Evolution over time of mackinawite generated on carbon steel by the SRB metabolic activity: an in-operando Raman study.

Mackinawite was biologically synthetized by immersing carbon steel coupons in artificial seawater containing Sulphate-Reducing Bacteria (SRB) for 6 months. These coupons were removed from the culture medium solution and some were stored in air while others were placed in SRB-free culture medium solution. In operando Raman spectroscopy was used to analyse all these coupons immediately after extraction from the incubation medium and nanocrystalline, well-crystallized and partially oxidized mackinawite was detected. The evolution of these corrosion products was also monitored as a function of ageing time with this technique. Nanocrystalline and well-crystallised mackinawite transformed into partially oxidised mackinawite, greigite and sulphate green rust for an ageing time between 4 and 72 h. After 120 h, maghemite, magnetite, lepidocrocite, goethite appeared on the coupons placed in SRB-free culture medium solution as opposed to those stored in air atmosphere. Greigite and sulphate green rust were not observed for Raman measurements performed in air.

Gender differences in dietary intakes: what is the contribution of motivational variables?

BACKGROUND: Differences between men and women with respect to dietary intakes and eating behaviours have been reported and could be explained by gender differences in motivational variables associated with the regulation of food intake. The main objectives of the present study were to identify gender differences in dietary intakes, eating behaviours and motivational variables and to determine how motivational variables were associated with dietary intakes and eating behaviours in men and women. METHODS: Sixty-four men and 59 premenopausal women were included in the present study and presented cardiovascular risk factors. The Regulation of Eating Behaviours scale was completed to assess motivational variables. A validated food frequency questionnaire was administered to evaluate dietary intakes and subjects completed the Three-Factor Eating questionnaire to assess eating behaviours. RESULTS: Men had higher energy intake, energy density and percentage of energy from lipids and lower percentage of energy from carbohydrates than women (P ≤ 0.04). Men also had a lower emotional susceptibility to disinhibition than women (P = 0.0001). Women reported a higher score for eating-related self-determined motivation [i.e., eating-related self-determination index (SDI)] than men (P = 0.002). The most notable gender difference in the pattern of associations was that eating-related SDI was negatively associated with energy density (r = -0.30; P = 0.02), only in women. CONCLUSIONS: Women had a better dietary profile and higher eating-related SDI than men. However, gender differences in dietary variables might be explained by a potential gender-specific pattern of association of eating-related SDI with dietary intakes and eating behaviours.

Effect of stress on clinical reasoning during simulated ambulatory consultations.

BACKGROUND: The goal of this study was to examine the impact of subjective and physiological stress responses on medical students' diagnostic reasoning and communication skills. METHOD: A prospective randomized quantitative study was undertaken, looking at ambulatory consultations in internal medicine. On the first day (baseline day), volunteer year 6 students (n = 41) participated in a simulated ambulatory consultation with standardized patients (SPs). On the second day (study day), one week later, they were randomly assigned to two groups: a low stress (n = 20) and a high stress (n = 21) simulated ambulatory consultation. Stress was measured using validated questionnaires and salivary cortisol. The SPs assessed the students' reasoning and communication. The students completed assessments of their clinical reasoning after the consultations. RESULTS: Although stress measures were all significantly higher in the high-stress condition (all p < 0.05), no differences were found in diagnostic accuracy and justification scores. However, correlational analyses revealed a negative correlation between multiple-stress measures and the students' ability to generate arguments for differential diagnoses. CONCLUSION: Stress was associated with impairments in clinical reasoning, of a nature typically suggestive of premature closure.

Prescribing for older people with chronic renal impairment.

BACKGROUND: Renal function is an important prescribing consideration. On average, glomerular filtration rate declines by about 10 mL/min every 10 years after the age of 40. Renal impairment may cause medicines to accumulate or cause toxicity, especially if the medicine has a narrow therapeutic index. OBJECTIVE: To present an overview of prescribing considerations in the primary care setting for patients with chronic renal impairment. DISCUSSION: Serum creatinine considered in isolation is not a reliable indicator of renal function. The estimated glomerular filtration rate provided in pathology reporting can alert prescribers to possible renal impairment and the need to consider dose adjustments. The Cockcroft-Gault equation should be used to adjust medicine doses. Renal function monitoring is recommended for patients using medicines that can impair renal function or cause nephrotoxicity (eg. NSAIDs, ACEIs, ARBs).

Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE).

OBJECTIVES: Patients with advanced ankylosing spondylitis (AS) experience disability because of reduced spinal mobility and pulmonary function impairment. This placebo-controlled study evaluated the effect of etanercept (ETN) in patients with advanced AS. METHODS: A multicentre randomised double-blind placebo-controlled trial of 12 weeks' duration was performed. Patients had definite (modified New York criteria), active (Bath AS Disease Activity Index (BASDAI) ≥40), severe (radiological intervertebral bridges) AS refractory to non-steroidal anti-inflammatory drugs and were antitumour necrosis factor naive. They were treated with ETN 50 mg once weekly or identical placebo (PBO). RESULTS: Of the 95 patients screened, 82 were randomised to receive ETN (n=39) or PBO (n=43). At baseline the disease was active (mean BASDAI 61.0±13.4, C reactive protein (CRP) 20.7±25.5 mg/l) and severe (mean Bath AS Metrology Index (BASMI) 5.7±1.3, mSASSS 36.5±20.5); forced pulmonary vital capacity (FVC) was 3.3±0.7 l. Improvement in BASDAI (normalised net incremental area under the curve between baseline and week 12, primary end point) was significantly greater in the ETN group than in the PBO group (-19.8±16.5 vs -11.0±16.4, p=0.019). Moreover, at week 12, ETN gave better results than PBO for the BASDAI (-26.4±19.7 vs -14.4±19.7; p=0.008), total back pain (-29.2±24.0 vs -14.9±24.0; p=0.010), BASFI (-21.7±17.6 vs -10.1±17.6; p=0.004), BASMI (-0.6±0.6 vs -0.2±0.6; p=0.011), CRP level (-15.7±14.2 vs -1.3±14.2; p<0.001) and FVC (+160±280 ml vs -20±280 ml; p=0.006). CONCLUSIONS: ETN has short-term efficacy for patients with advanced AS, as was previously reported for less advanced disease. The efficacy is observed for the main symptoms (pain) and on markers of inflammation (CRP), as well as disease severity in terms of spinal mobility and pulmonary function.

Assessment of the severity of infant crying and its impact on parents: Development and validation of the ColiQ Questionnaire in France.

OBJECTIVES: The purpose of this study was to develop and validate a questionnaire that comprehensively assesses symptoms and severity of crying, symptoms suggesting infant functional gastrointestinal discomfort, and its impact on parents' quality of life: the Infant Colic Questionnaire (ColiQ©). For the first time, parents had access to a web application to follow their infants' evolving symptoms with a daily questionnaire. METHODS: The ColiQ was developed with a board of clinical experts (physicians and psychologists) based on extensive parent input. A longitudinal, observational study was conducted in France for 3 months. ColiQ assessments were collected online at six different time points. Psychometric testing demonstrated that ColiQ has acceptable psychometric properties (reliability, internal consistency, construct validity, and responsiveness). RESULTS: The ColiQ is a 16-question instrument developed in French including ten questions describing symptoms (Infant score) and six questions describing impacts (Parent score). The ColiQ demonstrated good test-retest reliability (ICC >0.70), internal consistency for both the Symptom and Impact subscale scores (Cronbach's α >0.70), and construct validity. Responsiveness was good; the ColiQ was able to detect significant improvement in the target population as early as 1 month (p<0.05). The global ColiQ score discriminated between severity levels (mild, medium, severe). CONCLUSIONS: The ColiQ was developed with input from parents and healthcare professionals and has shown validity, reliably, and responsiveness to change. Parents can use the web application to follow how their infants' symptoms evolve. The ColiQ can help parents quantify and verbalize their concerns during consultations, and provides an opportunity to facilitate conversations between the physician and parents.

Efficacy of high-fidelity simulation debriefing on the performance of practicing anaesthetists in simulated scenarios.

BACKGROUND: Research into adverse events in hospitalized patients suggests that a significant number are preventable. The purpose of this randomized, controlled study was to determine if simulation-based debriefing improved performance of practicing anaesthetists managing high-fidelity simulation scenarios. METHODS: The anaesthetists were randomly allocated to Group A: simulation debriefing; Group B: home study; and Group C: no intervention and secondary randomization to one of two scenarios. Six to nine months later, subjects returned to manage the alternate scenario. Facilitators blinded to study group allocation completed the performance checklists (dichotomously scored checklist, DSC) and Global Rating Scale of Performance (GRS). Two non-expert raters were trained, and assessed all videotaped performances. RESULTS: Interim analysis indicated no difference between Groups B and C which were merged into one group. Seventy-four subjects were recruited, with 58 complete data sets available. There was no significant effect of group on pre-test scores. A significant improvement was seen between pre- and post-tests on the DSC in debriefed subjects (pre-test 66.8%, post-test 70.3%; F(1,57)=4.18, P=0.046). Both groups showed significant improvement in the GRS over time (F(1,57)=5.94, P=0.018), but no significant difference between the groups. CONCLUSIONS: We found a modest improvement in performance on a DSC in the debriefed group and overall improvement in both control and debriefed groups using a GRS. Whether this improvement translates into clinical practice has yet to be determined.

CON4EI: SkinEthic™ Human Corneal Epithelium Eye Irritation Test (SkinEthic™ HCE EIT) for hazard identification and labelling of eye irritating chemicals.

Assessment of ocular irritancy is an international regulatory requirement and a necessary step in the safety evaluation of industrial and consumer products. Although a number of in vitro ocular irritation assays exist, none are capable of fully categorizing chemicals as a stand-alone assay. Therefore, the CEFIC-LRI-AIMT6-VITO CON4EI (CONsortium for in vitro Eye Irritation testing strategy) project was developed with the goal of assessing the reliability of eight in vitro/alternative test methods as well as establishing an optimal tiered-testing strategy. One of the in vitro assays selected was the validated SkinEthic™ Human Corneal Epithelium Eye Irritation Test method (SkinEthic™ HCE EIT). The SkinEthic™ HCE EIT has already demonstrated its capacity to correctly identify chemicals (both substances and mixtures) not requiring classification and labelling for eye irritation or serious eye damage (No Category). The goal of this study was to evaluate the performance of the SkinEthic™ HCE EIT test method in terms of the important in vivo drivers of classification. For the performance with respect to the drivers all in vivo Cat 1 and No Cat chemicals were 100% correctly identified. For Cat 2 chemicals the liquids and the solids had a sensitivity of 100% and 85.7%, respectively. For the SkinEthic™ HCE EIT test method, 100% concordance in predictions (No Cat versus No prediction can be made) between the two participating laboratories was obtained. The accuracy of the SkinEthic™ HCE EIT was 97.5% with 100% sensitivity and 96.9% specificity. The SkinEthic™ HCE EIT confirms its excellent results of the validation studies.

Ras-GAP controls Rho-mediated cytoskeletal reorganization through its SH3 domain.

Proteins of the Ras superfamily, Ras, Rac, Rho, and Cdc42, control the remodelling of the cortical actin cytoskeleton following growth factor stimulation. A major regulator of Ras, Ras-GAP, contains several structural motifs, including an SH3 domain and two SH2 domains, and there is evidence that they harbor a signalling function. We have previously described a monoclonal antibody to the SH3 domain of Ras-GAP which blocks Ras signalling in Xenopus oocytes. We now show that microinjection of this antibody into Swiss 3T3 cells prevents the formation of actin stress fibers stimulated by growth factors or activated Ras, but not membrane ruffling. This inhibition is bypassed by coinjection of activated Rho, suggesting that the Ras-GAP SH3 domain is necessary for endogenous Rho activation. In agreement, the antibody blocks lysophosphatidic acid-induced neurite retraction in differentiated PC12 cells. Furthermore, we demonstrate that microinjection of full-length Ras-GAP triggers stress fiber polymerization in fibroblasts in an SH3-dependent manner, strongly suggesting an effector function besides its role as a Ras downregulator. These results support the idea that Ras-GAP connects the Ras and Rho pathways and, therefore, regulates the actin cytoskeleton through a mechanism which probably does not involve p190 Rho-GAP.

Patient-specific prescriber feedback can increase the rate of osteoporosis screening and treatment: results from two national interventions.

Osteoporosis interventions targeting older Australians and clinicians were conducted in 2008 and 2011 as part of a national quality improvement program underpinned by behavioural theory and stakeholder engagement. Uptake of bone mineral density (BMD) tests among targeted men and women increased after both interventions and sustained increases in osteoporosis treatment were observed among men targeted in 2008. PURPOSE: Educational interventions incorporating patient-specific prescriber feedback have improved osteoporosis screening and treatment among at-risk patients in clinical trials but have not been evaluated nationally. This study assessed uptake of BMD testing and osteoporosis medicines following two national Australian quality improvement initiatives targeting women (70-79 years) and men (75-85 years) at risk of osteoporosis. METHODS: Administrative health claims data were used to determine monthly rates of BMD testing and initiation of osteoporosis medicines in the 9-months post-intervention among targeted men and women compared to older cohorts of men and women. Log binomial regression models were used to assess differences between groups. RESULTS: In 2008 91,794 patients were targeted and 52,427 were targeted in 2011. There was a twofold increase in BMD testing after each intervention among targeted patients compared to controls (p < 0.001). Initiation of osteoporosis medicines increased by 21% among men targeted in 2008 and 34% among men targeted in 2011 compared to older controls (p < 0.01). Initiation of osteoporosis medicines among targeted women was similar to the older controls. CONCLUSION: Programs underpinned by behavioural theory and stakeholder engagement that target both primary care clinicians and patients can improve osteoporosis screening and management at the national level.

Multi-laboratory evaluation of SkinEthic HCE test method for testing serious eye damage/eye irritation using solid chemicals and overall performance of the test method with regard to solid and liquid chemicals testing.

A prospective multicentre study of the reconstructed human corneal epithelial tissue-based in vitro test method (SkinEthic™ HCE) was conducted to evaluate its usefulness to identify chemicals as either not classified for serious eye damage/eye irritation (No Cat.) or as classified (Cat. 1/Cat. 2) within UN GHS. The aim of this study was to demonstrate the transferability and reproducibility of the SkinEthic™ HCE EITS protocol for solids and define its predictive capacity. Briefly, 60 chemicals were three times tested (double blinded) in 3 laboratories and 35 additional chemicals were tested three times in one laboratory. Good within laboratory reproducibility was achieved of at least 95% (57/60) and 96.8% (92/95) for the extended data set. Furthermore, the overall concordance between the laboratories was 96.7% (58/60). The accuracy of the SkinEthic™ HCE EITS for the extended dataset, based on bootstrap resampling, was 81.0% (95% CI: 78.9% to 83.2%) with a sensitivity of 90.5% (95% CI: 88.1% to 92.9%) and specificity of 73.6% (95% CI: 71.7% to 75.5%). Overall, 200 chemicals were tested (105 liquids (EITL protocol) and 95 solids (EITS protocol)) resulting in a sensitivity of 95.2%, specificity of 72.1% and accuracy of 83.7%, thereby meeting all acceptance criteria for predictive capacity.

Multi-laboratory validation of SkinEthic HCE test method for testing serious eye damage/eye irritation using liquid chemicals.

A prospective multicentric study of the reconstructed human corneal epithelial tissue-based in vitro test method (SkinEthic™ HCE) was conducted to evaluate its usefulness to identify chemicals as either not classified for serious eye damage/eye irritation (No Cat.) or as classified (Cat. 1/Cat. 2) within UN GHS. The aim of this study was to demonstrate the transferability and reproducibility of the SkinEthic™ HCE EITL protocol for liquids and define its predictive capacity. Briefly, 60 chemicals were three times tested (double blinded) in 3 laboratories and 45 additional chemicals were tested three times in one laboratory. Good within laboratory reproducibility was achieved of at least 88.3% (53/60) and 92.4% (97/105) for the extended data set. Furthermore, the overall concordance between the laboratories was 93.3% (56/60). The accuracy of the SkinEthic™ HCE EITL for the extended dataset, based on bootstrap resampling, was 84.4% (95% CI: 81.9% to 87.6%) with a sensitivity of 99.0% (95% CI: 96.4% to 100%) and specificity of 68.5% (95% CI: 64.0% to 74.0%), thereby meeting all acceptance criteria for predictive capacity. This efficient transferable and reproducible assay is a promising tool to be integrated within a battery of assays to perform an eye irritation risk assessment.

Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells.

Oncogenes and tumour suppressor genes control the balance between apoptotic death and anti-apoptotic survival signals determining whether a cell proliferates or dies. Through which effectors might oncoproteins generate sensitivity to apoptosis remains to be determined. Ras GTPase activating protein (Ras-GAP) is a key element in the Ras signalling pathway, being both a negative regulator and possibly an effector of Ras. Ras-GAP acts as a regulator of transcription, and possibly connects Ras to stress-activated protein kinases. A role for Ras-GAP in cell survival has been suspected from the study of knock-out mouse embryos. In search for selective killing of tumour cells, we asked whether Ras-GAP inhibition by other means would lead to apoptosis in established cell lines. We injected a monoclonal antibody directed against the SH3 domain of Ras-GAP (mAb200) that has been shown to block Ras-GAP downstream signalling into various human normal and tumour cell lines. We show that inhibition of Ras-GAP induces apoptosis specifically in tumour, but not in normal cells, therefore pointing at a specific role for Ras-GAP in tumour cell survival. MAb200-induced apoptosis is largely prevented by coinjection of activated RhoA or Cdc42 proteins, by injection of a constitutively activated mutant of phosphoinositide 3-OH kinase (PI3-K), but not by injection of v-Raf. These results show that targeting of Ras-GAP could represent a novel anticancer approach.

Accumulation of an inactive form of p53 protein in cells treated with TNF alpha.

In MCF-7 cells, TNF alpha induces a G1 arrest with an increased expression of p21/Waf1, an activation of NF-kappa B and an accumulation of p53. NF-kappa B and p53 are two transcriptional factors known to activate p21/Waf1 gene expression. Here we show that p53 inhibition has no effect on p21/Waf1 mRNA accumulation following TNF alpha treatment. In contrast, inactivation of NF-kappa B inhibits p21/Waf1 expression without affecting G1 arrest. The fact that p21/Waf1 gene expression is still stimulated when p53 is inactivated strongly suggests that TNF alpha induces accumulation of an inactive form of p53 protein. This assumption was further supported by the following observations: (i) the p53 DNA-binding activity to its consensus sequence was not stimulated following TNF alpha treatment, (ii) phosphorylation at Ser-15, -20 or -392 was not detected in response to TNF alpha, (iii) the transcription rate of Ddb2, another p53 target gene, was not stimulated by TNF alpha. Finally, the accumulation of p53 in the nuclei of TNF alpha-treated MCF-7 cells was concomitant with an increase in p53 mRNA level, suggesting a regulation at the transcription level.

Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia.

Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.

Agrin and microvascular damage in Alzheimer's disease.

Heparan sulfate proteoglycans (HSPGs) are ubiquitously present within the perivascular basement membrane, and have been shown to be altered in patients with Alzheimer's Disease (AD). Although the HSPG agrin clearly orchestrates the differentiation of the neuromuscular junction, its role in the brain remains unclear. Growing evidence suggests that agrin may be an important vascular basement membrane (VBM)-associated HSPG. In previous studies, we demonstrated that agrin is present throughout the brain microvasculature, as well as in neuronal cell bodies. AD brains exhibited fragmentation of VBM-associated agrin. Agrin immunoreactivity was also seen within senile plaques and neurofibrillary tangles. These changes were accompanied by the appearance of an additional pool of insoluble agrin. In the present study, we provide further evidence for microvascular damage in AD, by examining the distribution of agrin and laminin within the VBM, and by measuring the agrin concentration within hippocampus and prefrontal cortex. Furthermore, we assessed blood-brain-barrier (BBB) leakage by examining the perivascular distribution of prothrombin immunoreactivity. Soluble agrin levels were increased approximately 30% in Braak stage III-VI AD patients relative to age-matched controls. Furthermore, agrin and laminin exhibited identical patterns of VBM fragmentation in AD and colocalized with beta-amyloid in senile plaques. Microvascular changes were associated with the appearance of perivascular prothrombin immunoreactivity. Our data suggest that agrin is an important VBM-associated HSPG in the brain and that agrin levels are altered in association with microvascular damage in AD.

Hepatocyte growth factor (HGF/SF) in Alzheimer's disease.

Hepatocyte growth factor (HGF/SF), is a heparin-binding polypeptide which stimulates DNA synthesis in a variety of cell types and also promotes cell migration and morphogenesis. HGF/SF mRNA has been found in a variety of tissues, including brain. In a previous study, we showed that basic fibroblast growth factor (bFGF), another heparin-binding protein is increased in Alzheimer's disease (AD), and appears to be associated with the heparan-sulfate proteoglycans bound to B/A4 amyloid (Biochem. Biophys. Res. Commun. 171 (1990) 690-696). In the present study, we examined the distribution of HGF/SF in 4% paraformaldehyde fixed samples of prefrontal cortex from control and Alzheimer patients, in order to assess the possibility that HGF/SF may be found in association with the pathologic changes which occur in Alzheimer's disease. A specific polyclonal antibody directed against HGF/SF revealed widespread HGF/SF-like immunoreactivity in both the cerebral cortex and white matter. Confocal microscopy confirmed that HGF/SF could be found in both GFAP positive astrocytes and LN3 positive microglia cells, as well as rare scattered cortical neurons. In the AD cases studied, the immunoreactivity was increased within both the astrocytes and microglial cells surrounding individual senile plaques. No staining was seen within the neurofibrillary tangles. Western blot analysis confirmed the normal molecular form of HGF/SF in Alzheimer's disease. Quantitative ELISA assay demonstrated a significant increase in HGF/SF in AD relative to age matched controls. These studies confirm the presence of HGF/SF immunoreactivity within neurons, astrocytes and microglial cells. They also indicate that HGF/SF may be increased within senile plaques as a function of the gliosis and microglial proliferation which occurs in association with these structures in Alzheimer's disease.

Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease.

APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimer's disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies, we have shown that the synaptic organizing protein agrin can be found in neurons, and is a major component of the brain microvascular basement membrane. Here, we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area (micro(2)) of prefrontal cortical microvessels. An average of 10 capillaries was measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9 micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimer's disease.

[Effectiveness and tolerance of three month sustained release leuprorelin in the treatment of metastatic prostatic cancer (comparative, randomized, multicentric study]. / Efficacité et tolérance de la leuproréline à libération prolongée sur 3 mois dans le traitement du cancer prostatique métastasé (etude comparative, randomisée, multicentrique).

OBJECTIVE: To establish the pharmacodynamic and safety equivalence between 2 sustained-release forms of leuprorelin 11.25 mg and 3.75 mg, in the treatment of metastatic prostatic carcinoma. METHODS: 44 patients received subcutaneous injections of leuprorelin for 9 months (randomization: 2/l): either 11.25 mg every three months (n = 29) or 3.75 mg monthly (n = 15). Main criterion: centralized monthly assay of plasma testosterone (T). RESULTS: The equivalence of the 2 forms in terms of mean plasma testosterone was demonstrated (p = 0.002): 1 month: T = 0.19 +/- 0.03 ng/ml; 3 months: T = 0.27 +/- 0.04 ng/ml. Exploratory analysis did not reveal any significant difference between the groups for the number of patients castrated at each visit or for the number of patients with all T values < or = 0.5 ng/ml, or for clinical responses or safety. CONCLUSION: The 2 forms have a comparable efficacy and safety.

[Tolerance and clinical and biological responses during the first 6 months of treatment with 1-month sustained release LHRH agonists leuprolerin and triptolerin in patients with metastatic prostate cancer]. / Tolérance et réponses clinique et biologique au cours des 6 premiers mois de traitement par la leuproréline ou la triptoréline, agonistes de la LHRH à libération prolongée sur 1 mois chez des patients présentant un cancer de la prostate métastasé.

OBJECTIVES: Comparative efficacy and safety of 2 LHRH analogues in metastatic prostatic carcinoma. METHODS: 68 patients received monthly injections for 6 months (randomization): either subcutaneous leuprolide 3.75 mg LP (n = 36), or intramuscular triptorelin 3.75 mg LP (n = 32). (Flare-up prevention: nilutamide). Parameters re-evaluated at 1.3 and 6 months: centralized assays of plasma testosterone (T), LH and serum PSA; clinical symptoms. Main criterion: proportion of patients with T < or = 0.5 ng/mL. RESULTS: The percentages of patients with T < or = 0.50 ng/mL was not significantly different between the two groups and were equal to 100 and 90%, 97 and 100%, and 100 and 96% at the 3 study times, for leuprolide or triptorelin, respectively. The difference was significant at 1 month on complementary analysis at the limit of T < 0.30 ng/mL: 86% with leuprolide versus 60% with triptorelin (p = 0.02) and for mean plasma testosterone: 0.16 +/- 0.10 ng/mL versus 0.33 +/- 0.44 ng/mL, respectively (p = 0.02). The clinical subjective efficacy was not significantly different. CONCLUSION: Both treatments were effective, although plasma testosterone fell more rapidly with leuprolide. No conclusion about the possible clinical or survival benefits can be formulated. Overall safety was satisfactory.