HIV: ageing, cognition and neuroimaging at 4-year follow-up.

OBJECTIVES: The aim of the study was to investigate the hypothesis of accelerated cognitive ageing in HIV-positive individuals using longitudinal assessment of cognitive performance and quantitative magnetic resonance imaging (MRI). METHODS: We assessed a broad cognitive battery and quantitative MRI metrics [voxel-based morphometry (VBM) and diffusion tensor imaging (DTI)] in asymptomatic HIV-positive men who have sex with men (15 aged 20-40 years and 15 aged ≥ 50 years), and HIV-seronegative matched controls (nine aged 20-40 years and 16 aged ≥ 50 years). RESULTS: Being HIV positive was associated with greater decreases in executive function and global cognition. Additionally, using DTI, we found that the HIV-positive group had a greater increase in mean diffusivity, but we did not find group differences in volume change using VBM. With respect to the HIV status by age group interaction, this was statistically significant for change in global cognition, with older HIV-positive individuals showing greater global cognitive decline, but there were no significant interaction effects on other measures. Lastly, change in cognitive performance was correlated with change in the DTI measures, and this effect was stronger for the HIV-positive participants. CONCLUSIONS: In the present study, we found some evidence for accelerated ageing in HIV-positive individuals, with a statistically significant HIV status by age group interaction in global cognition, although this interaction could not be explained by the imaging findings. Moreover, we also found that change in cognitive performance was correlated with change in the DTI measures, and this effect was stronger for the HIV-positive participants. This will need replication in larger studies using a similarly lengthy follow-up period.

Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013.

BACKGROUND: Although the incidence of severe local anaesthetic systemic toxicity (LAST) has been declining, the risk of LAST still remains. There are no national treatment guidelines for LAST in Finland. We performed a national survey of the occurrence of LAST and its treatment in 2011-2013. METHODS: A structured electronic questionnaire was sent to the anaesthesia department chiefs of all Finnish public hospitals (n = 45) in spring 2014. We collected information about the occurrence and outcome of LASTs and existence of treatment protocols. RESULTS: The questionnaire response rate was 100% covering approximately 95% of all regional anaesthesias managed by anaesthesiologists in Finnish hospitals. The total number of regional anaesthesias, excluding spinal anaesthesia, performed by anaesthesiologists was approximately 211,700 during the survey period. Fifteen cases of LAST were reported (0.7 : 10,000); all patients recovered without negative sequelae. Fourteen patients, in five of whom ultrasound guidance had been applied, developed central nervous system toxicity symptoms and only one cardiac symptoms. Lipid emulsion was given to this latter patient, and to four of the other 14. The relative risk (95% confidence intervals) for occurrence of LAST in non-academic hospital vs. university hospitals was 3.3 (1.0-10.3; P = 0.04). Treatment protocols for LAST included lipid emulsion in 47% of the departments. CONCLUSIONS: The incidence of LAST in Finland is very low. Several departments have adopted lipid emulsion treatment for LAST despite lack of national recommendations and knowledge of the possible mechanism of action.

Serious complications associated with spinal and epidural anaesthesia in Finland from 2000 to 2009.

BACKGROUND: Analyses of closed claims provide insight into the characteristics of rare complications. Serious complications related to spinal and epidural blocks are relatively rare. In Finland, all malpractice cases are primarily handled by the Patient Insurance Centre (PIC) within a 'no-fault scheme'. METHODS: All claims attributed to central neuraxial blocks and settled by the PIC during the period, 2000-2009 were analysed. The number of spinal and epidural procedures performed during this time was estimated based on a questionnaire sent to all surgical hospitals in Finland in 2009, surveying the numbers and types of neuraxial blocks carried out in 2008. RESULTS: During the study period, 216 closed claims were flagged with spinal or epidural blocks. In 41 of 216 instances, the neuraxial block was apparently responsible for a serious (fatal or critical or lasting >1 year) complication. These included six fatalities and 13 epidural haematomata (two in conjunction with fondaparinux, three with excessive doses of low molecular weight heparins, six where present guidelines were not observed). Fatalities occurred in 1 : 775,000 spinals for surgery, 1 : 62,000 in epidurals for surgery or acute pain relief, 1 : 12,000 epidurals for chronic pain relief, 1 : 89,000 in combined spinal and epidural for surgery, and 1 : 144,000 epidurals for labour. The incidence of neuraxial haematoma after spinal block was 1 : 775,000, that for epidural block 1 : 26,400, and in the case of combined spinal and epidural, 1 : 17,800. Irrespective of the method of neuraxial technique, the majority of patients suffering serious complications were the elderly having comorbidities. CONCLUSIONS: In this closed claims analysis, major problems related to neuraxial blocks were rare. Epidural or a combined spinal and epidural technique resulted in more complications than did spinal procedure.

Chloroprocaine 40 mg produces shorter spinal block than articaine 40 mg in day-case knee arthroscopy patients.

BACKGROUND: Articaine and chloroprocaine have recently gained interest as short-acting spinal anaesthetics. Based on previous work comparing articaine 60 mg with chloroprocaine 40 mg, we hypothesised that articaine 40 mg and chloroprocaine 40 mg would produce similar spinal anaesthesa regarding block onset, maximal spread, and recovery. METHODS: In this randomised, double-blind study, adult patients (18-70 years, American Society of Anaesthesiologists physical status I-III, BMI < 36 kg/m(2) ) scheduled for day-case knee arthroscopy received either articaine 40 mg (20 mg/ml) (group A40, n = 16) or chloroprocaine 40 mg (20 mg/ml) (group C40, n = 18) intrathecally. Telephone interviews were performed on the first and seventh postoperative day to disclose possible side effects, e.g. transient neurological symptoms (TNS). RESULTS: The groups were comparable regarding demographic data, onset and maximal spread of spinal anaesthesia, and duration of surgery. Surgery could be performed successfully under spinal anaesthesia except once in A40 (insufficient block) and once in C40 (prolonged surgery). Complete recovery was significantly slower in A40 vs. C40 for both motor block (105 (94/120) vs. 75 (71/90) min) [P < 0.001, Mann-Whitney U-test (MW-U)] and sensory block [135 (109/176) vs. 105 min (90/124)] (P < 0.02, MW-U), respectively [data are median (25th/75th percentiles)]. One patient from A40 showed mild TNS. CONCLUSION: Both A40 and C40 provided mainly adequate spinal anaesthesia for day-case knee arthroscopy. While onset and maximal spread were comparable, the recovery from motor block was clearly faster with chloroprocaine after equivalent doses of spinal articaine and chloroprocaine.

Local infiltration analgesia with levobupivacaine compared with intrathecal morphine in total hip arthroplasty patients.

BACKGROUND: Recently, local infiltration analgesia (LIA) has been promoted for pain control after total hip arthroplasty (THA). We hypothesized that LIA would offer equal analgesic efficacy but less adverse effects, e.g., nausea and vomiting, when compared with an established regimen [intrathecal morphine (it-M)] after THA. METHODS: This randomized controlled trial comprised 60 patients undergoing THA under spinal anaesthesia. For LIA, the surgeon administered levobupivacaine, ketorolac and epinephrine at the surgical site intraoperatively. LIA patients received a LIA top-up through a wound catheter on the morning of the 1st post-operative day (POD). In group it-M, 0.1 mg morphine was given together with the spinal anaesthetic. Study parameters included pain scores, vital parameters and side effects, e.g., post-operative nausea and vomiting (PONV). Besides, levobupivacaine plasma concentrations were determined in 10 LIA patients. RESULTS: The median (25th/75th percentiles) rescue oxycodone demand differed significantly with LIA 15 (10/25) mg vs. 8.5 (1.5/15) mg with it-M (P < 0.006) during the day of surgery, but not anymore on 1st or 2nd POD. The LIA top-up had no effect. However, both analgesic regimens resulted in comparable pain scores and patient satisfaction. PONV incidence and medication did not vary significantly. LIA offered certain advantages regarding early post-operative mobilization. Maximum levobupivacaine plasma concentrations (229-580 ng/ml) remained under the toxic level. CONCLUSIONS: While LIA might enable earlier mobilization after THA, it was not associated with less nausea as compared with it-M. Less rescue oxycodone was given early after it-M, but urinary retention was more common in that group.

Neuraxial techniques in patients with pre-existing back impairment or prior spine interventions: a topical review with special reference to obstetrics.

Many anaesthetists consider neurological disorders of all kinds as a contraindication for regional anaesthesia particularly for neuraxial techniques. This hesitation is partly rooted in fears of medicolegal problems but also in the heterogeneous literature. Therefore, the present topical review is an attempt to describe the feasibility and the risks of neuraxial techniques in patients with spinal injury, anatomical compromise, chronic back pain or previous spinal interventions, ranging from 'minor' types like epidural blood patches to major surgery such as Harrington fusions. Most reviews and case reports were describing experiences in obstetrics as these patients are more likely to insist on neuraxial blocks. In the acute phase of new neurologic injury, general anaesthesia may be the technique of choice to prevent further haemodynamic and respiratory deterioration. After the acute phase, current evidence is mostly reassuring with respect to the risks of neuraxial blocks as they may even be recommendable in some conditions. Ultrasound technology may be of additional help to increase the success rate. A careful pre-operative examination remains mandatory, while patients should be sufficiently informed about technical aspects and possible relapses or progression of their disease. When necessary, patients should have additional technical and clinical examinations as close as possible to surgery to establish the actual pre-operative status. Most patients may benefit more from spinal techniques rather than from less reliable epidural ones. High concentrations and volumes of local anaesthetics should be avoided at all times, especially in patients with nerve compression, large disc herniation or spinal stenosis.

Chloroprocaine vs. articaine as spinal anaesthetics for day-case knee arthroscopy.

BACKGROUND: Chloroprocaine and articaine have recently gained interest as short-acting spinal anaesthetics. They have not, however, previously been compared in an ambulatory surgery setting. METHODS: In this double-blind, randomised, controlled trial, adult patients (≤65 years, ASA I-II, body mass index<36 kg/m2) underwent day-case knee arthroscopy under spinal anaesthesia with either 40 mg of plain chloroprocaine (20 mg/ml) (group C40; n=39) or 60 mg of plain articaine (40 mg/ml) (group A60; n=39). Study parameters included the onset, degree, and regression of both sensory and motor block. Standardised telephone interviews on the first and seventh post-operative day were aimed at detecting any untoward sequelae, e.g., transient neurologic symptoms (TNSs). RESULTS: The groups were comparable regarding demographic data, onset and maximal spread of spinal anaesthesia, and duration of surgery. All arthroscopies were performed successfully under spinal anaesthesia, except for one patient (C40, unforeseen delay in the start of surgery). The duration of sensory block≥dermatome L1 was significantly shorter in C40 vs. A60. Correspondingly, complete recovery was significantly faster (P<0.0001, Mann-Whitney U-test) in C40 vs. A60 for both motor [75 (60/90) vs. 135 (105/150) min] and sensory [105 (105/135) vs. 165 (135/180) min] block, respectively [data are median (25th/75th percentiles)]. No TNSs were noted. CONCLUSIONS: Both anaesthetics used provided a rapid onset of spinal anaesthesia of about 1 h and were satisfactory for day-case knee arthroscopy. Recovery, however, was significantly faster in group C40. The data add to earlier results that TNSs seem to be uncommon after spinal chloroprocaine and articaine.

Unilateral spinal anaesthesia for outpatient surgery: a comparison between hyperbaric bupivacaine and bupivacaine-clonidine combination.

BACKGROUND: Low-dose hyperbaric bupivacaine has been used to produce unilateral spinal anaesthesia for outpatient surgery. Unilateral spinal anaesthesia is associated with reduction of hypotension, faster recovery and increased patient satisfaction. Small doses of clonidine have shown effectiveness in intensifying spinal anaesthesia. We investigated the effect of adding 15 microg of clonidine to 5 mg hyperbaric bupivacaine on unilaterality. METHODS: Sixty patients undergoing outpatient knee arthroscopy were randomly allocated to receive either 1.2 ml (6 mg) of hyperbaric bupivacaine or a 1.2 ml solution containing 1.0 ml (5 mg) hyperbaric bupivacaine, 0.1 ml (75 microg) clonidine and 0.1 ml sterile water. The motor block was assessed by a modified Bromage scale and the sensory block by a pinprick. RESULTS: There was a significant difference in the spread of anaesthesia between the operated and contralateral sides in both groups. Seventy-seven per cent of the blocks were unilateral in group B and 73% in group B-C. There was no significant difference between the groups, in unilaterality. The motor block was prolonged in group B-C but it did not affect home-readiness. Patients receiving clonidine needed more vasopressors. There was a significant difference in blood pressures between the groups, being lower in group B-C after 1 h 45 min. CONCLUSION: Using 5 mg hyperbaric bupivacaine with 15 microg of clonidine, the unilaterality can be achieved and spinal anaesthesia intensified without affecting home-readiness. More vasopressors are needed in the beginning, but after the surgery patients experienced less pain.

Spinal 2-chloroprocaine: effective dose for ambulatory surgery.

BACKGROUND: There is an interest in finding a safe, short-acting spinal anaesthetic, suitable for ambulatory surgery. In this prospective study, we evaluated the effective dose of plain 2-chloroprocaine (2-CP) for lower limb surgery, including knee arthroscopy and saphenectomy. METHODS: Sixty-four ASA physical status I-III patients undergoing elective lower limb surgery were randomly allocated to one of the four local anaesthetic groups for spinal anaesthesia in a double-blind manner. The patients (n=16 patients in each group) received 35, 40, 45 or 50 mg of 10 mg/ml isobaric 2-CP. RESULTS: In all patients, anaesthesia was sufficient for the planned surgery. The median peak block height (T9) was similar in all four groups (P=0.66). Time to complete sensory block regression was faster in the 35 mg group (111 min, mean) and in the 40 mg group (108 min) than in the 50 mg group (134 min, P=0.005). No differences in time to complete motor block regression were observed (P=0.3). Home discharge time was faster in the 35 mg group (123 min) and in the 40 mg group (122 min) than in the 50 mg group (165 min, P=0.001). No complications related to spinal anaesthesia were observed and no transient neurologic symptoms (TNS) were reported at the 3-day follow-up. CONCLUSION: Spinal 2-CP, 10 mg/ml 35, 40, 45 and 50 mg provide reliable sensory and motor block for ambulatory surgery, while reducing the dose of 2-CP to 35 and 40 mg resulted in a spinal block of faster ambulation.

Semi-automated International Cartilage Repair Society scoring of equine articular cartilage lesions in optical coherence tomography images.

BACKGROUND: Arthroscopic optical coherence tomography (OCT) is a promising tool for the detailed evaluation of articular cartilage injuries. However, OCT-based articular cartilage scoring still relies on the operator's visual estimation. OBJECTIVES: To test the hypothesis that semi-automated International Cartilage Repair Society (ICRS) scoring of chondral lesions seen in OCT images could enhance intra- and interobserver agreement of scoring and its accuracy. STUDY DESIGN: Validation study using equine cadaver tissue. METHODS: Osteochondral samples (n = 99) were prepared from 18 equine metacarpophalangeal joints and imaged using OCT. Custom-made software was developed for semi-automated ICRS scoring of cartilage lesions on OCT images. Scoring was performed visually and semi-automatically by five observers, and levels of inter- and intraobserver agreement were calculated. Subsequently, OCT-based scores were compared with ICRS scores based on light microscopy images of the histological sections of matching locations (n = 82). RESULTS: When semi-automated scoring of the OCT images was performed by multiple observers, mean levels of intraobserver and interobserver agreement were higher than those achieved with visual OCT scoring (83% vs. 77% and 74% vs. 33%, respectively). Histology-based scores from matching regions of interest agreed better with visual OCT-based scoring than with semi-automated OCT scoring; however, the accuracy of the software was improved by optimising the threshold combinations used to determine the ICRS score. MAIN LIMITATIONS: Images were obtained from cadavers. CONCLUSIONS: Semi-automated scoring software improved the reproducibility of ICRS scoring of chondral lesions in OCT images and made scoring less observer-dependent. The image analysis and segmentation techniques adopted in this study warrant further optimisation to achieve better accuracy with semi-automated ICRS scoring. In addition, studies on in vivo applications are required.

Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy.

The choice of the appropriate model and parameter set in determining the relation between the incidence of radiation pneumonitis and dose distribution in the lung is of great importance, especially in the case of breast radiotherapy where the observed incidence is fairly low. From our previous study based on 150 breast cancer patients, where the fits of dose-volume models to clinical data were estimated (Tsougos et al 2005 Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy Phys. Med. Biol. 50 3535-54), one could get the impression that the relative seriality is significantly better than the LKB NTCP model. However, the estimation of the different NTCP models was based on their goodness-of-fit on clinical data, using various sets of published parameters from other groups, and this fact may provisionally justify the results. Hence, we sought to investigate further the LKB model, by applying different published parameter sets for the very same group of patients, in order to be able to compare the results. It was shown that, depending on the parameter set applied, the LKB model is able to predict the incidence of radiation pneumonitis with acceptable accuracy, especially when implemented on a sub-group of patients (120) receiving [see text]|EUD higher than 8 Gy. In conclusion, the goodness-of-fit of a certain radiobiological model on a given clinical case is closely related to the selection of the proper scoring criteria and parameter set as well as to the compatibility of the clinical case from which the data were derived.

Hypertriglyceridemia in different degrees of glucose intolerance in a Finnish population-based study.

OBJECTIVE: To determine the prevalence of hypertriglyceridemia and the mean serum triglyceride concentrations in different degrees of glucose tolerance--non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). In addition, we analyzed the correlates of serum triglyceride concentration to explain why it is more prevalent in diabetic subjects. RESEARCH DESIGN AND METHODS: This study was a cross-sectional survey of 4000 people aged 45-64 yr randomly drawn from the population register of the Finnish population of the provinces of North Karelia and Kuopio in eastern Finland and Turku/Loimaa area in southwestern Finland and stratified by four 10-yr age- and sex groups. The final material comprised 96 subjects with NIDDM, 102 subjects with IGT, and 323 subjects with normal glucose tolerance classified on the basis of two 2-h oral glucose tolerance tests. The prevalence of hypertriglyceridemia by the glucose tolerance status and the variation in serum triglycerides associated with selected life-style and biochemical factors were executed as the main outcome measures. RESULTS: The prevalence of hypertriglyceridemia (greater than or equal to 2.3 mM) was 47.6% (95% confidence interval [CI] 32.5-62.7%) in NIDDM men, 21.9% (95% CI 7.6-36.2%) in IGT men, and 15.4% (95% CI 9.3-21.5%) in NGT. In women, hypertriglyceridemia was found in 51.9% (95% CI 38.6-65.2%) among those with NIDDM, 25.7% (95% CI 15.5-35.9%) among those with IGT, and 10.7% (95% CI 6.3-15.1%) in women with NGT. After adjusting for body mass index (BMI) and age, the difference in the prevalence of hypertriglyceridemia between the glucose tolerance groups remained significant in both men (P = 0.008) and women (P = 0.0001). High serum total cholesterol, high BMI, high waist-hip ratio, and low high-density lipoprotein (HDL) cholesterol were significantly associated with high serum triglycerides in all glucose tolerance groups. No synergistic effect between these parameters and glucose tolerance status was found. In multiple linear regression analyses, fasting plasma insulin, diabetes status, and serum uric acid were significant predictors of serum triglyceride concentration after taking into account age, BMI, and HDL and total cholesterol. The association between BMI and serum triglycerides in the regression analysis was significant only when plasma insulin was not included in the model. CONCLUSIONS: Hypertriglyceridemia is common in subjects with NIDDM and IGT and is often associated with low HDL cholesterol, high total cholesterol, hyperinsulinemia, and elevated serum uric acid concentration.

Quality control in health care: an experiment in radiotherapy planning for breast cancer patients after mastectomy.

PURPOSE: The importance of evaluating and improving quality in clinical practice is now generally acknowledged. In this study we estimated different sources of variation in radiotherapy planning for breast cancer patients after mastectomy and sought to test the applicability of a reproducibility and repeatability (R&R) study in a clinical context. METHODS: Eleven radiation oncologists planned radiotherapy three times for three different kinds of breast cancer patients without knowing they were handling the same patient three times. Variation was divided into different components: physicians as operators, patients as parts, and repeated measurements as trials. Variation due to difference across trials (repeatability), that across the physicians (reproducibility), and that across the patients (variability) were estimated, as well as interactions between physicians and patients. Calculation was based on the sum of squares, and analysis was supported by various graphical presentations such as range charts and box plots. RESULTS: Some parts of the planning process were characterized by higher and different kinds of variation than the others. Interphysician variation (i.e., reproducibility) was not high but there were some clearly outlying physicians. The highest variation was in repeatability (= intraphysician variation). The major part of the variation was, however, that from patient to patient: 33% of the total in Parameter 1 and 85% of the total in Parameter 2. CONCLUSIONS: R&R studies are applicable and are needed to evaluate and improve quality in clinical practice. This kind of analysis provides opportunities to establish which kinds of patients require particularly careful attention, which points in the process are most critical for variation, which are the most difficult aspects for each physician and call for more careful description in documents, and which physicians need further training.

Radiation-induced changes in regional blood flow in human tumors.

In 43 patients the blood flow in 48 superficial metastatic tumors was measured with the 133xenon wash-out method. In all cases the blood flow was measured before the start of radiotherapy and then one week later during radiotherapy. In 36 cases the blood flow was measured after 2 weeks during radiotherapy, and in six patients the follow-up lasted 5-6 weeks. The blood flow increased during the first week of radiotherapy in the whole series from 20.1 +/- 18.0 ml/min/100g to 31.3 +/- 24.9 ml/min/100g. The increase during the first week was significant (p less than 0.001). During the second week of radiotherapy the blood flow decreased to 27.0 +/- 19.3 ml/min/100g; the decrease was also significant (p less than 0.05). The changes in the different tumor groups during radiotherapy seemed to be in the same direction. In a longer follow-up the gradual decrease in the blood flow seemed to continue.

Comparison of performance standards for radiation beam uniformity characteristics of a linear accelerator.

The recent international standards published by the International Electrotechnical Commission (IEC) on the performance of medical electron accelerators describe suggested test procedures for the performance of radiotherapy accelerators. The recommendations of the Nordic Association of Clinical Physics for testing of the radiation beam characteristics include test conditions, methods and suggested tolerances that are different from those of the IEC. In this work the two publications were compared for acceptance testing of a Philips SL25 linear accelerator. It is important to gain experience on the practical use of these standards.

Intercomparison of radiotherapy treatment planning systems for external photon and electron beam dose calculations.

Dose distributions calculated by six different treatment planning systems (TPSs), used by the hospitals in Finland or in Russia, were compared with measured dose distributions. Five typical cases of irradiation were selected: regular fields, oblique incidence, irregular field, wedge field and inhomogeneity in a water equivalent phantom. The beam data for each TPS where those pertaining to the beam where the comparative relative measurements were performed. The results indicate that the dose distributions produced by different TPSs can differ from each other as well as from the measured dose distributions up to a level which is not acceptable in terms of the ICRU recommendations. Greatest differences seem to be related to the omission or undue consideration of the scatter components of the beam.

Prevalence of diabetes mellitus and impaired glucose tolerance in the middle-aged population of three areas in Finland.

The prevalence of diabetes mellitus and impaired glucose tolerance (IGT) was determined in a random sample of the population aged 45-64 years in three areas of Finland. The two-hour oral glucose tolerance test was repeated in subjects whose first test suggested abnormal glucose tolerance. In the final classification, based on the results of the two tests, the age-standardized prevalence of diabetes, according to the WHO criteria was 5.7% (95% confidence interval (CI): 4.3-7.1) in men and 4.6% (95% CI: 3.6-5.0) in women. The prevalence of IGT was 3.1% (95% CI: 2.1-4.1) in men and 5.1% (95% CI: 3.9-6.3) in women. Among those aged 55-64 years the prevalence was 6.9% in men and 7.5% in women. The prevalence of diabetes and IGT were not different between the three areas. The age-specific mean values of fasting and two-hour blood concentrations and the 90th percentiles of the blood glucose distributions were also not different between the areas. The prevalence of IGT and diabetes increased with age more steeply among women than men. The median of fasting blood glucose did not change, but the 90th percentile increased with increasing age. The entire distribution of two-hour blood glucose shifted towards higher values with ageing, but the major increase was seen for the 95th percentile. The majority of the diabetic subjects were aware of their condition. The awareness was better among men than women.

The induction of LTP increases BDNF and NGF mRNA but decreases NT-3 mRNA in the dentate gyrus.

We have investigated the expression of the mRNAs for brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in the hippocampus before and after induction of long term potentiation (LTP) of synaptic transmission in the dentate gyrus through stimulation of the perforant path (PP). A unilateral PP stimulation produced a bilateral increase in the mRNA for both BDNF and NGF in granular neurones of the dentate gyrus but not in other neurones in the hippocampus. The mRNA for neurotrophin-3 (NT-3) was bilaterally decreased by LTP but that of NT-4 remained at the basal level. These results suggest that individual neurotrophic factors may play different roles in neuronal plasticity.

Staurosporine, a protein kinase C inhibitor, inhibits atrial natriuretic peptide secretion induced by sarafotoxin, endothelin and phorbol ester.

We studied the effects of two peptides of the endothelin/sarafotoxin family, sarafotoxin-b (SRTX-b) and endothelin (ET-1), as well as the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on immunoreactive atrial natriuretic peptide (IR-ANP) release and on haemodynamic parameters (perfusion pressure, heart rate and contractile force) in isolated perfused rat hearts in order to examine the role of intracellular signals in the regulation of ANP secretion. Infusion of SRTX-b at doses of 0.9 and 2.7 nM for 30 min caused a gradual, dose-dependent increase in IR-ANP release and a more rapid coronary vasoconstriction similar to the infusions of ET-1 (2.7 nM) or TPA (46 nM), known to activate protein kinase C in heart cells. A transient inotropic response with a later decrease in contractile force was observed after infusion of each agent. SRTX-b and TPA produced a sustained chronotropic effect, while ET-1 did not significantly affect the heart rate. Infusion of 100 nM of staurosporine, a potent inhibitor of protein kinase C, did not affect basal IR-ANP release into the perfusion fluid but slightly decreased perfusion pressure, heart rate and contractile force. When infused together with SRTX-b, ET-1 or TPA, staurosporine significantly inhibited the ANP secretion, coronary vasoconstriction and changes in cardiac function induced by the peptides or phorbol ester. This study shows that SRTX-b stimulates ANP release with a potency similar to that of ET-1 and that the kinetics of their effects on ANP secretion resemble those of TPA.(ABSTRACT TRUNCATED AT 250 WORDS)

d-Cycloserine, a partial agonist at the glycine site, enhances the excitability of dentate granule cells in vivo in rats.

The present study investigated the dose-dependent effects of d-cycloserine, a partial agonist at the glycine modulatory site associated with the NMDA receptor complex, on the hippocampal field potentials of dentate granule cells in awake, freely moving rats. Five sequential field potentials were recorded from the dentate gyrus of the dorsal hippocampus, by stimulating the perforant path in the entorhinal cortex at 30-s intervals. The slope of the population excitatory postsynaptic potential (e.p.s.p.) and the amplitude of the population spike of these field potentials were analysed and averaged with a computer. The effects of d-cycloserine (1.0, 3.0, 9.0 mg/kg) were recorded 40 min and 24 h after the i.p. injection. Although the slope of the population e.p.s.p. showed no significant change after the administration of d-cycloserine, the high doses produced a substantial increase in the amplitude of the population spike. This increase was observed 40 min but not 24 h after the injection. These findings indicate that d-cycloserine does not change the synaptic input from the perforant path to the granule cells but dose dependently enhances the excitability of the hippocampal dentate granule cells. In addition, the data give further support to the suggestion that in the brain area where NMDA receptor density is relatively high, the glycine site of the NMDA receptor may not be fully saturated by endogenous glycine in normal in vivo conditions. This suggests that there is a possibility for pharmacological modulation of NMDA receptor-mediated synaptic events by exogenous glycine or glycine analogues.