Long-term Potentiation of NMDA Receptor-mediated EPSP in Guinea-pig Hippocampal Slices

Hippocampal slices from guinea-pigs were used to examine the long-term potentiation (LTP) of the N-methyl-d-aspartate (NMDA)-mediated excitatory postsynaptic potential (EPSP). Intracellular recordings were performed from CA1 pyramidal neurons in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 - 10 microM) and picrotoxin (50 microM). In these experimental conditions test stimuli applied at low frequency (0.1 Hz) to the Schaffer collateral - commissural pathway evoked a prolonged EPSP (150 - 200 ms). To obtain this CNQX-resistant EPSP, stimulus intensities had to be raised above the level required to evoke an EPSP of comparable amplitude in physiological solution. Tetanic stimulation (two trains of 100 Hz, 1 s every 20 s) led to a potentiation of the CNQX-resistant EPSP, and this potentiated response was abolished with d-(-)-2-amino-5-phosphonovaleric acid (50 microM). The potentiation of the NMDA receptor-mediated EPSP was more pronounced for strong than for weak test stimuli, and was suppressed when test EPSPs were evoked during membrane hyperpolarization. These results suggest that NMDA receptor-mediated responses can undergo LTP, and hence can contribute to the maintenance of LTP.     

The Scandinavian Multi-Infarct Dementia Trial: a double-blind, placebo-controlled trial on nimodipine in multi-infarct dementia

Vascular dementia is a major cause of mental and physical disability in Western countries. Treatment of vascular dementia is currently based on the recognition and control of vascular risk factors, while specific drugs have not been approved yet. The aim of the present multinational, double-blind, placebo-controlled study was to evaluate the safety and efficacy of nimodipine administered for as long as 26 weeks in improving cognition or slowing cognitive deterioration in patients defined as having multi-infarct dementia (DSM-III-R criteria). Two hundred and fifty-nine patients were included (128 nimodipine, 131 placebo), and 251 were available for the intention-to-treat analysis. No significant difference between drug-treated and placebo patients was noted on the Gottfries-Brane-Steen scale score (primary efficacy criterion), the remaining neuropsychological tests (Zahlen-Verbindungs-Test, Fuld-Object-Memory Evaluation, Word Fluency Test, Digit Span, Mini-Mental State Examination), and the functional scales (index of Activity of Daily Living, Instrumental Activity of Daily Living, Rapid Disability Scale, Clinical Dementia Rating), although the majority of changes were in favor of the active drug group. A lower incidence of cerebrovascular and cardiac events was observed in the nimodipine-treated patients in comparison with the placebo group. This study failed to show a significant effect of nimodipine on cognitive, social or global assessments in patients defined as affected by multi-infarct dementia according to the DSM-III-R criteria. A post-hoc analysis (presented in an accompanying paper) suggests that nimodipine may have a favorable effect in the subgroup of patients defined as affected by subcortical (small vessel) vascular dementia.     

Risk factors for urinary incontinence in women

OBJECTIVES: To review the epidemiological evidence on risk factors for urinary incontinence (UI) in women. METHODS: Using Medline and a manual search we identified the main papers published in English up to 1998. RESULTS: There is consistent evidence that the frequency of UI increases with age, but there is little information on the frequency of different types of UI in different age groups. With regard to other risk factors, there is a clinical consensus that vaginal delivery and, more in general, obstetric traumas are associated with UI, although epidemiological studies are not always consistent. Less defined is the role of race, menopausal status, history of gynecological surgery, body mass index, smoking, and coffee and alcohol consumption on the risk of UI. CONCLUSION: In the coming years, epidemiological research should focus particularly on the potential differences in the epidemiological characteristics of different types of UI in order to gain insight into the pathogenic mechanisms.     

Measuring complexity/level of care and appropriateness of resource use in intensive care units

BACKGROUND: Throughout the world, the cost of critical care medicine is increasing more than the overall health care cost. Thus, a higher attention to improve the efficiency of the use of ICU resources is indispensable. The objective of this study was the development of a simple and reliable tool for the evaluation of the appropriateness of ICU utilization. METHODS: Design: A repeated cross-sectional data collection was performed twice a week, during a 61-day study period. Setting: Twenty-three Italian general ICUs. Patients: All patients present in the 23 ICUs on the 17 index days. Interventions: On each index day, patients were checked for receiving ventilation/CPAP, pulmonary arterial pressure monitoring, intracranial pressure monitoring, vaso-active drug infusion and hemodialysis-ultrafiltration. Simultaneously, each ICU bed was assessed for its technical and personnel facilities in order to estimate the deliverable level of care. RESULTS: A total of 1250 patients were studied, for a total number of 7533 patient-days. The overall occupancy rate per ICU was 83.8% (-range: 54.4% to 96.1%). The high-level occupancy rate (rate of patients requiring high level of care and actually occupying high-facility beds) was 69.4% (range: 25.0% to 149.0%), while the corresponding low-level occupancy rate was 101.1% (range: 31.3% to 329.4%). CONCLUSIONS: Our model clearly showed up a certain degree of inappropriateness in the use of ICU resources. Most of the ICUs (69.6%) used a very large proportion of their high-facility beds for patients who did not need high-level care. Being very simple, our method could represent a useful tool for continuous evaluation of the appropriateness of resource utilization in the ICU.     

Involvement of the proliferating cell nuclear antigen (PCNA) in DNA repair induced by alkylating agents and oxidative damage in human fibroblasts

The involvement of the proliferating cell nuclear antigen (PCNA) in the process of DNA repair induced by alkylating agents or by oxidative damage was investigated in human quiescent fibroblasts by immunofluorescence and flow cytometry. Transition from soluble to the DNA-bound form of PCNA, was taken as the parameter to determine its involvement in repair DNA synthesis. Treatment with the alkylating agents methylmethane sulfonate and N-methyl-N'-nitro-N-nitrosoguanidine resulted in the rapid and dose-dependent increase in the nuclear binding of PCNA. Similar results were obtained with compounds such as hydrogen peroxide or tert-butyl hydroperoxide, which are known to induce oxidative DNA damage. Tert-butyl hydroperoxide may also generate malondialdehyde through a reaction of lipid peroxidation. This mutagenic and carcinogenic product has been previously shown to form adducts with DNA. Therefore, the possibility that tert-butyl hydroperoxide could induce DNA damage through this pathway was investigated by incubating cells directly in the presence of malondialdehyde. Such treatment resulted in an increase in immunofluorescence associated with nuclear-bound PCNA. The ability of oxidative and alkylating agents to induce the nuclear binding of PCNA was also assessed in proliferating cells. In these conditions, treatment with hydrogen peroxide or methylmethane sulfonate, resulted in an increase in nuclear-bound PCNA in the G1 and in the G2 + M compartments, but not in S phase. At longer times after treatment, PCNA immunostaining was reduced to basal levels, while an increase in nuclear binding of p21(waf1/cip1) protein was found in concomitance with cell-cycle arrest. These results indicate that agents inducing DNA base alterations in vivo, promote the nuclear binding of PCNA. These lines of evidence support the role of a PCNA-dependent reaction in the base excision repair system.      

Multimodality imaging assessment of meniscal ossicle

A case of meniscal ossicles occurring in the left knee of a 23-year-old woman is presented. Radiographs showed two calcified lesions at the posteromedial aspect of the knee which were interpreted as loose bodies. Sonography, computed tomography arthrography and magnetic resonance imaging showed the fragments within the posterior horn of the medial meniscus permitting a diagnosis of meniscal ossicles. These techniques can detect meniscal ossicles and exclude intra-articular loose bodies. Received: 7 February 2000 Revision requested: 14 March 2000 Revision received: 18 April 2000 Accepted: 24 April 2000     

Phytoestrogens possess a weak antioxidant activity on low density lipoprotein in contrast to the flavonoid quercetin in vitro in postmenopausal women.

BACKGROUND: Phytoestrogens are a family of plant-derived compounds with weak estrogenic and antiestrogenic properties. The antioxidant capacity of phytoestrogens has been proposed as one of the important mechanisms that explain their health benefits. OBJECTIVE: To determine the in vitro potency of three phytoestrogens, ubiquitous in food, (biochanin A, daidzein and genistein) as antioxidants of low density lipoprotein (LDL) and to compare them with the well-established antioxidant actions of estradiol and quercetin, an ubiquitous flavonoid which is found in high concentration in onions, tea and berries. METHODS: LDL was isolated by ultracentrifugation from the plasma of ten healthy postmenopausal women who were not on hormone therapy. Aliquots containing 0.5 mg of protein were incubated for 4 h with CuSO4 15 micromol/l to induce oxidative stress and with one of the five compounds studied: estradiol, quercetin, biochanin A, daidzein, and genistein, in doses of 0, 5, 15, 50, 500, 1000 and 2000 micromol/l. In addition, we studied the combined effect of estradiol 1 micromol/l plus quercetin 1 micromol/l, comparing their antioxidant action with that of each compound separately. Malonaldehyde (MDE nmol/ mg protein) was measured as a marker of LDL oxidation. RESULTS: Estradiol and quercetin induced a dose-dependent decrease in MDE concentration (p < 0.01). Comparing the areas under the curve, the antioxidant effect of quercetin was 8 times higher than the one observed with estradiol (p < 0.01). A 50% decrease in MDE was reached by quercetin at a concentration of 3.4 micromol/l, estradiol at 29 micromol/l, genistein at 280 micromol/l, biochanin at 1312 mmol/l and daidzein at 8007 mmol/l. Estradiol 1 micromol/l and quercetin 1 micromol/l did not modify MDE generation separately, but, when incubated combined, there was a significant decrease of MDE (p < 0.02). CONCLUSION: The phytoestrogens studied showed a weak antioxidant activity in vitro. The flavonoid quercetin, in contrast, showed the most potent antioxidant activity in vitro, higher than estradiol. Estradiol and quercetin showed additive antioxidant activity. We speculate that different compounds with variable antioxidant effects could amplify their antioxidant capacity when acting combined.