[Correlation analysis between prostate imaging report and data system score and pathological results of prostate cancer].

Objective: To explore the correlation between prostate imaging report and data system (PI-RADS) score and international society of uological pathology (ISUP) grade of prostate cancer (PCa) and the role of PI-RADS score in predicting the pathological features of clinically significant PCa (csPCa), positive surgical margin and pathological upgrade. Methods: The pathologically positive patients with multi-parameter magnetic resonance image (mpMRI) were included in this study. The patients with prostate specific antigen (PSA)<100 µg/L were divided into two groups: biopsy group (n=523) and RP group (n=215). The correlation between PI-RADS score and ISUP grade and the accuracy of predicting csPCa in the two groups were evaluated. In the RP group, the correlation between PI-RADS score and postoperative pathological grade or degradation and positive incisal margin was further discussed. The patients with PSA≥100 µg/L (171cases in biopsy group and 6 cases in RP group) were not included in the statistical analysis, and the results were simply described. Results: The age, prostate volume, and PSA level of biopsy group and RP group was (72±8) years vs (68±7) years, 48.3 (32-57) cm(3) vs 47.2 (32-54) cm(3), and 26.3(10.2-34.2)µg/L vs 21.7 (9.24-23.95)µg/L, respectively. The PI-RADS scores ≤ 3,4, and 5 in the biopsy group were 109,97, and 317 respectively, and those in the RP group were 61,55, and 99 respectively. There were significant differences in the composition of ISUP grades of different PI-RADS scores between the two groups (P<0.001), and there was a positive correlation between the two groups (r=0.493 in the biopsy group, r=0.671 in the RP group, both P<0.001). Using PI-RADS score to predict csPCa, biopsy group (AUC=0.764, P<0.001, 95%CI:0.710-0.819) and RP group (AUC=0.807, P<0.001, 95%CI:0.735-0.879) had certain accuracy. The PI-RADS score combined with PSA could improve the accuracy of csPCa prediction in the biopsy group (AUC=0.795,P<0.001, 95% CI:0.746-0.843) and the RP group (AUC=0.852, P<0.001, 95%CI:0.789-0.915). Compared with the pathological results of biopsy in the RP group, 52.6% of the patients showed upgrade and degrade of ISUP, and there was insignificant difference in the composition of PI-RADS scores between upgraded and degraded patients (P>0.05). However, 41.7%(27/65) of the patients with ISUP grade 1 biopsies had pathological upgrades that the patients with PI-RADS ≤ 3 accounted for 33.3%, while the patients with PI-RADS>3 accounted for 66.7%, and there was significant difference between the two groups (P<0.05). After RP, 43.3% of the patients had positive surgical margins, and the patients with PI-RADS score ≤ 3, 4 and 5 were 13 (14%), 24 (25.8%) and 56 (60.2%), respectively, while the PI-RADS scores of patients with negative surgical margin were 48 (39.3%), 31(25.4%) and 43(35.2%), respectively. There was significant difference between the two groups (P<0.001). The higher the PI-RADS score, the greater the possibility of the positive surgical margin. For the patients with PSA ≥ 100 µg/L, 98.8% (169/171) patients in the biopsy group had a PI-RADS score 5. The pathological results of all patients were csPCa, of which 85.4% (146/171) had ISUP grade ≥ 4. Among them, 6 cases underwent RP, 5 cases had ISUP grade ≥ 4, all surgical margin were positive, 5 cases had seminal vesicle invasion, 3 cases had capsule invasion and 3 cases had positive pelvic lymph nodes. Conclusion: ThePI-RADS score is correlated with the ISUP grade of PCa. Combined with PSA can accurately predict csPCa. At the same time, the higher PI-RADS score, the more likely the patients with positive incisal margin after RP and Gleason score of 3+3=6 at the time of puncture will be upgraded pathologically.

[CD40/TNF receptor associated factor 1 expression and NF-κB-dependent proinflammatory gene expression in rheumatoid arthritis].

Objective: To investigatea cellular/molecular mechanism of the CD40/TRAF1 signalling pathway involved in Rheumatoid arthritis (RA). Methods: 16 patients with active RA and 9 patients with Fractures who underwent total knee or hip replacement in The First Affiliated Hospital of Soochow University were included in the study. Synovial tissues (ST) and serum were obtained from each patient. The CD40, TRAF1, NF-κB p65 were detected by ELISA and Immunohistochemistry in serum and tissue respectively. Real time-PCR (RT-PCR) was applied to measure NF-κB-related gene expression. Results: CD40 and TRAF1 positive area (%) in RA patients were 28.7±5.4, 34.3±4.8 respectively, which were significantly higher (P<0.05) than Fracture controls (21.2±9.5, 21.6±8.7 respectively). The expression of total NF-κB p65, and phospho-NF-κB p65 proteins, as well as NF-κB-related gene expression, including cytokines (TNFα, IL-6), chemokines (MCP-1),and adhesion molecules (ICAM-1) were significantly higher in the ST of RA patients compared to Fracture controls. Conclusion: It is thus possible that the CD40/TRAF1 pathway acted as a positive regulator through NF-κB activation and NF-κB-dependent proinflammatory genes in RA.

[Effect of multimodal analgesia using periprostatic nerve block anesthesia combined with flurbiprofen in transperineal template-guided prostate biopsy].

Objective: To evaluate the effect of multimodal analgesia using periprostatic nerve block anesthesia (PNB) combined with flurbiprofen in patients undergoing transperineal template-guided prostate biopsy (TTPB). Methods: Totally 166 patients (aged (68.2±9.1) years, range: 47 to 81 years) who received TTPB from October 2017 to June 2018 at Department of Urology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University were enrolled prospectively. All the patients were randomly divided into 2 groups. The observation group (n=79) was given flurbiprofen axetil 1 mg/kg intravenously for half an hour before operation and lidocaine was used for PNB before the biopsy. The control group (n=87) was given normal saline combined with PNB. A visual analog scale (VAS) and visual numeric scale (VNS) were used to assess the patients' pain and quantify their satisfaction at two time points: VAS-1 and VNS-1: during biopsy procedure, VAS-2 and VNS-2: 30 min after the procedure. The date were compared by t test, χ(2) test, Fisher exact test and two-way repeated measures anova analysis between the 2 groups. Results: The age, total prostate volume, serum prostate-specific antigen and the number of cores were comparable among the 2 groups (P>0.05). The VAS-1 scores of the control group and the observation group were 2.8±1.7, 1.9±1.2, respectively, and the VNS-1 were 3.1±0.7, 3.4±0.3, respectively. The VAS-1 were significantly lower in observation group than in control group (F=3.904, P=0.000). Conversely, the VNS-1 were higher in observation group (F=3.526, P=0.000). At 30-minute postoperative, the VAS-2 and VNS-2 were 0.7±0.4 and 3.7±0.2 in the control group, respectively. The VAS-2 and VNS-2 were 0.6±0.5 and 3.8±0.1 in the observation group, respectively. There were no significant differences in the pain scores or the satisfaction scores between the 2 groups (F=1.429, 2.825; P=0.136, 0.083). The incidence of overall complications was 26.4% (23/87) in the control group and 25.3% (20/79) in the observation group, with no statistical difference between the 2 groups (χ(2)=0.027, P=0.869). And the complications had no statistically significant difference among the 2 groups including hematuria, urinary retention, infection, hematospermia, vascular and neurological reactions, nausea, vomiting, dizziness, headache, and respiratory depression (P>0.05). Conclusion: The multimodal analgesia induced by PNB and flurbiprofen could effectively relieve the pain for patients who received TTPB.

[Complications of transperineal template-guided prostate mapping biopsy].

Objective: To assess the complications of transperineal template-guided prostate mapping biopsy (TTMB). Methods: Between May 2017 and March 2018, 142 consecutive patients with prior negative transrectal biopsy results and persistently elevated prostate-specific antigen (PSA) were divided into the observation group and the control group randomly. The observation group underwent TTMB and the control group underwent transperineal template-guided prostate saturation biopsy (TTSB). Bleeding, infection, urinary function were recorded after prostate biopsy. Erectile function (ED) was measured at baseline, 1 month, 3 months and 6 months after prostate biopsy using the International Index of Erectile Function (IIEF-5). Results: A mean of 59 cores (from 33 to 116 cores) were obtained in TTMB, and a mean of 23 cores (from 11 to 44 cores) were obtained in TTSB. The positive rate was 50.0% (30/60) in TTMB, and 32.9% (27/82) in TTSB, and there were significant differences between two groups (P<0.05). The incidence of severe hematuria and urinary retention was 8.3% (5/60) and 11.7% (7/60) respectively in TTMB, while 1.2% (1/60) and 11.7% (7/60) respectively in TTSB. There were significant differences between two groups (P<0.05). But there were no significant differences between two groups in the incidence of mild, moderate and total hematuria, hematospermia, perineal hematoma, infection (P>0.05). Rectal bleeding was not observed. In TTMB group, the IIEF-5 scores at baseline, 1 month, 3 months and 6 months were (19.1±4.5), (17.4±4.8), (18.6±4.5), (19.0±4.0), respectively. In TTSB group, the IIEF-5 scores at baseline, 1 month, 3 months and 6 months were (19.7±4.3), (18.2±4.5), (19.1±4.1), (19.6±4.2), respectively. There were significant differences between baseline and 1 month after prostate biopsy in two groups (P<0.05), but there were no significant differences of IIEF-5 score between the two groups (P>0.05). Conclusions: TTMB can improve the positive rate for patients with prior negative transrectal biopsy results and persistently elevated PSA. TTMB has low complication rates, and most side-effects are self-limited. Compared with TTSB, the incidence of urinary retention and severe hematuria increases, but they can be recovered after clinical intervention. ED is transient, and affected for 1 month after the biopsy, but it will be recovered to the baseline after 3 to 6 months. Therefore, TTMB is a safe and reliable procedure.

[The expression and significance of microtubule - driven protein KIF2A in epithelial ovarian cancer].

Objective: To investigate the protein and mRNA expression of KIF2A in ovarian cancer, and to investigate the migration and invasion ability changes in ovarian cancer cell line HO-8910 transfected by KIF2A-siRNA. Methods: Immunohistochemical method was used to detect the expression of KIF2A in 30 cases of ovarian cancer and 20 cases of ovarian normal tissues. The expression of KIF2A mRNA was detected by RT-PCR. The mRNA and protein expression of KIF2A in cell line HO-8910 was detected by RT-PCR and Western blot after transfected by KIF2A-siRNA in vitro. After the transfection, the cell migration and invasion ability were observed by scratch test and transwell experiments. Result: The expression of KIF2A mRNA and protein in HO-8910 was significantly lower than that in normal ovarian tissue (P<0.05). The capacities of migration and invasion of HO-8910 was suppressed notably after the knockdown of KIF2A (P<0.05). Conclusion: KIF2A gene expression was increased in ovarian cancer, and knockdown of KIF2A gene can inhibit the migration and invasion of ovarian cancer cells. It suggested that KIF2A gene may be a new target for the development of ovarian cancer.

[Arthroscopic treatment of eldly with massive rotator cuff tear].

Objective: To investigate the surgical technique and clinical efficacy of arthroscopic treatment of the elderly patients with massive rotator cuff tear. Methods: From June 2012 to June 2015, thirty-six patients with massive rotator cuff tear were treated with arthroscopic and followed up. The visual analog scale(VAS)pain score, University of California Los Angeles (UCLA) scores, Constant scores and American Shoulder and Elbow Surgeons scale(ASES)were used before and after the arthroscopic surgery. Results: All the patients were followed up for average of 18.5 (12 to 30) months.Before arthroscopic surgery, the VAS, UCLA, Constant, ASES were (6.1±2.2), (10.6±4.3), (40.3±10.5) and (28.8±18.5) points; the average flexion of the shoulder was (76.5±42.6)°, the average abduction of the shoulder was (72.4±35.2)°, the average external rotation of the shoulder was(26.6±22.2)° and the average internal rotation of the shoulder was (20.2±6.2)° respectively.These scores were improved to (1.4±1.2), (30.4±5.2), (82.6±12.6), and (78.8±22.6) points, the average flexion of the shoulder was improved to (152.8±25.6)°, the average abduction of the shoulder was improved to (120.6±32.8)°, the average external rotation of the shoulder was improved to (42.6±16.2)° and the average internal rotation of the shoulder was improved to (38.4±5.6)° after one-year follow-up period.Improvement in these scores and range of motion(ROM) were significant difference(P<0.05). Conclusion: Arthroscopic repair can effectively treat the eldly patient with massive rotator cuff tear and obviously improve the function of shoulder joint. The surgery has a clinical application value.

Characterization and effects of miR-21 expression in esophageal cancer.

The aim of this study was to investigate the expression of miR-21 in esophageal cancer and the impact of miR-21 on apoptosis, invasion, and the expression of target genes in esophageal cancer cells. Fluorescence quantitative polymerase chain reaction analysis was used to detect the expression of miR-21 in human esophageal tissues, adjacent tissues, and an esophageal cancer cell line (TE-13). The antisense miR-21 oligonucleotide was generated commercially using the solid-phase chemical synthesis method. Transient transfection was used to transfect esophageal cancer cells (TE-13 antisense and TE-13 control cells). Flow cytometry and Transwell cell assays were used to detect the apoptosis and invasion of esophageal cancer cells, respectively. The western blot method was used to detect the expression of PTEN, PDCD4, and K-ras proteins. These analyses determined that mir-21 expression significantly increased in esophageal cancer tissues and in TE-13 cells, and that this phenomenon was not associated with staging or lymph node metastasis. The apoptosis rate of TE-13 control cells was lower than that of antisense TE-13 cells indicating an enhanced invasive ability. In tissues adjacent to esophageal cancer and in TE-13 antisense cells, the expression of PTEN and PDCD4 was found to be higher than that in the control group, whereas the expression of K-ras showed the opposite pattern. Together, these results suggest that miR- 21 might be involved in the development and metastasis of esophageal cancer, through interaction with its PDCD4 and K-ras target genes.

Association of miR-21 with esophageal cancer prognosis: a meta-analysis.

The present study aimed to explore the relationship between miRNA expression and survival in patients with esophageal cancer (EC) using meta-analysis. We searched PubMed, EMBASE, CNKI, Wanfang, and ISI Web of Science databases without time restrictions, and extracted relevant data, such as the name of first author, publication year, age, gender, number of case, etc. from the studies included. We calculated the pooled hazard ratios (HRs) using the RevMan 5.2 software. A total of five studies involving 504 subjects were included in the meta-analysis, with the purpose of analyzing the association of miRNA-21 expression with EC prognosis. The pooled HR of elevated versus decreased miR-21 expression in EC was 1.87 [95% confidence interval (CI): 1.37-2.55, P < 0.001], with elevated miR-21 expression being associated with poorer prognosis for patients with EC. Our results support a prognostic role for miR-21 in EC.

Alterations of orexinergic and melanin-concentrating hormone neurons in experimental sleeping sickness.

Human African trypanosomiasis or sleeping sickness is a severe, neglected tropical disease caused by the extracellular parasite Trypanosoma brucei. The disease, which leads to chronic neuroinflammation, is characterized by sleep and wake disturbances, documented also in rodent models. In rats and mice infected with Trypanosoma brucei brucei, we here tested the hypothesis that the disease could target neurons of the lateral hypothalamus (LH) containing orexin (OX)-A or melanin-concentrating hormone (MCH), implicated in sleep/wake regulation. In the cerebrospinal fluid of infected rats, the OX-A level was significantly decreased early after parasite neuroinvasion, and returned to the control level at an advanced disease stage. The number of immunohistochemically characterized OX-A and MCH neurons decreased significantly in infected rats during disease progression and in infected mice at an advanced disease stage. A marked reduction of the complexity of dendritic arborizations of OX-A neurons was documented in infected mice. The evaluation of NeuN-immunoreactive neurons did not reveal significant neuronal loss in the LH of infected mice, thus suggesting a potential selective vulnerability of OX-A and MCH neurons. Immunophenotyping and quantitative analysis showed in infected mice marked activation of microglial cells surrounding OX-A neurons. Day/night oscillation of c-Fos baseline expression was used as marker of OX-A neuron activity in mice. In control animals Fos was expressed in a higher proportion of OX-A neurons in the night (activity) phase than in the day (rest) phase. Interestingly, in infected mice the diurnal spontaneous Fos oscillation was reversed, with a proportion of OX-A/Fos neurons significantly higher at daytime than at nighttime. Altogether the findings reveal a progressive decrease of OX-A and MCH neurons and dysregulation of OX-A neuron diurnal activity in rodent models of sleeping sickness. The data point to the involvement of these peptidergic neurons in the pathogenesis of sleep/wake alterations in the disease and to their vulnerability to inflammatory signaling.

Effects of metallothionein-3 and metallothionein-1E gene transfection on proliferation, cell cycle, and apoptosis of esophageal cancer cells.

Metallothionein (MT)-3 has cell growth inhibitory activity, and is the only currently known MT subtype with unique physiological functions. The expression levels of MT-1E, a subtype of MT-1, were positively correlated with the degree of esophageal cancer malignancy. The present study aimed to investigate the effects of MT-3 and MT-1E gene transfection on the proliferation, cell cycle, and apoptosis of esophageal cancer cells. The cationic liposome method was used to transfect the esophageal cancer strains Eca-109 and TE13. Reverse transcription-polymerase chain reaction was used to detect target gene expression, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction was applied to detect cell proliferation, and flow cytometry was used for cell cycle and apoptosis detection. Esophageal cancer cells with MT-3 and MT-1E gene transfection showed high expression of the foreign target gene and mRNA. Cells with MT-3 gene transfection showed markedly inhibited proliferation (P < 0.05), a significantly higher proportion of cells in the G0/G1 phase (P < 0.05), a significantly lower proportion of cells in the S phase (P < 0.05), and a significantly increased apoptosis rate (P < 0.05). Cells with MT-1E gene transfection did not show significant changes in proliferation, cell cycle, or apoptosis rate (P > 0.05). Therefore, the upregulation of MT-3 gene expression can inhibit esophageal cancer cell proliferation and induce apoptosis, which may be achieved by blocking the tumor cell growth cycle, whereas effects of the MT-1E gene on the proliferation of esophageal cancer cells were not evident.

Protection against titanium particle-induced osteoclastogenesis by cyclooxygenase-2 selective inhibitor.

Wear particle-induced osteoclastogenesis is the most common cause of aseptic loosening in total joint arthroplasty. Although cyclooxygenase (COX)-2, an inducible regulator of prostaglandin E2 (PGE2) synthesis, is known to be involved in osteoclast differentiation, its effect on osteoclastogenesis in response to wear particles remains unclear. In this study, we investigated the role of COX-2 in the regulation of osteoclast differentiation in the osteoclast precursor cell line RAW264.7 stimulated with titanium (Ti) particles. The results showed COX-2 expression in the early stages of RAW264.7 differentiation when stimulated with receptor activator of nuclear factor kappa B ligand (RANKL) and Ti particles. Blockade of COX-2 by celecoxib, a COX-2 selective inhibitor, effectively reduced the expression of PGE2 and inhibited differentiation of RAW264.7 cells into tartrate-resistant acid phosphatase-positive (TRAP+) osteoclastic cells. Quantitative real-time polymerase chain reaction revealed that celecoxib inhibited mRNA expression of RANK, cathepsin K (CPK), TRAP, and the nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells stimulated by Ti particles and RANKL. Moreover, exogenous PGE2 reversed the inhibitory effects of celecoxib. These results provide direct evidence that COX-2 dependent PGE2 induced by RANKL and Ti particles is required for osteoclastogenesis and suggests that reduced production of PGE2 by inactivation of COX-2 would provide a promising therapeutic target for the treatment of osteoclastogenesis induced by wear particles.

Thiothymidine combined with UVA as a potential novel therapy for bladder cancer.

BACKGROUND: Thiothymidine (S(4)TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S(4)TdR and UVA could be an effective treatment for bladder cancer. METHODS: Uptake and incorporation of S(4)TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S(4)TdR and UVA was investigated in an orthotopic model of bladder cancer in rats. RESULTS: Thiothymidine (200 µM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S(4)TdR (10-200 µM) and UVA (1-5 kJ m(-2)) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S(4)TdR into DNA (up to 20-fold at IC(5)) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S(4)TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated. CONCLUSION: These data indicate that the combination of S(4)TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components.

Inhibition of titanium particle-induced inflammatory osteolysis through inactivation of cannabinoid receptor 2 by AM630.

Wear particle could induce inflammatory osteolysis and is the primary pathological factor for aseptic loosening. Although it is known that cannabinoid receptor 2 (CB2) inhibits osteoclast differentiation, the effect on inflammatory osteolysis induced by wear particles remains unclear. This study examined the effect of CB2 in the regulation of osteoclast differentiation in a murine macrophage cell line (RAW264.7), which has been shown to be stimulated by titanium (Ti) particles and receptor activator of the NF-kappaB ligand (RANKL). Results showed that CB2 expression in RAW cells cultured with Ti particles and RANKL. CB2 inactivation by AM630, a CB2 selective antagonist, effectively inhibited osteoclastogenesis in the differentiation medium system. AM630 treatment (> or =100 nM) significantly reduced the number of tartrate-resistant acid phosphatase-positive cells when compared with the control. Real-time reverse transcription polymerase chain reaction analysis revealed that AM630 (100 nM) inhibited mRNA expression of RANK and cathepsin K in RAW cells stimulated by Ti particles and RANKL. Moreover, enzyme-linked immunosorbent assay showed that AM630 (100 nM) reduced protein expression of interleukin-1beta and tumor necrosis factor-alpha in RAW cells cultured with Ti particles. In addition, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide revealed that AM630 had no toxic effect on RAW cells. These results suggested that CB2 inactivation by AM630 could provide a promising therapeutic target for treating or preventing aseptic loosening.

Beneficial effect of recombinant human growth hormone on the intestinal mucosa barrier of septic rats

The objective of the present study was to investigate the effects of recombinant human growth hormone (rhGH) on the intestinal mucosa barrier of septic rats and explore its possible mechanism. Female Sprague-Dawley rats were randomized into three groups: control, Escherichia coli-induced sepsis (S) and treatment (T) groups. Groups S and T were subdivided into subgroups 1d and 3d, respectively. Expression of liver insulin-like growth factor-1 (IGF-1) mRNA, Bcl-2 and Bax protein levels and the intestinal Bax/Bcl-2 ratio, and plasma GH and IGF-1 levels were determined. Histological examination of the intestine was performed and bacterial translocation was determined. rhGH significantly attenuated intestinal mucosal injuries and bacterial translocation in septic rats, markedly decreased Bax protein levels, inhibited the decrease of Bcl-2 protein expression and maintained the Bax/Bcl-2 ratio in the intestine. rhGH given after sepsis significantly improved levels of plasma GH (T1d: 1.28 ± 0.24; T3d: 2.14 ± 0.48 æg/L vs S1d: 0.74 ± 0.12; S3d: 0.60 ± 0.18 æg/L; P < 0.05) and IGF-1 (T1d: 168.94 ± 65.67; T3d: 201.56 ± 64.98 æg/L vs S1d: 116.72 ± 13.96; S3d: 107.50 ± 23.53 æg/L; P < 0.05) and expression of liver IGF-1 mRNA (T1d: 0.98 ± 0.20; T3d: 1.76 ± 0.17 vs S1d: 0.38 ± 0.09; S3d: 0.46 ± 0.10; P < 0.05). These findings indicate that treatment with rhGH had beneficial effects on the maintenance of the integrity of the intestinal mucosa barrier in septic rats.

Cytokine-induced activation of glial cells in the mouse brain is enhanced at an advanced age.

Numerous neurological diseases which include neuroinflammatory components exhibit an age-related prevalence. The aging process is characterized by an increase of inflammatory mediators both systemically and in the brain, which may prime glial cells. However, little information is available on age-related changes in the glial response of the healthy aging brain to an inflammatory challenge. This problem was here examined using a mixture of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha, which was injected intracerebroventricularly in young (2-3.5 months), middle-aged (10-11 months) and aged (18-21 months) mice. Vehicle (phosphate-buffered saline) was used as control. After a survival of 1 or 2 days (all age groups) or 4 days (young and middle-aged animals), immunohistochemically labeled astrocytes and microglia were investigated both qualitatively and quantitatively. In all age groups, astrocytes were markedly activated in periventricular as well as in deeper brain regions 2 days following cytokine treatment, whereas microglia activation was already evident at 24 h. Interestingly, cytokine-induced activation of both astrocytes and microglia was significantly more marked in the brain of aged animals, in which it included numerous ameboid microglia, than of younger age groups. Moderate astrocytic activation was also seen in the hippocampal CA1 field of vehicle-treated aged mice. FluoroJade B histochemistry and the terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling technique, performed at 2 days after cytokine administration, did not reveal ongoing cell death phenomena in young or aged animals. This indicated that glial cell changes were not secondary to neuronal death. Altogether, the findings demonstrate for the first time enhanced activation of glial cells in the old brain, compared with young and middle-aged subjects, in response to cytokine exposure. Interestingly, the results also suggest that such enhancement does not develop gradually since youth, but appears characterized by relatively late onset.

The influence of developmental period of aluminum exposure on synaptic plasticity in the adult rat dentate gyrus in vivo.

Previous studies from our group have demonstrated that chronic aluminum exposure from parturition throughout life impairs both long-term potentiation (LTP) and long-term depression (LTD) of the excitatory postsynaptic potential (EPSP) slope and reduces the population spike (PS) amplitude in the rat dentate gyrus in vivo. The present study sought to extend these findings by evaluating the developmental periods critical for aluminum-induced impairment of synaptic plasticity. Rats were exposed to aluminum (gestational, lactational and postlactational) through drinking 0.3% aluminum chloride in water over different developmental intervals: (1) prenatal exposure; (2) beginning from birth and terminating at weaning; (3) beginning at weaning throughout life; (4) beginning at birth and continuing throughout life. As adults (postnatal day 80-100), field potentials were measured in the dentate gyrus of hippocampus in response to stimulation applied to the lateral perforant path. The results showed: (1) Prenatal aluminum exposure had no effect on the magnitude of LTP as measured by the EPSP slope and LTD as measured for the PS amplitude, while it had a small effect on the magnitude of LTP as measured for the PS amplitude and LTD as measured by the EPSP slope. (2) Lactational, postlactational and throughout life exposure to aluminum impaired both LTP and LTD of the EPSP slope and PS amplitude, except that LTD of PS amplitude was not significantly changed in animals postlactationally exposed. (3) Aluminum exposure from parturition throughout life caused the greatest impairment of the range of synaptic plasticity, while prenatal aluminum exposure caused the least. From these results we conclude that the lactational period was the most susceptible to aluminum-induced impairment of synaptic plasticity and that chronic aluminum exposure from parturition throughout life is extremely disruptive to synaptic plasticity and should be avoided.

Photoactivation of DNA thiobases as a potential novel therapeutic option.

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.

Distinguishing malignant from normal oral tissues using FTIR fiber-optic techniques.

Oral tissue samples were studied using mid-IR fiber-optic attenuated total reflectance spectroscopy and other spectral techniques. The 1745 cm(-1) band, which is assigned to the ester group (C==O) vibration of triglycerides, is a reliable marker that is present in normal tissues but absent or a weak band in malignant oral tissues. Other bands such as C--H stretching bands and the amide bands are also helpful in distinguishing malignant tissues from normal tissues. Subtraction spectra confirmed the above conclusion. In addition, Raman spectroscopic measurements were in agreement with the results observed from FTIR spectra.

Vasopressin reverses aluminum-induced impairment of synaptic plasticity in the rat dentate gyrus in vivo.

Aluminum (Al), an important neurotoxin, contributes to a variety of cognitive dysfunction and mental diseases. Previous studies have demonstrated that Al impairs hippocampal long-term potentiation (LTP) in vitro and in vivo. In the present study, both LTP and LTD (long-term depression) were recorded in the same animal to investigate the Al-induced impairment of synaptic plasticity. Another aim of the present research was to verify whether the impairment of synaptic plasticity induced by Al could be reversed by vasopressin (VP) treatment. Neonatal Wistar rats were exposed to Al from parturition through adulthood (pre- and post-weaning) by the drinking of 0.3% aluminum chloride (AlCl(3)) solution. The input-output (I/O) function, paired-pulse reaction (PPR), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (60-90 days) in response to stimulation applied to the lateral perforant path. The results showed: (1) Al reduced the amplitudes of both EPSP LTP (control: 132+/-7%, n=7; Al-exposed: 115+/-10%, n=8, P<0.05) and PS LTP (control: 242+/-18%, n=7; Al-exposed: 136+/-7%, n=8, P<0.01) significantly. The amplitudes of EPSP LTD (control: 82+/-6%, n=7; Al-exposed: 92+/-7%, n=8, P<0.05) and PS LTD (control: 81+/-4%, n=7; Al-exposed: 98+/-5%, n=8, P<0.05) were also decreased by Al treatment. The Al-induced impairments of PS LTP and PS LTD were more serious than that of EPSP LTP and EPSP LTD. (2) In control rats, VP had an increase in the PS LTP amplitude (control: 242+/-18%, n=7; control+VP: 358+/-23%, n=6, P<0.01), while it had no significant effects on PS LTD (control: 81+/-4%, n=7; control+VP: 76+/-7%, n=6, P>0.05). (3) In Al-exposed rats, VP had a significant increase in the amplitudes of both PS LTP (Al-exposed: 136+/-7%, n=8, Al-exposed+VP: 255+/-16%, n=6, P<0.01) and PS LTD (Al-exposed: 98+/-5%, n=8; Al-exposed+VP: 81+/-6%, n=6, P<0.05). After the application of VP, the range of synaptic plasticity (PS LTP+PS LTD) in Al-exposed rats increased from 38% to 174%, which surpassed that in control rats (161%). It was suggested that VP could reverse Al-induced impairment of synaptic plasticity and might be an effective medicine to cure Al-induced neurological disorders.