we found that the expression patterns of bone matrix proteins were two types: one is the expression pattern of type I collagen and TGF-beta 1, which was higher in the maturation period than that in both the proliferation and mineralization periods. The other is the expression pattern of fibronectin and osteonectin, which was higher in the maturation and mineralization periods than in the proliferation period. Alkaline phosphatase activity was high during the early matrix formation/maturation period (day 10) and was followed by a decrease to a level still significantly above the baseline level seen at day 4. During the mineralization period (days 16-30), the number of nodules and the expression of osteocalcin were high. Osteocalcin gene expression was increased up to 28 days. Our results show that the expression patterns of bone-related proteins are temporally regulated during the MC3T3-E1 cell differentiation and their regulations are unique compared with other systems. Thus, this cell line provides a useful in vitro system to study the developmental regulation of bone-related proteins in relation to the different stages during the osteoblast differentiation.

Okadaic acid inhibits alkaline phosphatase activity in MC3T3-E1 cells.

Alkaline phosphatase activity is regulated by various hormones and growth factors at least in part through the phosphorylation of target proteins during the bone cell differentiation. To investigate the role of protein phosphorylation in alkaline phosphatase activity in MC3T3-E1 osteoblast, we used okadaic acid which is a potent specific inhibitor of serine/threonine protein phosphatases to type 1 and 2A. Alkaline phosphatase activity in cellular layer was measured by spectrophotometer using p-nitrophenyl phosphate as substrate and data were expressed as p-nitrophenyl of nmol/min/mg of protein. Okadaic acid (1-50 ng/ml) caused the inhibition of alkaline phosphatase activity in MC3TC-E1 cells. At 50 ng/ml of okadaic acid showed the maximal inhibitory effect on alkaline phosphatase activity. Okadaic acid (50 ng/ml) also inhibited alkaline phosphatase activity in all differentiation stages. These results indicate that okadaic acid inhibits alkaline phosphatase activity in MC3T3-E1 cells.

Plasma type IV collagen and fibronectin concentrations in diabetic patients with microangiopathy.

In diabetes mellitus, thickening of basement membrane in capillaries and small vessels is a well-known finding and important in the progression of diabetic microangiopathy. We evaluated whether the plasma levels of type IV collagen and fibronectin, which are important factors of basement membrane, are related with the presence of diabetic microangiopathy. Plasma type IV collagen and fibronectin levels were measured in 40 healthy controls (Mean +/- SD, age; 50.3 +/- 5.5 yr) and 94 diabetic patients (age; 52.4 +/- 13.5 yr) with and without microvascular complications. The mean plasma levels of type IV collagen (5.3 +/- 2.9 ng/ml) and fibronectin (474.4 +/- 119.4 ug/ml) in diabetic patients were significantly higher (p < 0.01) than in healthy controls (3.7 +/- 1.3 ng/ml and 319 +/- 50.9 ug/ml). The mean plasma level of type IV collagen in diabetic patients with complications (6.6 +/- 3.7 ng/ml) was significantly higher (p < 0.01) than in those without complications (4.3 +/- 1.7 ng/ml) and became higher in more complicated patients. Furthermore, the severity of retinopathy and several indicators of nephropathy such as serum BUN, creatinine and proteinuria were closely associated with plasma type IV collagen level and a significant correlation was found between plasma type IV collagen and creatinine clearance (r = -0.31, p < 0.001). There was no significant difference in plasma fibronectin concentrations, however, between the diabetic patients with complications and those without complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective inhibition of collagen synthesis by okadaic acid in cultured human fibroblasts.

To determine whether protein phosphatases can affect collagen synthesis, we examined the effect of okadaic acid, a potent specific inhibitor of protein phosphatases 1 and 2A, on collagen synthesis. Okadaic acid significantly decreased the [3H]proline incorporation into the collagenase-digestible protein and the percent collagen synthesis. These effects were synergistic with phorbol myristate acetate (PMA). The time course study showed that okadaic acid inhibited collagen synthesis after a 12 h treatment while PMA inhibited at 3 h. Down-regulation of protein kinase C by chronic treatment with PMA did not abrogate the okadaic acid-dependent inhibition. These results provide evidence for the involvement of protein phosphatases in the regulation of collagen synthesis.

Clinical efficacy of topical homologous fibronectin in persistent corneal epithelial disorders.

The clinical efficacy was investigated of topical homologous fibronectin on persistent corneal epithelial defects of various etiologies. Fibronectin was purified from blood bank homologous plasma by gelatin-Sepharose 4B affinity chromatography. Twenty eight eyes of twenty five patients with persistent corneal epithelial defects and sterile corneal ulcers that failed to improve with standard therapy were treated by the instillation of homologous fibronectin eyedrops 5 times a day (500 micrograms/ml). Complete reepithelialization was achieved in all patients except two eyes due to uncontrolled glaucoma and the taking of steroids. The healing time tended to be different depending on the duration of persistent corneal epithelial defects and the severity of underlying diseases. The mean +/- standard deviation duration of epithelial defect was 68.18 +/- 77.80 days. Average healing time was 42.07 +/- 17.47 days. Ocular symptoms were relieved significantly and no side effects were observed. Over an average follow-up period of about 8 months, two cases of recurrences were noted. These results show that homologous fibronectin was also effective in patients with persistent corneal epithelial defects and corneal ulcers.

Homologous fibronectin enhances healing of excised wounds in rats.

In order to evaluate the effects of a topical application of homologous fibronectin on the healing of skin wounds, we made 2 excisional wounds on the back skin of each rat, applied ointment with or without fibronectin purified from citrated homologous plasma, and evaluated the effect according to wound size and microscopic findings. Excised lesions treated with carrier alone, but the difference was significant only in the early phase of wound healing, 2 and 3 days, according to wound size and microscopic changes. A significant decrease in wound size could be found in both groups, treated with ointment containing and not containing fibronectin, between day 4 and 9 when wound contraction was a major contributor to wound closure. Therefore it can be concluded that topical application of fibronectin has a beneficial effect on wound healing during its early phase, but no significant influence on wound contraction.

Topical fibronectin treatment in persistent corneal epithelial defects and corneal ulcers.

Topical fibronectin, autologous and homologous, was used to treat nine patients (eleven eyes) with persistent corneal epithelial defects and corneal ulcers that failed to improve with standard therapy. The fibronectin was purified from autologous and homologous plasma by gelatin-Sepharose 4B affinity chromatography and administered topically, 500 micrograms/ml five times a day, for three weeks. Complete or nearly complete reepithelialization was achieved in all patients regardless of the source of fibronectin, autologous or homologous. But healing times varied. The average healing time was 41.7 +/- 14.7 days (35.7 +/- 12.4 days for autologous, 50.8 +/- 14.4 days for homologous). Ocular symptoms were relieved significantly, and no side effects were observed. Over an average follow-up period of 5.2 months, no recurrences were noted. The results showed that homologous, as well as autologous, fibronectin was effective in patients with persistent corneal epithelial defects and corneal ulcers.