2-(4,5,6,7,8,9-Hexahydro-6a-aza-phenyl-en-2-ylmethyl-ene)indan-1,3-dione.

The title compound, C(22)H(19)NO(2), has potential for use as a new nonlinear optical material. Mol-ecules are almost planar. One C atom of the heterocyclic ring system is disordered over two positions; the site occupancy factors are 0.6 and 0.4.

Neurophysiological investigation of the basis of the fMRI signal.

Functional magnetic resonance imaging (fMRI) is widely used to study the operational organization of the human brain, but the exact relationship between the measured fMRI signal and the underlying neural activity is unclear. Here we present simultaneous intracortical recordings of neural signals and fMRI responses. We compared local field potentials (LFPs), single- and multi-unit spiking activity with highly spatio-temporally resolved blood-oxygen-level-dependent (BOLD) fMRI responses from the visual cortex of monkeys. The largest magnitude changes were observed in LFPs, which at recording sites characterized by transient responses were the only signal that significantly correlated with the haemodynamic response. Linear systems analysis on a trial-by-trial basis showed that the impulse response of the neurovascular system is both animal- and site-specific, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses. These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output.

Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p.

Eight extended dyslexic families with at least four affected individuals were genotyped with twelve genetic markers spanning the Rh (rhesus factor) locus. Eleven of these markers were located on the short arm and the other was on the long arm of chromosome 1. Five theoretically derived phenotypes were used in the linkage analyses: 1) phonemic awareness; 2) phonological decoding; 3) rapid automatized naming; 4) single word reading; and 5) vocabulary. In addition, a lifetime diagnosis of dyslexia was used as a phenotype. Both parametric and non-parametric genetic analyses were completed. The results supported the importance of a putative locus on 1p. In addition, two-locus analyses assuming the interaction between a 1p locus and a 6p locus, previously shown to be of interest for dyslexia, were conducted. As a result, the nonparametric linkage (NPL) scores for rapid automatized naming and phonological decoding were significantly increased. In particular, the NPL scores for rapid automatized naming exceeded 5.0 for certain markers. These results provide strong evidence for separate but jointly acting contributions of the 1p and 6p loci to the reading impairments associated with rapid naming and suggestive evidence for a similar mechanism involving phonological decoding.

Lithium amidohydridoaluminates.

The amidohydridometalates [Li(THF)4][HAl(NPh2)3] (1), [Li(DME)3][HAl(N(CH2Ph)2)3] (2), and [((THF)3Li)-(H2Al(NcHex2)2)].0.5toluene (3.0.5toluene; cHex = C6H11) have been prepared by reaction of the corresponding amines with LiAlH4 in THF. For 2 recrystallization from DME is required to obtain crystals, suitable for X-ray diffraction. The new compounds have been characterized by elemental analyses, IR, NMR, and MS techniques, and X-ray structure analyses. According to this the anions of 1, 2, and 3x0.5toluene possess distorted tetrahedral coordination spheres. In 3x0.5toluene a Li...H contact of 184(4) pm was detected to complete the tetrahedral coordination of the Li+ center.

Diurnal variation of cortisol in panic disorder.

In patients with panic disorder (n=23), daytime salivary cortisol levels were determined in 2-h spans on 3 consecutive days and compared with 23 age- and sex-matched healthy controls. Additionally, nocturnal urinary free cortisol levels were measured. Daytime salivary cortisol levels were numerically higher in the patients, although the difference did not reach statistical significance. In a subgroup of 14 patients with higher illness severity (as expressed by a score >/=22 on the Panic and Agoraphobia Scale), salivary cortisol levels were significantly higher than in the controls. Mean nocturnal urinary cortisol levels were significantly higher in the whole group of patients and also in the more severely ill subgroup when compared with controls. Cortisol elevations seem to be more pronounced during the night and occurred mainly in more severely ill panic patients.

Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral aspirin challenges in aspirin-sensitive asthmatics.

BACKGROUND: Leukotrienes (LTs) have been implicated as major mediators of aspirin-(ASA)-induced respiratory reactions. It was therefore logical to assume that an inhibitor of 5-lipoxygenase (5-LO), such as zileuton, given before and during oral challenges with ASA, might prevent ASA-induced respiratory reactions. Indeed, in prior studies, pretreatment of ASA-sensitive respiratory disease patients with leukotriene modifiers eliminated or attenuated respiratory reactions upon re-challenge with the previously established provoking dose of ASA. However, doses higher than the provoking doses were not administered during these reported studies. OBJECTIVE: We wished to determine whether zileuton pretreatment could prevent ASA-induced respiratory reactions in our six volunteers with aspirin-sensitive respiratory disease when ASA challenge doses were started below the usual provoking dose of 60 mg and then increased until a respiratory reaction occurred. METHOD: Aspirin sensitivity was established previously in all six patients during a prior ASA oral challenge. In this study, pretreatment with zileuton 600 mg qid was initiated 7 days prior to, and continued during oral ASA challenges. Patients underwent single-blind oral ASA challenges with escalating doses of ASA, every 3 hours, according to our standard protocol. RESULTS: All six patients reacted to doses of ASA between 45 and 325 mg. Four patients experienced bronchospasm (FEV1 declined 19% to 53%) while receiving zileuton. All six had naso-ocular reactions. Concentrations of urine LTE4 also increased significantly (mean 334 pg/mg Cr at baseline, increasing to 1024 pg/mg Cr at respiratory reactions). CONCLUSIONS: During ASA challenges, zileuton, in standard doses of 600 mg qid was associated with increased synthesis of LTs in five of six patients and naso-ocular reactions in all six patients, as well as bronchospasm in four patients.

Self-association of human protein S.

Protein S functions as a cofactor with activated protein C in the down-regulation of the blood coagulation cascade. In vitro studies have historically produced conflicting data with regard to the extent of various protein S activity in clotting assays which typically involve adding CaCl(2) to initiate reactions. We report here that protein S reversibly self-associates in the absence of Ca(2+). Sedimentation experiments showed a transition in sedimentation velocity from 7.2 to 4.2 S with a transition midpoint (T(m)) of 0.42 mM Ca(2+) for intact protein S. Studies of thrombin cleaved (Arg(70)) protein S revealed similar results with a transition in sedimentation velocity from 7.9 to 4.4 S with a T(m) of 0.42 mM Ca(2+). This transition is reversible with the addition of 10 mM EDTA. Sedimentation equilibrium data suggest at a minimum, a monomer-dimer-trimer association. Sedimentation velocity experiments were also performed on mixtures of protein S and prothrombin which showed no heterodimer formation in either Ca(2+) or EDTA solutions. These data suggest that previous interpretations of protein S structure and function may have been confounded by the self-associative behavior of protein S in non-Ca(2+) solutions.

Salivary cortisol in panic attacks.

OBJECTIVE: Documentation of hypothalamic-pituitary-adrenal (HPA) axis disturbance in panic disorder has been inconsistent. Increased cortisol levels have been associated with altered HPA function due to stress. The authors examined salivary cortisol levels in spontaneously occurring, unprovoked panic attacks. METHOD: Patients with panic disorder (N=25) collected saliva samples when panic attacks occurred. Levels of cortisol in the saliva samples were determined and were compared with levels in comparison samples of saliva obtained 24 hours after the panic attack occurred. RESULTS: During spontaneous panic attacks there was a subtle but significant elevation of cortisol levels, compared with levels obtained 24 hours later. No significant correlations were found between the cortisol elevations during panic attacks and the severity of the attack as measured by using the Acute Panic Inventory or the severity of illness as measured by using the Panic and Agoraphobia Scale. CONCLUSIONS: Saliva sampling may be a useful method for investigating neuroendocrine parameters during spontaneously occurring panic attacks.

A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease.

Cathepsin D (catD) is an intracellular acid protease possibly involved in Alzheimer's disease (AD)-related neurodegeneration through cleavage of amyloid precursor protein into amyloidogenic components. We studied whether an exonic polymorphism of the catD gene (C --> T [Ala --> Val] transition at position 224), which possibly influences pro-catD secretion and intracellular maturation of the enzyme, was associated with the risk for the development of AD in 127 demented patients and 184 controls. The catD*T allele was significantly overrepresented in demented patients (11.8%) compared with nondemented controls (4.9%). Carriers of the catD*T allele had a 3.1-fold increased risk for developing AD than noncarriers. Carriers of the apolipoprotein E (ApoE) epsilon4 allele (ApoE*4) had a 3.9-fold increased risk than non-carriers. The adjusted odds ratio for subjects with the ApoE*4 and the catD*T allele was 19.0 compared with subjects with neither of these two alleles. Our data confirm the results of a recently performed pilot study in an independent sample and suggest that the catD genotype is strongly associated with the risk for AD.

Polymorphism of the gene of angiotensin converting enzyme: lack of association with mood disorder.

The insertion/deletion polymorphism of the gene of angiotensin-converting enzyme (ACE) was investigated in a case-control study including 169 patients with suffering from either bipolar disorder type I or unipolar recurrent major depression (DSM-IV) and 169 healthy controls. No significant association was found with bipolar disorder type I or unipolar recurrent depression and the polymorphism of the ACE gene. A previously reported genetic association (Arinami et al., 1996) was not confirmed by the present study.

Functional imaging of the monkey brain.

Functional magnetic resonance imaging (fMRI) has become an essential tool for studying human brain function. Here we describe the application of this technique to anesthetized monkeys. We present spatially resolved functional images of the monkey cortex based on blood oxygenation level dependent (BOLD) contrast. Checkerboard patterns or pictures of primates were used to study stimulus-induced activation of the visual cortex, in a 4.7-Tesla magnetic field, using optimized multi-slice, gradient-recalled, echo-planar imaging (EPI) sequences to image the entire brain. Under our anesthesia protocol, visual stimulation yielded robust, reproducible, focal activation of the lateral geniculate nucleus (LGN), the primary visual area (V1) and a number of extrastriate visual areas, including areas in the superior temporal sulcus. Similar responses were obtained in alert, behaving monkeys performing a discrimination task.

Mastocytosis: diverse presentations and outcomes.

Within the general category of mastocytosis lies an array of clinical presentations with differing prognostic implications. We report 3 cases of systemic mastocytosis distinguished by novel aspects of the disease. Case 1 documents the first successful orthotopic liver transplantation in a patient with mastocytosis; case 2 depicts a potential hereditary component of mastocytosis; and case 3 documents the progression of mastocytosis with hematologic abnormality to mast cell leukemia. Future investigations, such as the early definition of c-kit receptor mutations, may provide additional insight as to the molecular basis for this heterogeneous disease and guidance for prognostic implications and targeted therapies.

Postnatal body weight curves for infants below 1000 g birth weight receiving early enteral and parenteral nutrition.

UNLABELLED: No body weight curves are available for preterm infants < 1000 g birth weight receiving early enteral and parenteral nutrition. Postnatal weight changes of 136 infants with a birth weight < 1000 g were analysed retrospectively. Body weight curves for the first 30 days of life were generated for five separate birth weight groups (430-599 g, 600-699 g, 700-799 g, 800-899 g, 900-999 g). All infants had received intravenous glucose and amino acids from day 1 and intravenous lipids from day 2. Enteral feeding was started on day 1. Thus caloric intake (+/-SD) was advanced to 384+/-46 kJ/kg per day (92+/-11 kcal/kg/day) in the 1st week of life. In 136 preterm infants mean postnatal weight loss was 10.1%+/-4.6% of birth weight, birth weight was regained at a mean postnatal age of 11+/-3.7 days, but significantly earlier (7.8+/-3.5 days) in the lowest compared to the highest weight group. Mean subsequent weight gain was 15.7+/-7.2 g/ kg per day. This was accomplished by exclusive enteral nutrition from day 20 (median). CONCLUSION: Our body weight curves are more adequate to evaluate growth of preterm infants than older published reference values because they are based on infants treated according to current nutritional standards.

Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol.

BACKGROUND: Left ventricular dysfunction after myocardial infarction is associated with an increased risk of death. Other studies have suggested that a potassium-channel blocker might reduce this risk with minimal adverse effects. We investigated whether d-sotalol, a pure potassium-channel blocker with no clinically significant beta-blocking activity, could reduce all-cause mortality in these high-risk patients. METHODS: Patients with a left ventricular ejection fraction of 40% or less and either a recent (6-42 days) myocardial infarction or symptomatic heart failure with a remote (> 42 days) myocardial infarction were randomly assigned d-sotalol (100 mg increased to 200 mg twice daily, if tolerated) or matching placebo twice daily. FINDINGS: After 3121 of the planned 6400 patients had been recruited, the trial was stopped. Among 1549 patients assigned d-sotalol, there were 78 deaths (5.0%) compared with 48 deaths (3.1%) among the 1572 patients assigned placebo (relative risk 1.65 [95% CI 1.15-2.36], p = 0.006). Presumed arrhythmic deaths (relative risk 1.77 [1.15-2.74], p = 0.008) accounted for the increased mortality. The effect was greater in patients with a left ventricular ejection fraction of 31-40% than in those with lower (

Shape representation in the inferior temporal cortex of monkeys.

BACKGROUND: The inferior temporal cortex (IT) of the monkey has long been known to play an essential role in visual object recognition. Damage to this area results in severe deficits in perceptual learning and object recognition, without significantly affecting basic visual capacities. Consistent with these ablation studies is the discovery of IT neurons that respond to complex two-dimensional visual patterns, or objects such as faces or body parts. What is the role of these neurons in object recognition? Is such a complex configurational selectivity specific to biologically meaningful objects, or does it develop as a result of extensive exposure to any objects whose identification relies on subtle shape differences? If so, would IT neurons respond selectively to recently learned views of features of novel objects? The present study addresses this question by using combined psychophysical and electrophysiological experiments, in which monkeys learned to classify and recognize computer-generated three-dimensional objects. RESULTS: A population of IT neurons was found that responded selectively to views of previously unfamiliar objects. The cells discharged maximally to one view of an object, and their response declined gradually as the object was rotated away from this preferred view. No selective responses were ever encountered for views that the animal systematically failed to recognize. Most neurons also exhibited orientation-dependent responses during view-plane rotations. Some neurons were found to be tuned around two views of the same object, and a very small number of cells responded in a view-invariant manner. For the five different objects that were used extensively during the training of the animals, and for which behavioral performance became view-independent, multiple cells were found that were tuned around different views of the same object. A number of view-selective units showed response invariance for changes in the size of the object or the position of its image within the parafovea. CONCLUSION: Our results suggest that IT neurons can develop a complex receptive field organization as a consequence of extensive training in the discrimination and recognition of objects. None of these objects had any prior meaning for the animal, nor did they resemble anything familiar in the monkey's environment. Simple geometric features did not appear to account for the neurons' selective responses. These findings support the idea that a population of neurons--each tuned to a different object aspect, and each showing a certain degree of invariance to image transformations--may, as an ensemble, encode at least some types of complex three-dimensional objects. In such a system, several neurons may be active for any given vantage point, with a single unit acting like a blurred template for a limited neighborhood of a single view.

Psychophysical and physiological evidence for viewer-centered object representations in the primate.

A key question concerning the perception of 3D objects is the spatial reference frame used by the brain to represent them. The celerity of the recognition process could be explained by the visual system's ability to quickly transform stored models of familiar 3D objects, or by its ability to specify the relationship among viewpoint-invariant features or volumetric primitives that can be used to accomplish a structural description of an image. Alternatively, viewpoint-invariant recognition could be realized by a system endowed with the ability to perform an interpolation between a set of stored 2D templates, created for each experienced viewpoint. In the present study we set out to examine the nature of object representation in the primate in combined psychophysical-electrophysiological experiments. Monkeys were trained to recognize novel objects from a given viewpoint and subsequently were tested for their ability to generalize recognition for views generated by mathematically rotating the objects around any arbitrary axis. The perception of 3D novel objects was found to be a function of the object's retinal projection at the time of the recognition encounter. Recognition became increasingly difficult for the monkeys as the stimulus was rotated away from its familiar attitude. The generalization field for novel wire-like and spheroidal objects extended to about +/- 40 degrees around an experienced viewpoint. When the animals were trained with as few as three views of the object, 120 degrees apart, they could often interpolate recognition for all views resulting from rotations around the same axis. Recordings from inferotemporal cortex during the psychophysical testing showed a number of neurons with remarkable selectivity for individual views of those objects that the monkey had learned to recognize. Plotting the response of neurons as a function of rotation angle revealed systematic view-tuning curves for rotations in depth. A small percentage of the view-selective cells responded strongly for a particular view and its mirror-symmetrical view. For some of the tested objects, different neurons were found to be tuned to different views of the same object; the peaks of the view-tuning curves were 40-50 degrees apart. Neurons were also found that responded to the sight of unfamiliar objects or distractors. Such cells, however, gave nonspecific responses to a variety of other patterns presented while the monkey performed a simple fixation task.

View-dependent object recognition by monkeys.

BACKGROUND: How do we recognize visually perceived three-dimensional objects, particularly when they are seen from novel view-points? Recent psychophysical studies have suggested that the human visual system may store a relatively small number of two-dimensional views of a three-dimensional object, recognizing novel views of the object by interpolation between the stored sample views. In order to investigate the neural mechanisms underlying this process, physiological experiments are required and, as a prelude to such experiments, we have been interested to know whether the observations made with human observers extend to monkeys. RESULTS: We trained monkeys to recognize computer-generated images of objects presented from an arbitrarily chosen training view and containing sufficient three-dimensional information to specify the object's structure. We subsequently tested the trained monkeys' ability to generalize recognition of the object to views generated by rotation of the target object around any arbitrary axis. The monkeys recognized as the target only those two-dimensional views that were close to the familiar, training view. Recognition became increasingly difficult for the monkeys as the stimulus was rotated away from the experienced viewpoint, and failed for views farther than about 40 degrees from the training view. This suggests that, in the early stages of learning to recognize a previously unfamiliar object, the monkeys build two-dimensional, viewer-centered object representations, rather than a three-dimensional model of the object. When the animals were trained with as few as three views of the object, 120 degrees apart, they could often recognize all the views of the object resulting from rotations around the same axis. CONCLUSION: Our experiments show that recognition of three-dimensional novel objects is a function of the object's retinal projection. This suggests that non-human primates, like humans, may accomplish view-invariant recognition of familiar objects by a viewer-centered system that interpolates between a small number of stored views. The measures of recognition performance can be simulated by a regularization network that stores a few familiar views, and is endowed with the ability to interpolate between these views. Our results provide the basis for physiological studies of object-recognition by monkeys and suggest that the insights gained from such studies should apply also to humans.

Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group.

OBJECTIVES: To study the effect of angiotensin converting enzyme inhibition on the rate of progression to clinical proteinuria and the rate of change of albumin excretion rates in patients with insulin-dependent diabetes mellitus and persistent microalbuminuria. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial of 2 years' duration at 12 hospital-based diabetes centers. PATIENTS: Ninety-two patients with insulin-dependent diabetes mellitus and persistent microalbuminuria but no hypertension. INTERVENTION: The patients were randomly allocated in blocks of two to receive either captopril, 50 mg, or placebo twice per day. MEASUREMENTS: Albumin excretion rate, blood pressure, glycosylated hemoglobin level, and fructosamine level every 3 months; urinary urea nitrogen excretion every 6 months; and glomerular filtration rate every 12 months. RESULTS: Twelve patients receiving placebo and four receiving captopril progressed to clinical proteinuria, defined as an albumin excretion rate persistently greater than 200 micrograms/min and at least a 30% increase from baseline (P = .05). The probability of progression to clinical proteinuria was significantly reduced by captopril therapy (P = .03 by log-rank test). Albumin excretion rate rose from a geometric mean (95% confidence interval) of 52 (39 to 68) to 76 (47 to 122) micrograms/min in the placebo group but fell from 52 (41 to 65) to 41 (28 to 60) micrograms/min in the captopril group, a significant difference (P < .01). Mean blood pressure was similar at baseline in the two groups and remained unchanged in the placebo group but fell significantly, by 3 to 7 mm Hg, in the captopril group. Glycosylated hemoglobin levels and glomerular filtration rate remained stable in the two groups. CONCLUSIONS: Captopril therapy significantly impeded progression to clinical proteinuria and prevented the increase in albumin excretion rate in nonhypertensive patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.

Identification of a subset of patients with scleroderma with severe pulmonary and vascular disease by the presence of autoantibodies to centromere and histone.

OBJECTIVES: The role of autoantibodies in the investigation and management of rheumatic diseases is well recognised. The objective of this study was to determine the clinical significance of the co-occurrence of antibodies to centromere and histone in serum samples from patients investigated for systemic rheumatic diseases. METHODS: Serum samples from 1316 consecutive patients were screened for antinuclear antibodies and the clinical findings in patients with antibodies to centromere alone were compared with those with antibodies to both centromere and histone. RESULTS: Twenty six patients had antibodies to centromere. Fourteen patients had antibodies to centromere alone and 12 patients had antibodies to centromere and histone. Four of the 12 patients with antibodies to centromere and histone had diffuse scleroderma with severe pulmonary or vascular disease. CONCLUSIONS: A subset of patients with scleroderma with antibodies to centromere and histone has been identified retrospectively, who have severe pulmonary or vascular disease. It will be of interest to follow up the clinical course of other patients with scleroderma who have both antibodies for the development of pulmonary or vascular disease.