Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age.

Associations between brain cortical tissue volume and cognitive function in old age are frequently interpreted as suggesting that preservation of cortical tissue is the foundation of successful cognitive aging. However, this association could also, in part, reflect a lifelong association between cognitive ability and cortical tissue. We analyzed data on 588 subjects from the Lothian Birth Cohort 1936 who had intelligence quotient (IQ) scores from the same cognitive test available at both 11 and 70 years of age as well as high-resolution brain magnetic resonance imaging data obtained at approximately 73 years of age. Cortical thickness was estimated at 81 924 sampling points across the cortex for each subject using an automated pipeline. Multiple regression was used to assess associations between cortical thickness and the IQ measures at 11 and 70 years. Childhood IQ accounted for more than two-third of the association between IQ at 70 years and cortical thickness measured at age 73 years. This warns against ascribing a causal interpretation to the association between cognitive ability and cortical tissue in old age based on assumptions about, and exclusive reference to, the aging process and any associated disease. Without early-life measures of cognitive ability, it would have been tempting to conclude that preservation of cortical thickness in old age is a foundation for successful cognitive aging when, instead, it is a lifelong association. This being said, results should not be construed as meaning that all studies on aging require direct measures of childhood IQ, but as suggesting that proxy measures of prior cognitive function can be useful to take into consideration.

TP-10 (AVANT Immunotherapeutics).

AVANT Immunotherapeutics is developing TP-10, a recombinant soluble complement receptor type 1 (sCR1), for the potential treatment of reperfusion injury (following surgery, ischemic disease and organ transplantation), organ rejection, acute inflammatory injury to the lungs and autoimmune diseases [348669]. TP-10 has been awarded Orphan Drug status from the FDA for the prevention and reduction of adult respiratory distress syndrome (ARDS) and as a treatment for infants undergoing cardiac surgery [180849], [359588]. A placebo-controlled phase II trial, conducted at approximately 30 sites in the US and involving approximately 600 adult patients undergoing cardiac surgery utilizing cardiopulmonary bypass, was initiated in November 2000. This safety and efficacy study was designed to assess the ability of TP-10 to mitigate the injury to the heart, brain and other organs that occurs when patients are placed on cardiopulmonary bypass circuits, thus potentially improving postoperative outcomes [391437]. In September 2000, the company was planning a double-blind, placebo controlled phase IIb trial in infants undergoing cardiac surgery; AVANT expected to initiated in 30 infants in January 2001 [395086]. The data from this trial will enable the company to further define its clinical endpoints before inititating a pivotal phase III trial in 2001 [382529]. A phase I/II trial of TP-10 involving 15 infants, under 12 months of age, undergoing cardiac surgery for congenital heart defects was initiated by the company in September 1999. The trial will evaluate the ability of TP-10 to mitigate the injury to the heart and other organs when patients are placed on cardiopulmonary bypass circuits [340602]. Enrollment was complete by January 2000 [352458]. Phase I safety trials of TP-10, including studies in adult patients at risk for adult respiratory distress syndrome (ARDS), adult patients with first-time myocardial infarction (heart attack), and pediatric patients undergoing cardiac surgery demonstrated that TP-10 is well tolerated. However, after completion, in December 1997, of a phase IIa trial in nine patients with ARDS, AVANT decided to cease development for this indication. TP-10 was licensed to Novartis AG for use in xeno- and allotransplantation in July 1999. Extensive animal studies have shown TP-10 to have potential in a wide variety of complement-mediated conditions, including organ transplantation, multiple sclerosis, rheumatoid arthritis and lupus [238093]. Early work demonstrated favorable results in animal models of reperfusion injury [180849] and hyperacute xenograft rejection in guinea pig to rat and pig to primate organ transplants [191552]. AVANT has received Notices of Allowance (July 1998) from the USPTO for three separate patent applications covering pharmaceutical compositions of TP-10, methods of purification and methods of certain TP-10 glycoforms for treating diseases or disorders resulting from inappropriate complement activation [291776]. In January 1999, the company was awarded US-05856297 which covers pharmaceutical compositions of TP-10. US-05856300 was also awarded covering compositions and methods of producing the drug [312267].

Premorbid IQ estimates from a multiple aptitude test battery: regression vs. equating.

Estimation of premorbid abilities remains an integral part of neuropsychological evaluations. Several methods of indirect estimation have been suggested in the literature. Many of these methods are based in prediction via linear regression. Unfortunately, linear regression has the well-reported tendency to underpredict high IQ scores and overpredict low IQ scores. This can be shown to be an unavoidable statistical artifact of linear regression. We demonstrate a procedure to estimate premorbid IQ without the regression artifact. The procedure has two steps: confirmation of construct equivalence and psychometric equating. An example using real data is presented which shows the regression to the mean problem with prediction and compares it to the results from equating.

Use of brook char (Salvelinus fontinalis) physiological responses to stress as a teaching exercise.

Fish hematological changes during osmotic and cold stress are used to introduce the physiological reactions of the animal to an acute stress. Brook char (Salvelinus fontinalis) were subjected to 1 h of stress before being anesthetized and having blood taken from their caudal vein. Glucose, hemoglobin, hematocrit, and osmolarity were determined in the blood samples. Analyses showed that glucose concentration tends to increase and hematocrit tends to decrease in stressed fish. Changes in hemoglobin concentration occurred only in cold-stressed fish. A rise in blood glucose concentration is the result of cortisol secreted by the hypothalamic-pituitary-adrenal axis. The glucose produced is used as an osmolyte or energy source to resist or combat the stress. In stressed fish, changes in hematocrit could be the result of the osmoconcentration of the blood plasma, as shown by the increase in osmolarity for the same group. In cold-stressed fish, a decrease in hemoglobin concentration could be the result of hemodilution by body cell water.

Clinical trials in pharmacogenetics and pharmacogenomics: methods and applications.

Clinical and other aspects of pharmacogenetics and pharmacogenomics are discussed. Pharmacogenetics is the study of the impact of heritable traits on pharmacology and toxicology. An extension of pharmacogenetics is the discovery that genetic polymorphisms have the potential to affect a drug's action. The interplay of genotype and drug efficacy has been defined as pharmacogenomics. For most drugs, variations in patient response have until recently been considered a result of pharmacokinetic rather than pharmacodynamic differences. However, it now seems that pharmacodynamic variability in humans is large, reproducible, and usually more pronounced than pharmacokinetic variability. Some examples of the impact of pharmacogenomics on pharmacokinetics involve cytochrome P-450 isoenzymes, dihydropyrimidine dehydrogenase, and thiopurine methyltransferase; some examples of the impact on pharmacodynamics involve cholesteryl ester transfer protein, angiotensin-converting enzyme, and serotonin transporter. There are no specific statistical techniques for analyzing data from pharmacogenomic clinical trials. However, a tabulated relationship for the determination of the maximum possible gain in response rate for the highest-responding genotypic subgroup of patients is provided as an aid to determining whether it is worth having a pharmacogenomic strategy for a given drug. Ethical issues in pharmacogenomics tend to be based on the general concern that the ability to diagnose a genetic disorder before any treatment is available does more harm than good to the patient. Pharmacogenomic approaches to drug discovery and delivery have been recognized by FDA. Pharmacogenomics cannot improve the efficacy of a given drug, but it helps in selecting patients who are likely to respond well. Pharmacogenomics provides a view of drug behavior and sensitivity useful to improving the efficacy of drug development and utilization.

Selective killing of cancer cells based on loss of heterozygosity and normal variation in the human genome: a new paradigm for anticancer drug therapy.

Most drugs for cancer therapy are targeted to relative differences in the biological characteristics of cancer cells and normal cells. The therapeutic index of such drugs is theoretically limited by the magnitude of such differences, and most anticancer drugs have considerable toxicity to normal cells. Here we describe a new approach for developing anticancer drugs. This approach, termed variagenic targeting, exploits the absolute difference in the genotype of normal cells and cancer cells arising from normal gene sequence variation in essential genes and loss of heterozygosity (LOH) occurring during oncogenesis. The technology involves identifying genes that are: 1) essential for cell survival; 2) are expressed as multiple alleles in the normal population because of the presence of one or more nucleotide polymorphisms; and 3) are frequently subject to LOH in several common cancers. An allele-specific drug inhibiting the essential gene remaining in cancer cells would be lethal to the malignant cell and would have minimal toxicity to the normal heterozygous cell that retains the drug-insensitive allele. With antisense oligonucleotides designed to target two alternative alleles of replication protein A, 70-kDa subunit (RPA70) we demonstrate in vitro selective killing of cancer cells that contain only the sensitive allele of the target gene without killing cells expressing the alternative RPA70 allele. Additionally, we identify several other candidate genes for variagenic targeting. This technology represents a new approach for the discovery of agents with high therapeutics indices for treating cancer and other proliferative disorders.

CAMPATH-1H (Cambridge University).

CAMPATH-1H, a T-cell-depleting, humanized monoclonal antibody, is under development by LeukoSite and ILEX for the potential treatment of chronic lymphocytic leukemia (CLL). In August 1998, ILEX completed enrollment of a pivotal clinical trial of CAMPATH-1H in the treatment of CLL. The study has enrolled 94 patients at 20 centers in the US and Europe. It is anticipated that achievement of the target response would result in a biologics license application being filed with the FDA in mid-1999. Preliminary unaudited results reported by one of the clinical sites were positive. Additional potential therapeutic areas include vasculitis and multiple sclerosis. Preliminary studies have also shown the antibody may reverse acute renal transplant rejection episodes and be useful in ex vivo purging of bone marrow to remove potentially malignant cells. The US FDA has granted Fast Track designation to CAMPATH. The product has orphan drug status.

Genome structure and gene content in protist mitochondrial DNAs.

Although the collection of completely sequenced mitochondrial genomes is expanding rapidly, only recently has a phylogenetically broad representation of mtDNA sequences from protists (mostly unicellular eukaryotes) become available. This review surveys the 23 complete protist mtDNA sequences that have been determined to date, commenting on such aspects as mitochondrial genome structure, gene content, ribosomal RNA, introns, transfer RNAs and the genetic code and phylogenetic implications. We also illustrate the utility of a comparative genomics approach to gene identification by providing evidence that orfB in plant and protist mtDNAs is the homolog of atp8 , the gene in animal and fungal mtDNA that encodes subunit 8 of the F0portion of mitochondrial ATP synthase. Although several protist mtDNAs, like those of animals and most fungi, are seen to be highly derived, others appear to be have retained a number of features of the ancestral, proto-mitochondrial genome. Some of these ancestral features are also shared with plant mtDNA, although the latter have evidently expanded considerably in size, if not in gene content, in the course of evolution. Comparative analysis of protist mtDNAs is providing a new perspective on mtDNA evolution: how the original mitochondrial genome was organized, what genes it contained, and in what ways it must have changed in different eukaryotic phyla.

The Organelle Genome Database Project (GOBASE).

The taxonomically broad organelle genome database (GOBASE) organizes and integrates diverse data related to organelles (mitochondria and chloroplasts). The current version of GOBASE focuses on the mitochondrial subset of data and contains molecular sequences, RNA secondary structures and genetic maps, as well as taxonomic information for all eukaryotic species represented. The database has been designed so that complex biological queries, especially ones posed in a comparative genomics context, are supported. GOBASE has been implemented as a relational database with a web-based user interface (http://megasun.bch.umontreal.ca/gobase/gobas e.html ). Custom software tools have been written in house to assist in the population of the database, data validation, nomenclature standardization and front-end design. The database is fully operational and publicly accessible via the World Wide Web, allowing interactive browsing, sophisticated searching and easy downloading of data.

Risk factors associated with suicide attempt in young French people.

Demographic data, personal and familial characteristics, as well as DSM-III-R-based psychiatric diagnoses were collected in 369 adolescents and young adults aged between 15 and 29 years, referred to an Emergency Department for psychological problems. In total, 60% of them were suicide attempters. Separations before the age of 12 years and depression in the family emerged as the main features distinguishing the suicidal group from the psychiatric control group. Fifty per cent of suicide attempters were repeaters. Fostering during childhood, suicide attempts and depression in the family were found to be risk factors for repeated self-attempts. These results support the view that significant levels of dysfunction, together with increased psychiatric morbidity, especially suicidal behaviour, characterize the families of young self-attempters.

Suicide attempts and job insecurity: a complex association.

OBJECTIVE: Since Durkheim, epidemiological studies have revealed a significant, complex association between unemployment and suicidal behaviour. The aim of this study was to analyse the relationship between parasuicide and job instability, including unemployment, French social measures against unemployment and occasional work. METHOD: Demographic data, personal and familial characteristics were collected in 541 suicide attempters. RESULTS: Seventy-seven per cent were socially active, with 61.5% in regular employment, and 38.5% in precarious employment. The female-to-male ratio approached 2 in the securely employed sample, and fell to 1 for those with poor social and professional integration. Depression, parasuicide, and alcohol abuse were more common in the families of repeaters in secure employment. The impact of the familial psychiatric background was no longer significant in the job insecurity group. Fostering in childhood was a risk factor for repeat suicidal behaviour in the group with job insecurity.

Early versus late coronary stenting following acute myocardial infarction: results of the STENTIM I Study (French Registry of Stenting in Acute Myocardial Infarction).

This study was undertaken to determine the feasibility and safety of coronary stenting in acute myocardial infarction (AMI). In AMI, primary percutaneous transluminal coronary angioplasty (PTCA) is accepted as the preferred method of reperfusion for patients presenting at highly experienced centres. Until recently, however, stenting has been avoided during AMI because of a potential high risk of thrombosis. This prospective observational study carried out in 20 centres and included 648 consecutive patients who underwent PTCA with stent implantation for AMI. Of these 648 patients, 269 (41.5%, Group 1) were dilated early (< 24 hr) after the onset of the symptoms (75% treated by direct PTCA) and 379 (58.5%, Group 2) were dilated between 24 hr and 14 days after AMI. Combined therapy with ticlopidin and aspirin was used after the procedure. Bailout stenting occurred more often in Group 1 than in Group 2 (17% vs. 9.5%)(P < 0.05). Angiographic successful stenting was similar in both groups of patients (96% vs. 97%). During the hospital follow-up period, stent thrombosis occurred in eight patients (3%) in Group 1 and in six patients (1.6%) in Group 2 (NS). There was 14 deaths (5.2%) in Group 1 and 11 deaths (3.9%) in Group 2 (NS). After multivariate analysis bailout stenting was identified as the sole predictor of stent thrombosis (P < 0.0001). Vascular access-site complications occurred in six patients (1%) with no difference between the two groups. This study indicates that patients who receive a coronary stent in AMI can be managed safely with antiplatelet therapy. Randomized studies are needed to determine the precise indication for coronary stenting as an adjunct to primary PTCA.

[Prospective study of attempted suicide]. / Enquête prospective sur les tentatives de suicide.

The present study involves a prospective review of all patients who visited the Emergency Psychiatric Service during the period from December, 6, 1993 to June, 5, 1994. A questionnaire was proposed to 1073 subjects (57.2% females; 42.8% males; mean age = 36.6 +/- 0.89). Demographic data, familial and personal characteristics, previous contacts with professional health services, and diagnosis (DSM III-R criteria) were collected. 52% of them were self-attempters, significatively younger (mean age 34.03 +/- 1.14) and more frequently females (61.5%). The parasuicides were more frequent in their families and in their personal past history. The previous contacts with health services (hospitalizations, consultations) were more frequent among patients who were admitted for psychological and/or psychiatric problems. 54% of self-attempters were repeating suicidal patients. There were more depressive disorders, parasuicides and drug/alcohol abuse in their families. A logistic regression analysis (stepwise) revealed the role of these factors in the repetition of parasuicides. This data supports the significance of a better knowledge of the potential significant factors for parasuicide. Preventive measures are necessary.

Relationships between high oxygen extraction fraction in the acute stage and final infarction in reversible middle cerebral artery occlusion: an investigation in anesthetized baboons with positron emission tomography.

Studies in humans suggest that regions that show maximal increases in brain oxygen extraction fraction (OEF) in the hours following an ischemic episode are those most vulnerable for infarction and are often, although not always, associated with the final site of infarction. To clarify this issue, we followed the hemodynamic and metabolic characteristics of regions with an initially maximally increased OEF and compared them with the ultimately infarcted region in an experimental stroke model. Positron emission tomography (PET) was used to obtain functional images of the brain prior to and following reversible unilateral middle cerebral artery occlusion (MCAO) in 11 anesthetized baboons. To model early reperfusion, the clips were removed 6 h after occlusion. Successive measurements of regional CBF (rCBF), regional CMRO2 (rCMRO2), regional cerebral blood volume, and regional OEF (rOEF) were performed during the acute (up to 2 days) and chronic (> 15 days) stage. Late magnetic resonance imaging (MRI) scans (co-registered with PET) were obtained to identify infarction. Reversible MCAO produced an MRI-measurable infarction in 6 of 11 baboons; the others had no evidence of ischemic damage. Histological analysis confirmed the results of the MRI investigation but failed to show any evidence of cortical ischemic damage. The lesion was restricted to the head of the caudate nucleus, internal capsule, and putamen. The infarct volume obtained was 0.58 +/- 0.31 cm3. The infarcts were situated in the deep MCA territory, while the area of initially maximally increased OEF was within the cortical mantle. The mean absolute rCBF value in the infarct region of interest (ROI) was not significantly lower than in the highest-OEF ROI until 1-2 days post-MCAO. Cerebral metabolism in the deep MCA territory was always significantly lower than that of the cortical mantle; decreases in CMRO2 in the former region were evident as early as 1 h post-MCAO. In the cortical mantle, the rOEF was initially significantly higher than in the infarct-to-be zone. Subsequently, the OEF declined in both regions. The differences in the time course of changes in CMRO2 and OEF between these two regions, with the eventually infarcted area showing earlier metabolic degradation and in turn decline in OEF, presumably underlie their different final outcomes. In conclusion, following MCAO, the region that shows an early maximal increase in the OEF is both topographically and physiologically distinct from the region with final consolidated infarction if reperfusion is allowed at 6 h. This high OEF, although indicative of a threatened condition, is not an indicator of inescapable consolidated infarction and is thus a situation in which therapy could be envisaged. Whether or not it is at risk of infarction and thus constitutes one target for therapy remains to be seen.

Unilateral eyeball enucleation differentially alters AMPA-, NMDA- and kainate glutamate receptor binding in the newborn rat brain.

The aim of the present work was to evaluate the neurochemical effects of early unilateral visual deprivation as a model of impaired visual maturation. For this purpose, binding to the different ionotropic glutamate receptor subtypes was quantified in vision-related and vision-unrelated brain structures of control and unilaterally deprived newborn rats. At post-natal (PN) day 10, male Sprague-Dawley rats underwent either unilateral eyeball enucleation (enucleation group, n = 12) or sham operation (control group, n = 12). In each group, brains were obtained either at post-natal day 20 (n = 6) or post-natal day 30 (n = 6) and processed for quantitative in vitro autoradiography selective for NMDA, kainate, and AMPA glutamate-binding sites, as well as for the presynaptic adenosine A1 receptor as a control of the deafferentation efficacy. In control animals, quantitative autoradiography revealed an increase in NMDA (e.g. +45% in superior colliculus) and kainate receptor binding (e.g. +55% in visual cortex, layer IV) from post-natal day 20 to post-natal day 30, associated with stable levels of AMPA receptor binding, in the vision-related structures. In the deafferented visual structures, monocular enucleation induced a marked decrease in A1 site density (e.g. -38 to -52%, in the superficial layer of superior colliculi, at PN day 20 and PN day 30, respectively) in parallel with a mild increase in both NMDA (e.g. +8 to 9%, in superior colliculi and visual cortex, layer IV at PN day 30, respectively) and AMPA (e.g. +16%, in layer IV of the visual cortex at PN day 30). Superimposed on marked bilateral decreases at PN day 30 in the enucleated rats, kainate receptor binding also revealed a slight but significant decrease (-5%) in the deafferented superior colliculus as compared to the non-deafferented side. The present findings (different time-courses of, and differential effects of deafferentation on, the NMDA, kainate and AMPA glutamate receptor subtypes throughout the visual brain structures) further support the involvement of these receptors in distinctive roles during maturation of the visual system.

Intracoronary stent implantation without ultrasound guidance and with replacement of conventional anticoagulation by antiplatelet therapy. 30-day clinical outcome of the French Multicenter Registry.

BACKGROUND: Stenting reduces both acute complications of coronary angioplasty and restenosis rates but increases subacute thrombosis rates and hemorrhagic complications when used with coumadin anticoagulation. METHODS AND RESULTS: To simplify postcoronary stenting treatment and to reduce these drawbacks, we evaluated the 1-month outcome of a prospective registry of 2900 patients in whom successful coronary artery stenting was performed without coumadin anticoagulation. Patients received 100 mg/d aspirin and 250 mg/d ticlopidine for 1 month. Low-molecular-weight heparin (LMWH) treatment was progressively reduced in four consecutive stages, from 1-month treatment to none. Event-free outcome at 1 month was achieved in 2816 patients (97.1%). Major stent-related cardiac events were subacute closure in 51 patients (1.8%), including death in 12 (0.5%), acute myocardial infarction in 17 (0.6%), and coronary artery bypass graft surgery in 9 (0.3%). Stent thrombosis was more frequent with balloon size of < 3.0 mm (< or = 2.5 mm, 10%; 3.0 mm, 2.3%; > or = 3.5 mm, 1.0%; P < .001), bail-out situations (6.67% versus 1.38%, P < .001), and patients with unstable angina or acute myocardial infarction (2.2% versus 1.12%, P = .02). Bleeding complications that required transfusion, surgical repair, or both occurred in 55 patients (1.9%). Bleeding complications were related to female gender (4.0% versus 1.51%, P < .001), duration of LMWH treatment (3.83% in phase II/III versus 0.69% in phase IV/V, P < .001), sheath size (6F, 0.52%; 7F, 1.04%; > or = 8F, 4.23%; P < .001), bail-out situations (4.76% versus 1.67%, P < .01), and saphenous graft stenting (4.38% versus 1.75%, P = .04). CONCLUSIONS: These results suggest that poststenting treatment by ticlopidine/aspirin is an effective alternative to coumadin anticoagulation, achieving low rates of subacute closure and bleeding complications. LMWH treatment does not improve subacute reocclusion rates but increases bleeding complications. Furthermore, as bleeding complications were independently related to sheath size, we suggest that stenting with 6F guiding catheters may prevent local complications. Furthermore, the ticlopidine/aspirin combination allows a low-cost stenting strategy without ultrasound assessment of stent deployment and permits short inhospital stay.

[Epidemiological study of patients and suicidal patients admitted to a psychiatric emergency department of a general hospital]. / Etude épidémiologique des patients et suicidants admis aux urgences psychiatriques d'un hôpital général.

The present study involves a review of all patients who visited the Emergency Psychiatric Service during the period from December, 6, 1993 to June, 5, 1994. A questionnaire was proposed to 1073 subjects (57.2% females; 42.8% males; mean age = 36.6). Demographic data, familial and personal characteristics, previous contacts with professional health services, and diagnosis (DSM III R criteria) were collected. 52% of them were self-attempters, younger than the general population and more frequently females (61.5%). The parasuicides were more frequent in their families and in their personal past history. The previous contacts with health services (hospitalizations, consultations) were more frequent among patients who were admitted for psychological and/or psychiatric problems. 54% of self-attempters were repeating suicidal patients. There were more depressive disorders, parasuicides and drug/alcohol abuse in their families. A logistic regression analysis (stepwise) revealed the role of these factors in the repetition of parasuicides. This study supports the significance of a better knowledge of the potential significant factors for parasuicide. Preventive measures are necessary.

Memory disorders in Alzheimer's disease and the organization of human memory.

The Squire and Zola-Morgan parallel organization model of the memory and the Tulving hierarchical model were developed mainly through the study of amnesic patients. The predictions of these two models are different, the first being more open to double dissociations and less restrictive than the second. Alzheimer's Disease is characterized by a differential impairment of the memory systems and by an interindividual variability which may take the form of dissociations between preserved and disturbed abilities in some patients. The objective of this study was to use the memory dysfunctions of patients with AD to test the validity of the two models. Analysis of the group data provided an average profile of memory disturbance consistent both with much of the data given in AD literature and with the two models. Using a multiple single-case strategy, we demonstrated several simple dissociations which are for the greater part compatible with the two models. Two of the dissociations underline the limits of the Tulving model, which otherwise accounts for a lot of results. The study supports the relevance of AD for the understanding of the cognitive architecture of the human memory.