Brain structural and functional signatures of impulsive-compulsive behaviours in Parkinson's disease.

This study assessed brain structural and functional alterations in patients with Parkinson's disease and impulsive-compulsive behaviours (PD-ICB) compared with controls and PD no-ICB cases. Eighty-five PD patients (35 PD-ICB) and 50 controls were recruited. All subjects underwent three-dimensional T1-weighted, diffusion tensor (DT), and resting state functional magnetic resonance imaging (RS fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes using FIRST, DT MRI metrics using region of interest and tractography approaches, and RS fMRI using a model free approach. Compared with controls, both PD groups showed a pattern of brain structural alterations in the basal ganglia (more evident in PD no-ICB patients), sensorimotor and associative systems. Compared with PD no-ICB, PD-ICB cases showed left precentral and superior frontal cortical thinning, and motor and extramotor white matter tract damage. Compared with controls, all patients had an increased functional connectivity within the visual network. Additionally, PD no-ICB showed increased functional connectivity of bilateral precentral and postcentral gyri within the sensorimotor network compared with controls and PD-ICB. Severity and duration of PD-ICB modulated the functional connectivity between sensorimotor, visual and cognitive networks. Relative to PD no-ICB, PD-ICB patients were characterised by a more severe involvement of frontal, meso-limbic and motor circuits. These data suggest ICB in PD as the result of a disconnection between sensorimotor, associative and cognitive networks with increasing motor impairment, psychiatric symptoms, and ICB duration. These findings may have important implications in understanding the neural substrates underlying ICB in PD.

Transcranial sonography in dopa-responsive dystonia.

BACKGROUND AND PURPOSE: Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder. METHODS: Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs). RESULTS: Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group. CONCLUSIONS: We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.

Concerted nitrogen inversion and hydrogen bonding to Glu451 are responsible for protein-controlled suppression of the reverse reaction in human DPP III.

Human dipeptidyl-peptidase III (h.DPP III) is a zinc-exopeptidase that hydrolyses dipeptides from the N-terminus of its substrates. Its mechanism of action was assumed to be similar to that of thermolysin, but was never thoroughly investigated. This study presents the first insight into the reaction mechanism of h.DPP III, determined on the model and real (hydrated enzyme with Leu-enkephalin bound in the active site) systems. The Glu451-assisted water addition on amide carbon atoms and nitrogen inversion (i.e. change of pyramidalization on the leaving nitrogen) are shown to be the rate-determining steps with the activation energies in a good agreement with the experimental results for the Leu-enkephalin hydrolysis. The energy barrier for nucleophilic attack is about 28 kJ mol-1, while barriers for the N-inversion differ as a consequence of the number of hydrogen bonds that have to be changed, which is smaller in the model active site than in the solvated enzyme. Although precisely defined geometry of the enzyme binding site puts an additional restraint on the hydrogen bonding interactions, at the same time it stimulates the forward reaction towards the final hydrolytic product. Namely, different from the model, the N-inversion is in a concerted fashion followed by favourable hydrogen bonding with Glu451 that immediately "locks" the system into the configuration where reversion to the enzyme-substrate complex is hardly achievable. Therefore we propose that the functional significance of DPP III is dual: to lower the energy barrier of the peptide hydrolysis and to suppress the reverse reaction.

Molecular simulations reveal that the long range fluctuations of human DPP III change upon ligand binding.

The experimentally determined structures of human dipeptidyl peptidase III (DPP III) for the wild-type protein and for the complex of its E451A mutant with the peptide substrate, tynorphin, differ significantly in their overall shape. The two domains of the enzyme are separated by a wide cleft in the structure of the ligand-free enzyme, while in the ligand-bound mutant they are very close to each other, and the protein structure is extremely compact. Here, we applied a range of molecular dynamics simulation techniques to investigate the DPP III conformational landscape and the influence of ligand binding on the protein structure and dynamics. We used conventional, accelerated and steered methods to simulate DPP III and its complexes with tynorphin and with the preferred, synthetic, substrate Arg-Arg-2-naphthylamide. We found that DPP III can adopt a number of different forms in solution. The compact forms are more stable, but the open and partially closed states, spanning a wide range of conformations, can more effectively recognize the substrate which preferentially binds to the five-stranded ß-core of the lower DPP III domain. The simulations indicated the existence of a dynamic equilibrium between open and semi-closed states and revealed two ways that the protein can close, leading to two distinct compact structures. The way in which the protein closes depends on the presence of the ligand.

Transcranial brain sonography findings in two main variants of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) can occur with two main clinical presentations, classified as classical Richardson's syndrome (PSP-RS) and as PSP-parkinsonism (PSP-P), the most common atypical PSP variant. The differential diagnosis between them is challenging. Therefore, we studied different ultrasound markers by transcranial sonography in individuals with PSP-RS and PSP-P, to test their value in the diagnostic work up of these patients. METHODS: Transcranial sonography was performed in 21 patients with PSP-RS and 11 patients with PSP-P. Echogenic sizes of the substantia nigra (SN) and the lenticular nuclei (LN), as well as the width of the third ventricle, were measured. RESULTS: Among the patients with PSP-RS and PSP-P, three (14%) and eight (73%) patients had a hyperechogenic SN (P = 0.020), respectively. Uni- or bilateral hyperechogenicity of the LN was observed in 67% and 36% of patients with PSP-RS and PSP-P, respectively (P = 0.101). Third ventricle was significantly wider in patients with PSP-RS (11.2 ±â€…2.3 mm) when compared with patients with PSP-P (7.5 ±â€…1.4 mm; P = 0.001). CONCLUSION: Our data, possibly reflecting pathological differences, primarily contribute supporting the view that the neurodegenerative process differs in the two PSP variants.

Long-term outcome in Serbian patients with Wilson disease.

BACKGROUND AND PURPOSE: To investigate survival rates, prognostic factors, and causes of death in Wilson disease (WD). METHODS: In the years 1980-2007, a cohort of 142 patients with WD was prospectively registered (54 presented with neurologic symptoms, 49 with hepatic symptoms, 33 had mixed form, and data were missing for six patients). The duration of follow-up for patients alive was 11.1 +/- 8.8 years. RESULTS: After initiation of treatment (d-penicillamine and zinc salts), 79% of patients had a stable or improved course of disease. Despite early diagnosis and appropriate therapy, 15 patients still had a relentlessly progressive course. Thirty patients died. The cumulative probability of survival in a 15-year period for the whole group was 76.7 +/- 4.9%. Better prognosis of WD was associated with male sex, younger age at onset, neurologic form of the disease, and treatment continuity. Causes of death were predominantly related to hepatic failure (16 patients), but also suicide (four patients) and cancer (three patients). CONCLUSION: Despite the relatively early diagnosis and treatment of our patients with WD, mortality was still considerably high.

Local atomic structure and discommensurations in the charge density wave of CeTe3.

The local structure of in the incommensurate charge density wave (IC-CDW) state has been obtained using atomic pair distribution function analysis of x-ray diffraction data. Local atomic distortions in the Te nets due to the CDW are larger than observed crystallographically, resulting in distinct short and long Te-Te bonds. Observation of different distortion amplitudes in the local and average structures is explained by the discommensurated nature of the CDW, since the pair distribution function is sensitive to the local displacements within the commensurate regions, whereas the crystallographic result averages over many discommensurated domains. The result is supported by STM data. This is the first quantitative local structural study within the commensurate domains in an IC-CDW system.

The first bluetongue virus isolation in Yugoslavia.

Catarrhal fever in sheep or bluetongue (BT) has not been recorded in Yugoslavia until recently. During the first incidence of BT disease in Serbia and Montenegro in 2001, the authors conducted field studies on suspected cases of the disease and collected samples for laboratory diagnosis. BT virus (BTV) was isolated and identified as serotype 9 by the Institute for Animal Health in Pirbright, United Kingdom (the Office International des Epizooties BT reference laboratory).

[Aortocaval fistulas]. / Aortokavalne fistule.

Aortocaval fistulas most frequently occur as a consequence of ruptured abdominal aortic aneurysms due to the additional trauma, spontaneous or iatrogenic. The basic symptomatology is the consequence of local irritation of spinal nerves, and major hemodynamic disturbances. In this paper we have presented two cases of aortocaval fistulas, treated at the Military Medical Academy with presentation of their preoperative status, performed diagnostic procedures, applied surgical procedures, and postoperative course and outcome.

[Indications and results of fasciotomy in vascular injuries of the lower extremities]. / Indikacije i rezultati fasciotomija kod vaskularnih povreda donjih ekstremiteta.

Aim of this study was to re-evaluate the indications for fasciotomy in war vascular injuries of the lower extremities. Retrospective and partially prospective analysis of 31 patients with surgical revascularisation performed during 1999 was done. Fasciotomy has been used as a prophylactic measure against development of Compartment Syndrome (CSy) in three out of ten patients within the first group where ischemia time was less than six hours before the time of repair. The second group, where ischemia time was longer than six hours before the time of repair, prophylactic fasciotomy (measured compartmental pressure lower than 30 mmHg) was performed in 8 patients. In 13 patients with already developed CSy fasciotomy was performed as the delayed treatment (measured compartmental pressure higher than 30 mmHg). Neither one of patients from the first group developed CSy. All patients who developed CSy had necrosis of neuromuscular tissues at the time of surgery. Musculectomy was required in five and limb amputation in six patients. The conclusion of this study is that when the ischemia time is less than six hours before the time of repair fasciotomy is not necessary. When the period from injury to the revascularisation is longer than six hours the prophylactic fasciotomy is recommended.

Aspectos morfo-funcionales de arterias y venas mamarias usadas en revascularización cardíaca / Morphologic and functional aspects of mammary arteries and veins used for myocardial revascularization surgery

Los vasos sanguíneos están inervados por el sistema nervioso simpático autonómico. La fisiología y neuroquímica de los nervios perivasculares humanos ha sido poco estudiada. Con el propósito de contribuir a las investigaciones sobre la fisiología de la co-transmisión simpática humana, esta investigación se concentró en: i) estudiar el contenido de los neurotransmisores simpáticos, noradrenalina (NA) y neuropéptido y (NPY) en vasos de arteria y vena mamaria interna humana; ii) detectar mediante técnicas inmunohistoquímicas la presencia de los nervios simpáticos perivasculares de estos vasos; iii) caracterizar la reactividad vascular de la arteria mamaria interna, como un modelo usado en implantes de revascularización cardíaca. Se estudió además, la vena mamaria derivada de la misma biopsia. La arteria y vena mamaria contienen 50 veces más NA que NPY, el contenido de NA y NPY en la arteria y en la vena es muy similar. La detección inmunohistoquímica de los nervios simpáticos demuestra que éstos se localizan entre las capas musculares de los vasos. La estimulación de los filetes nerviosos perivasculares produce respuestas vasomotoras sensibles a tetrodotoxina y guanetidina, lo que es consistente con la naturaleza simpática de la respuesta, confirmando que parte de los nervios perivasculares son simpáticos. Los músculos lisos se estimulan por NA y por ATP, que sólo no contrae, facilita las respuestas vasomotoras de la NA. Estos resultados permiten concluir que en la arteria y la vena mamaria interna humana NA, ATP y NPY cooperan en la respuesta vasomotora, evidenciando la co-transmisión simpática en humanos