[The role of the nucleus accumbens in psychiatric disorders].

The nucleus accumbens is the most inferior part of the striatum and is mainly connected to the limbic system. It is neurochemically and immunohistochemically divided into a shell laterally and a core medially. As a functionally central structure between amygdala, basal ganglia, mesolimbic dopaminergic regions, mediodorsal thalamus and prefrontal cortex, the nucleus accumbens appears to play a modulative role in the flow of the information from the amygdaloid complex to these regions. Dopamine is a major neurotransmitter of the nucleus accumbens and this nucleus has a modulative function to the amygdala-basal ganglia-prefrontal cortex circuit. Together with the prefrontal cortex and amygdala, nucleus accumbens consists a part of the cerebral circuit which regulates functions associated with effort. It is anatomically located in a unique way to serve emotional and behavioral components of feelings. It is considered as a neural interface between motivation and action, having a key-role in food intake, sexual behavior, reward-motivated behavior, stress-related behavior and substance-dependence. It is involved in several cognitive, emotional and psychomotor functions, altered in some psychopathology. Moreover it is involved in some of the commonest and most severe psychiatric disorders, such as depression, schizophrenia, obsessive-compulsive disorder and other anxiety disorders, as well as in addiction, including drugs abuse, alcoholism and smoking. Nucleus accumbens has also a role in other psychiatric disorders such as bipolar disorder, attention deficit/ hyperactivity disorder and post-traumatic stress disorder. Because of its rich dopaminergic projections, this nucleus has been subject of many studies in animals as well as in humans, connecting its malfunction with the disturbed reward process observed in depression. Neuromodulation interventions targeting the nucleus accumbens are nowadays applied in strictly selected patients suffering from treatment-resistant depression, obsessive-compulsive disorder, Tourette syndrome and addiction to drugs or alcohol. Specifically, bilateral and unilateral (right) deep brain stimulation of the nucleus accumbens has been applied in obsessive-compulsive patients resulting into significant improvement of their symptoms and their quality of life. Nucleus accumbens deep brain stimulation has been also associated with antidepressant and anxiolytic effect, as well as quality of life improvement in patients suffering from severe resistant depression. Finally, this minimally invasive stereotactic procedure has been proved beneficial for all phenotypic components of the Tourette syndrome, with remarkable reduction of the syndrome's motor manifestations, including tics.

The safest electrode trajectory for deep brain stimulation of the human nucleus accumbens: a stereotactic anatomic study.

BACKGROUND: The primary purpose of our stereotactic anatomic study was to determine the safest electrode trajectory for deep brain stimulation (DBS) of the human nucleus accumbens (NA). Considering NA DBS together with the complications related to surgical implantation and based on methods for assessing the electrode trajectory we tried to reveal the secret of a trajectory for targeting the NA with the highest possible level of safety. MATERIAL AND METHODS: Our material consisted of 30 cerebral hemispheres we have in our Department from cadaver donors for students' education. We identified the electrode's target point in coronal sections. As safe we considered a trajectory from the cerebral cortex to the NA, which traverses the anterior limb of the internal capsule (AIC) without passing through either the caudate nucleus or putamen. We measured the minimum, maximum and safest coronal angles of the electrode trajectory (between the trajectory and the midline), as well as the AIC angle and width of the trajectory angle. We also measured trajectory projection length from the cerebral surface to the superior (d1) and inferior (d2) margins of the NA. RESULTS: The safest trajectory angle for NA DBS was found to have a mean value of 29.10 degrees, ranging from 23.80 to 35.40 degrees. The mean AIC angle was 33.78 degrees. We found no statistically significant difference between right and left hemispheres and a strong statistical relation between the safest electrode trajectory and AIC angle. Mean values of d1 and d2 were found to be 53.57 mm and 60.86 mm respectively. The mean value of the length of the electrode trajectory in coronal projection within the NA (d2-d1) was found to be 7.29 mm. CONCLUSION: The new knowledge that our stereotactic anatomic study offers is a definition of the safest electrode trajectory for NA DBS, its coronal angle width, as well as an estimation of its length.

The human nucleus accumbens as a target for deep brain stimulation: anatomic study of electrode's target point and stereotactic coordinates.

INTRODUCTION: The nucleus accumbens (NA), a "pleasure center", is the most inferior part of the ventral striatum. NA, related to the limbic and extrapyramidal motor system, is involved in some of the most common neuropsychiatric disorders. Nowadays it is a target for deep brain stimulation (DBS), in some carefully selected patients. Our purpose was to evaluate the accuracy of its position within the NA, in relation to the stereotactic target point that is today used. METHODS AND MATERIALS: We identified, studying 25 cerebral hemispheres, the target point of the NA DBS electrode, at a specific level that is important for its imaging. We also identified the stereotactic coordinates of the NA and made a statistical analysis and comparisons. RESULTS: We found that in 3 out of 25 cases, the used stereotactic coordinates fail to offer a target point within the limits of the NA. DISCUSSION: We present the first stereotactic anatomic study evaluating the precise position where the electrode for human NA DBS is to be placed and the only anatomic study of the human NA performed on such a large number of cases. The stereotactic coordinates used for NA DBS are accurate. However, we suggest that the electrode's final position should be considered to be slightly less deep.

Developing a Public Key Infrastructure for a secure regional e-Health environment.

OBJECTIVES: Internet technologies provide an attractive infrastructure for efficient and low cost communications in regional health information networks. The advantages provided by the Internet come however with a significantly greater element of risk to the confidentiality and integrity of information. This is because the Internet has been designed primarily to optimize information sharing and interoperability, not security. The main objective of this paper is to propose the exploitation of public-key cryptography techniques to provide adequate security to enable secure healthcare Internet applications. METHODS: Public-key cryptography techniques can provide the needed security infrastructure in regional health networks. In the regional health-care security framework presented in this paper, we propose the use of state-of-art Public Key Infrastructure (PKI) technology. Such on e-Health PKI consists of regional certification authorities that are implemented within the central hospitals of each region and provide their services to the rest of the healthcare establishments of the same region. RESULTS: Significant experience in this area has been gained from the implementation of the PKI@AUTH project. CONCLUSIONS: The developed PKI infrastructure already successfully provides its security services to the AHEPA university hospital. The same infrastructure is designed to easily support a number of hospitals participating in a regional health information network.

Access control based on attribute certificates for medical intranet applications.

BACKGROUND: Clinical information systems frequently use intranet and Internet technologies. However these technologies have emphasized sharing and not security, despite the sensitive and private nature of much health information. Digital certificates (electronic documents which recognize an entity or its attributes) can be used to control access in clinical intranet applications. OBJECTIVES: To outline the need for access control in distributed clinical database systems, to describe the use of digital certificates and security policies, and to propose the architecture for a system using digital certificates, cryptography and security policy to control access to clinical intranet applications. METHODS: We have previously developed a security policy, DIMEDAC (Distributed Medical Database Access Control), which is compatible with emerging public key and privilege management infrastructure. In our implementation approach we propose the use of digital certificates, to be used in conjunction with DIMEDAC. RESULTS: Our proposed access control system consists of two phases: the ways users gain their security credentials; and how these credentials are used to access medical data. Three types of digital certificates are used: identity certificates for authentication; attribute certificates for authorization; and access-rule certificates for propagation of access control policy. Once a user is identified and authenticated, subsequent access decisions are based on a combination of identity and attribute certificates, with access-rule certificates providing the policy framework. CONCLUSIONS: Access control in clinical intranet applications can be successfully and securely managed through the use of digital certificates and the DIMEDAC security policy.

The dimeric complex of cyclomaltoheptaose with 1,14-tetradecanedioic acid. Comparison with related complexes.

The structure of the complex of cyclomaltoheptaose (beta-cyclodextrin, betaCD) with 1,14-tetradecanedioic acid has been determined and refined to a final R=0.0693 based on 9824 observed reflections. Each diacid molecule threads through two betaCD monomers arranged in dimers thus, forming a [3]pseudorotaxane. The end carboxylic groups of adjacent dimers, far apart and fully hydrated, are associated indirectly through water molecules. The positioning of the carboxylic groups with respect to the betaCD dimer and the H-bonds with water molecules are very similar to these of the corresponding complexes of the diacids with 12 and 13 carbon atoms. The bending in the middle of the aliphatic chain is more prominent, compared to that of the corresponding guests with less carbon atoms, thus the end carboxylic groups stay in the same height of the primary faces of the betaCD dimeric complex. As a consequence of the present structure, more close contacts are observed between calculated H-atoms of the guest and O-atoms of the host inside the cavity. This bending is allowed by the width of the betaCD dimer cavity at the secondary interface region.

Structure of the complex of beta-cyclodextrin with beta-naphthyloxyacetic acid in the solid state and in aqueous solution.

The structure of the complex of beta-cyclodextrin (cyclomaltoheptaose) with beta-naphthyloxyacetic acid was studied in solid state by X-ray diffraction and in aqueous solution by 1H NMR spectroscopy. The complex crystallizes in the channel mode, space group C2, with a stoichiometry of 2:1; two beta-cyclodextrin molecules related by a twofold crystal axis form dimers, in the cavity of which one guest molecule is found on average. The above stoichiometry indicates one guest per beta-CD dimer statistically oriented over two positions or two guest molecules in pi-pi interactions in half of the beta-CD dimers and the rest of the beta-CD dimers empty. In addition, occupancy of 0.5 for the guest per every beta-CD dimer is in accord with the occupancy of the two disordered primary hydroxyls. These two hydroxyl groups, to which the carboxylic oxygen atoms of the guest are hydrogen bonded, point towards the interior of the beta-CD cavity. In aqueous solution, the 1H NMR spectroscopic study indicated that there is a mixture of complexes with host-guest stoichiometries both 1:1 and 2:1.

Non-covalent interactions in the crystallization of the enantiomers of 1,7-dioxaspiro.

The enantiomers of racemic olive fly sex pheromone 1,7-dioxaspiro[5.5]undecane (1) have been isolated by crystallization with enantiospecific cyclodextrin hosts: (S)-(1) crystallizes with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD) and (R)-(1) with hexakis(2,3,6-tri-O-methyl)-alpha-cyclodextrin (TMalphaCD). The crystal structure of TMbetaCD/(S)-(1) from synchrotron radiation data at 100 K, determined for the first time, proves that TMbetaCD crystallizes with only the (S)-enantiomer from the racemic mixture. Comparison with the 100 K structure of TMalphaCD/(R)-(1) redetermined with synchrotron data has provided insight into the interactions between each of the hosts with the corresponding enantiomeric guests. Owing to the high resolution of the data and the unusually high quality of the crystals, localization of the H atoms has been achieved, a rare accomplishment for cyclodextrin X-ray structures. This made possible, apart from the geometry of the complexes, the detailed description of a five-membered-ring water cluster with very well ordered hydrogen bonding. The enantiospecificity exhibited by the described systems reveals the subtle differences of the weak intermolecular forces involved in the selective binding of the two optical antipodes by the two hosts. The binding geometry in the two complexes is different, but it is effected in both by numerous host-guest C-H.O interactions, resulting from induced fit of the hosts toward each of the enantiomeric guests. In TMalphaCD/(R)-(1) two of these H.O host-guest distances, directed toward the acetal O atoms defining the chirality of the guest, are much shorter than the rest and also shorter than all the H.O distances in TMbetaCD/(S)-(1). Moreover, (R)-(1) interacts not only with the enclosing host, but with other hosts in the crystal lattice, in contrast to (S)-(1) in the TMbetaCD/(S)-(1) complex which is isolated inside channels formed by the host molecules. The above differences are reflected in the much higher binding constant of TMalphaCD/(R)-(1) compared with that of TMbetaCD/(S)-(1) ( approximately 6800 and approximately 935 M(-1), respectively), determined by NMR in aqueous solution, and the ability of TMalphaCD to selectively precipitate (R)-(1) from racemic (1) in much higher yield than TMbetaCD precipitates (S)-(1).

The crystal structure of the inclusion complex of cyclomaltoheptaose (beta-cyclodextrin) with 4-tert-butyltoluene.

The crystal of the 1:1 complex of 4-tert-butyltoluene with cyclomaltoheptaose (beta-cyclodextrin, beta CD) is triclinic P1 with a = 15.562(2), b = 15.564(4), c = 15.835(3) A, alpha = 102.11(2), beta = 102.15(1), gamma = 103.64(2) degrees, V = 3505(1) A3, and Z = 2. The two independent beta CD molecules in the asymmetric unit form a dimer by hydrogen bonding involving HO-3, which accommodates two molecules of the guest. The hydrophobic guests are enclosed completely in the beta CD cavities with the tert-butyl groups in the hydrophobic region beneath the primary hydroxyl groups. The aromatic rings have two orientations and their toluene methyl moieties could not be located but were calculated to be at the interface of the two monomers. The dimers form channels along the c axis. The inter-dimer space is filled with 17 molecules of water distributed over 25 sites. A dense network of hydrogen bonds is formed, involving the beta CD hydroxyl groups and water molecules.

The crystal structure of the inclusion complex of cyclo-maltoheptaose (beta-cyclodextrin) with 3,3-dimethylbutylamine.

The crystal of the 1:1 complex of 3,3-dimethylbutylamine with cyclomaltoheptaose (beta CD, beta-cyclodextrin) is monoclinic C2 with a = 19.187(9), b = 24.56(1), c = 15.893(7) A, beta = 108.77(4) degrees, V = 7091 A3, and Z = 4. Two beta CD molecules, held together by intermolecular hydrogen bonds involving HO-3, form dimers, in the cavities of which two 3,3-dimethylbutylamine and two water molecules are accommodated. The guest molecule is completely enclosed in the cavity. The amino group is located at the secondary-hydroxyl-group side, and is hydrogen-bonded to the entrapped water molecules. The dimers form channels along the c axis. The inter-dimer space is filled with 10.7 water molecules that are distributed over 14 sites, and there is a dense network of hydrogen bonds involving the water molecules and the beta CD hydroxyl groups.

Expression of functionality of alpha-chymotrypsin. An alternate binding mode in the substrate specificity site.

Three-dimensional 2.8 A resolution x-ray crystallographic studies show that toluenesulfonamide and pipsylamide bind isomorphously in the aromatic specificity binding site of alpha-chymotrypsin. However, their orientation differs by about 90 degrees from that usually associated with substrate-like molecules, suggesting a nonproductive binding mode. A secondary binding site is also operative in one molecule of the dimer of the pipsylamide derivative and it is located some 22 A from the active site; however, this site is not operative in the toluenesulfonamide derivative. Binding of toluenesulfonamide and pipsylamide in the specificity site occurs without inducing any significant changes in the native enzyme structure, in contrast to the behavior observed upon tosylation or upon transition state analogue binding of phenylethaneboronic acid. The structural changes accompanying the formation of the latter derivatives are generally asymmetric with respect to the dimeric structure of alpha-chymotrypsin and are generally confined to the binding domain or cylinder 2 of the enzyme (sequence greater than 122). These changes are displayed in a new way via diagonal distance map representation.

The folding and quaternary structure of trimeric 2-keto-3-deoxy-6-phosphogluconic aldolase at 3.5-A resolution.

An X-ray crystallographic structure determination has been carried out on 2-keto-3-deoxy-6-phosphogluconic (KDPG) aldolase at 3.5-A resolution using the multiple isomorphous replacement method with three heavy atom derivatives along with anomalous dispersion contributions from two of the derivatives. Crystals grown from ammonium sulfate-phosphate buffered (pH 3.5) solutions were: cubic, a= 103.40 (4) A, space group P213. KDPG aldolase consists of trimeric heterologous assemblages utilizing crystallographic threefold symmetry. The overall profile of the oligomeric structure viewed down the threefold axis resembles that of a ship propeller while the subunits are approximate irregular oblate ellipsoids (25 X 45 X 45 A). The folding of most of the polypeptide chain was traced unambiguously. Secondary structural features consist of nine helical regions (75 residues, 35%) and a pair of two parallel chains. The subunit contains a long empty channel which is about 9 X 9 X 30 A with one of the pair of parallel chains forming part of the wall. Three mercury binding sites are located in this channel. These might correspond to the two readily accessible and one of the two buried cysteine residues of each subunit. The channel terminates with another cavity of about 8 X 10 X 25 A near the surface of the oligomeric structure. The regions of the subunits near the threefold axis are characterized by a high degree of secondary structural organization and these make close intersubunit contacts. Quarternary interactions are due mainly to side-chain interactions of helices.