Assignment of the absolute configuration at the sulfur atom of thioridazine metabolites by the analysis of their chiroptical properties: The case of thioridazine 2-sulfoxide

Thioridazine (THD) is a commonly prescribed phenotiazine neuroleptic drug, which is extensively biotransformed in the organism producing as main metabolites sulfoxides and a sulfone by sulfur oxidation Significant differences have been observed in the activity of the THD enantiomers as well as for its main metabolites, and enantioselectivity phenomena have been proved in the metabolic pathway. Here the assignment of the absolute configuration at the sulfur atom of enantiomeric THD-2-sulfoxide (THD-2-SO) has been carried out by circular dichroism (CD) spectroscopy The stereoisomers were separated by HPLC on Chiralpak AS column, recording the CD spectra for the two collected enantiomeric fractions The theoretical electronic CD spectrum has been obtained by the TDDFT/B3LYP/6-31G*. as Boltzmann averaging of the contributions calculated for the most stable conformations of the drug The comparison of the simulated and experimental spectra allowed the absolute configuration at the sulfur atom of the four THD-2-SO stereoisomers to be assigned The developed method should be useful for a reliable correlation between stereochemistry and activity and/or toxicity

Distinct conformational properties determined by implicit and explicit representation of protein-solvent interactions. An analytical and computer simulation study

In the protein folding problem, solvent-mediated forces are commonly represented by intra-chain pairwise contact energy. Although this approximation has proven to be useful in several circumstances, it is limited in some other aspects of the problem. Here we show that it is possible to achieve two models to represent the chain-solvent system. one of them with implicit and other with explicit solvent, such that both reproduce the same thermodynamic results. Firstly, lattice models treated by analytical methods, were used to show that the implicit and explicitly representation of solvent effects can be energetically equivalent only if local solvent properties are time and spatially invariant. Following, applying the same reasoning Used for the lattice models, two inter-consistent Monte Carlo off-lattice models for implicit and explicit solvent are constructed, being that now in the latter the solvent properties are allowed to fluctuate. Then, it is shown that the chain configurational evolution as well as the globule equilibrium conformation are significantly distinct for implicit and explicit solvent systems. Actually, strongly contrasting with the implicit solvent version, the explicit solvent model predicts: (i) a malleable globule, in agreement with the estimated large protein-volume fluctuations; (ii) thermal conformational stability, resembling the conformational hear resistance of globular proteins, in which radii of gyration are practically insensitive to thermal effects over a relatively wide range of temperatures; and (iii) smaller radii of gyration at higher temperatures, indicating that the chain conformational entropy in the unfolded state is significantly smaller than that estimated from random coil configurations. Finally, we comment on the meaning of these results with respect to the understanding of the folding process. (C) 2009 Elsevier B.V. All rights reserved.

Endophytic fungi found in association with Smallanthus sonchifolius (Asteraceae) as resourceful producers of cytotoxic bioactive natural products

Smallanthus sonchifolius is a traditional Andean plant which has been cultured mainly in Brazil, Japan and New Zealand due to its medicinal properties. A study of the endophytic fungi associated to the plant was carried out in order to characterize new cytotoxic agents. Thirty two fungal strains were isolated and submitted to cultivation and extraction producing 186 extracts. Of these, 12% displayed moderate to high cytotoxic activities and were considered promising anticancer compound sources. The ethyl acetate fractions of Nigrospora sphaerica and Phoma betae liquid fermentations contained the synergistic compounds 8-hydroxy-6-methoxy-3-methylisocoumarin and (22E,24R)-ergosta-4,6,8(14),22-tetraen-3-one which are potential compounds for drug discovery. Another isolated compound, pimara-7,15-dien-3-beta-ol diterpene is being characterized for the first time through a detailed spectroscopic analysis including GC/MS, homo- and hetero-nuclear correlated NMR experiments (HMQC, HMBC, COSY and NOEdiff) along with its optical rotation.

Microdialysis study of striatal dopamine in MPTP-hemilesioned rats challenged with apomorphine and amphetamine

Motor impairments of Parkinson`s disease (PD) appear only after the loss of more than 70% of the DAergic neurons of the substantia nigra pars compacta (SNc). An earlier phase of this disease can be modeled in rats that received a unilateral infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) into the SNc. Though these animals do not present gross motor impairments, they rotate towards the lesioned side when challenged with DAergic drugs, like amphetamine and apomorphine. The present study aimed to test whether these effects occur because the drugs disrupt compensatory mechanisms that keep extracellular levels of dopamine in the striatum (DA(E)) unchanged. This hypothesis was tested by an in vivo microdialysis study in awake rats with two probes implanted in the right and left striatum. Undrugged rats did not present turning behaviour and their basal DA(E) did not differ between the lesioned and sham-lesioned sides. However, after apomorphine treatment, DA(E) decreased in both sides, but to a larger extent in the lesioned side at the time the animals started ipsiversive turning behaviour. After amphetamine challenge, DA(E) increased in both sides, becoming significantly higher in the non-lesioned side at the time the animals started ipsiversive turning behaviour. These results are in agreement with the hypothesis that absence of gross motor impairments in this rat model of early phase PD depends on maintenance of extracellular DA by mechanisms that may be disrupted by events demanding its alteration to higher or lower levels. (C) 2010 Elsevier B.V. All rights reserved.

ISPRM`S WAY FORWARD

This paper outlines approaches to developing the International Society of Physical and Rehabilitation Medicine (ISPRM) and addresses many current challenges Most importantly, these approaches provide the basis for ISPRM to develop its leadership role within the field of Physical and Rehabilitation Medicine (PRM) and in relation to the World Health Organization (WHO) and the United Nations (UN) system at large. They also address a number of specific critiques of the current situation. A positioning of ISPRM within the world architecture of the UN and WHO systems, as well as the consideration and fostering of respective emerging regional PRM societies, is central to establishing networking connections at different levels of the world society. Yearly congresses, possibly in co-operation with a regional society, based on a defined regional rotation, are suggested. Thus, frustration with the current bidding system for a biennial congress and an intermediate meeting could be overcome. Yearly congresses are also an important step towards increasing the organization`s funding base, and hence the possibility to expand the functions of ISPRM`s central office. ISPRM`s envisioned leadership role in the context of an international web of PRM journals complementing the formally defined official journal of ISPRM, regional societies and so forth, is an inclusive rather than exclusive approach that contributes to the development of PRM journals worldwide. An important prerequisite for the further development of ISPRM is the expansion and bureaucratization of its Central Office, adding professionalism and systematic allocation of resources to the strengths of the voluntary engagement of individual PRM doctors.

Evaluation of Primary Cleft Nose Repair: Severity of the Cleft Versus Final Position of the Nose

Background: Since 1957, when the concept of rotation-advancement repair was introduced by Millard, this technique has become the procedure of choice for unilateral cleft lip worldwide. More recently, modifications described by Noordhoof, Mohler, Skoog, and McComb started being jointly performed so that better results could be obtained. In this study, the nasal position was evaluated and related to the size of the cleft. The primary unilateral cleft lip repair was performed through a modified technique. Methods: Forty-five patients with unilateral cleft lip underwent primary surgical repair through this technique. To analyze aesthetic results, a severity classification of deformities and a scoring system for evaluation of the results were established based on nasal alar lateralization, dome position, alignment of bone segments, and deviation of the columella. Results: By means of the established system, 26.6% of mild forms, 13.4% of moderate forms, and 60% of severe forms were observed. Among aesthetic results, 17.8% were found to be good, and 82.2% were considered excellent. Among aspects considered negative, late deformity of the lower lateral cartilage prevailed. Conclusions: Through the presented evaluation, the authors observed that there was no relation between severity of the cleft and final position of the nose. Among the 27 patients considered to have had severe forms of cleft deformity, 22 were classified as excellent results (81.5%). To obtain better results along time, technical refinements and the critical analysis of results must be performed on a routinely basis.

Musculoskeletal Dysfunction and Pain in Adults with Asthma

Background. The mechanical alterations related to the overload of respiratory muscles observed in adults with persistent asthma might lead to the development of chronic alterations in posture, musculoskeletal dysfunction and pain; however, these changes remain poorly understood. Objective. This study aimed to assess postural alignment, muscle shortening and chronic pain in adults with persistent asthma. Methods. This cross-sectional and controlled study enrolled 30 patients with mild (n = 17) and severe ( n = 13) persistent asthma. Fifteen non-asthmatic volunteers were also assessed. Asthma was classified by the Global Initiative for Asthma (GINA) guidelines. Postural alignment and muscle shortening were evaluated by head and shoulder positions, chest wall mobility, and posterior ( trunk and lower limb) muscle flexibility. In addition, the measures used were previously tested for their reproducibility. Pain complaints were also assessed. Results. In comparison with non-asthmatic subjects, patients with mild or severe persistent asthma held their head and shoulders more forward and had lower chest wall expansion, decreased shoulder internal rotation, and decreased thoracic spine flexibility. Chronic lower thoracic, cervical, and shoulder pain was significantly increased in patients with mild or severe asthma compared with non-asthmatic subjects (p < 0.05). Conclusion. Adults with persistent asthma have musculoskeletal dysfunction and chronic pain that is independent of the severity of their disease but that might be related to their age at the onset of disease symptoms.

Ipsilateral Lung Volumes Assessed by Three-Dimensional Ultrasonography in Fetuses with Isolated Congenital Diaphragmatic Hernia

Objective: To evaluate the precision of three-dimensional ultrasonography (3DUS) in estimating the ipsilateral lung volume and the potential of this measurement to predict neonatal death in congenital diaphragmatic hernia (CDH). Methods: Between January 2002 and December 2004, the ipsilateral lung volumes were assessed by 3DUS using the technique of rotation of the multiplan imaging in 39 fetuses with CDH. The observed/ expected ipsilateral lung volume ratios (o/e-IpsiFLVR) were compared to the lung/head ratios (LHR) and to the observed/ expected total fetal lung volume ratios (o/e-TotFLVR) as well as to postnatal death. Results: Ipsilateral lung volumes (median 0.12, range 0.01-0.66) were more reduced than the total lung volumes (median 0.52, range 0.11-0.95, p < 0.001) in CDH. The bias and precision of 3DUS in estimating ipsilateral lung volumes were -0.61 and 0.99 cm 3, respectively, with absolute limits of agreement from -2.56 to +1.33 cm(3). The o/e-IpsiFLVR was lower in neonatal death cases (median 0.09, range 0.01-0.46) than in survivals (median 0.18, range 0.01-0.66), but this difference was not statistically significance (p > 0.05). The sensitivity, speci-ficity, (positive and negative) predictive values and accuracy of o/e-IpsiFLVR in predicting neonatal death was 52.6% (10/19), 83.3% (10/12), 83.3% (10/12), 52.6% (10/19) and 64.5% (20/31), respectively. Conclusion: Although the ipsilateral lung volume can be measured by 3DUS, it cannot be used to predict neonatal death when considering it alone. However, it is important to measure it to calculate the total fetal lung volumes as the o/e-TotFLVR has the best efficacy in predicting neonatal death in isolated CDH. Copyright (C) 2008 S. Karger AG, Basel

One-dimensional point interaction with three complex parameters

For a pair of non-Hermitian Hamiltonian H and its Hermitian adjoint H(dagger), there are situations in which their eigenfunctions form a biorthogonal system. We illustrate such a situation by means of a one-particle system with a one-dimensional point interaction in the form of the Fermi pseudo-potential. The interaction consists of three terms with three strength parameters g(i) (i = 1, 2 and 3), which are all complex. This complex point interaction is neither Hermitian nor PT-invariant in general. The S-matrix for the transmission reflection problem constructed with H (or with H(dagger)) in the usual manner is not unitary, but it conforms to the pseudo-unitarity that we define. The pseudounitarity is closely related to the biorthogonality of the eigenfunctions. The eigenvalue spectrum of H with the complex interaction is generally complex but there are cases where the spectrum is real. In such a case H and H(dagger) form a pseudo-Hermitian pair.

Hypomania: a transcultural perspective

This study examined the transcultural robustness of a screening instrument for hypomania, the Hypomania Checklist-32. first revised version(HCL-32 R1) It was carried out in 2606 patients from twelve countries in five geographic regions (Northern, Southern and Eastern Europe, South America and East Asia) In addition, GAMIAN Europe contributed data from its members Exploratory and confirmatory factor analyses were used to examine the transregional stability of the measurement properties of the HCL-32 R 1, including the influence of sex and age as covariates A cross cultures, a two-factor structure was confirmed the first factor (F 1) reflected the more positive aspects of hypomania (being more active, elated, self-confident, and cognitively, enhanced), the second factor (F2) reflected the more negative aspects (being irritable, impulsive, careless. more substance use). The measurement properties of the HCL-32 R1 were largely invariant across cultures Only few items showed transcultural differences in their relation to hypomania as measured by the test F2 was higher among men and in more severe manic syndromes, F1 was highest in North and East Europe and lowest in South America Vie scores decreased slightly with age The frequency of the 32 items showed remarkable similarities across geographic areas, with two exceptions. South Europeans had lower symptom frequencies in general and East Europeans higher rates of substance use These findings support the international applicability of the HCL-32 R1 as a screening instrument for hypomania

Factors associated with pelvic asymmetry in transverse plane during gait in patients with cerebral palsy

The purpose of this study was to describe the patterns of pelvic rotational asymmetry in the transverse plane and identify the possible factors related to this problem. One thousand and forty-five patients with cerebral palsy (CP) and complete documentation in the gait laboratory were reviewed in a retrospective study. Pelvic asymmetry in the transverse plane was observed in 52.7% of the patients; and to identify the possible causes of pelvic retraction, clinical (Thomas test, popliteal angle, and gastrocnemius tightness) and dynamic parameters (mean rotation of the hip in stance, minimum hip flexion, minimum knee flexion, and peak ankle dorsiflexion) were evaluated. The association between these parameters and pelvic retraction was assessed statistically. The results showed that 75.7% of patients with asymmetric pattern of the pelvis had clinical diagnosis of diplegic spastic CP. Among the patients with asymmetrical CP, the most common pattern was pelvic retraction on the affected side. The relationship between pelvic retraction and internal hip rotation was stronger in patients with asymmetrical diplegic CP than in those with hemiplegic (P<0.001) or symmetrical diplegic CP (P=0.014). All of the patients exhibited a significant association among clinical parameters (Thomas test, popliteal angle, and gastrocnemius tightness) and pelvic retraction. In conclusion, pelvic retraction seems to be a multifactorial problem, and the etiology can change according to topographic classification, which must be taken into account during the decision-making process in patients with CP. J Pediatr Orthop B 18:320-324 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

TRANSFER OF A FASCICLE FROM THE POSTERIOR CORD TO THE SUPRASCAPULAR NERVE AFTER INJURY OF THE UPPER ROOTS OF THE BRACHIAL PLEXUS: TECHNICAL CASE REPORT

OBJECTIVE: A new nerve transfer technique using a healthy fascicle of the posterior cord for suprascapular nerve reconstruction is presented. This technique was used in a patient with posttraumatic brachial plexopathy resulting in upper trunk injury with proximal root stumps that were unavailable for grafting associated with multiple nerve dysfunction. CLINICAL PRESENTATION: A 45-year-old man sustained a right brachial plexus injury after a bicycle accident. Clinical evaluation and electromyography indicated upper trunk involvement. Trapezius muscle function and triceps strength were normal on physical examination. INTERVENTION: The patient underwent a combined supra- and infraclavicular approach to the brachial plexus. A neuroma-in-continuity of the upper trunk and fibrotic C5 and C6 roots were identified. Electrical stimulation of the phrenic and spinal accessory nerves produced no response. The suprascapular nerve was dissected from the upper trunk, transected, and rerouted to the infraclavicular fossa. A healthy fascicle of the posterior cord to the triceps muscle was transferred to the suprascapular nerve. At the time of the 1-year follow-up evaluation, arm abduction against gravity and external rotation reached 40 and 34 degrees, respectively. CONCLUSION: The posterior cord can be used as a source of donor fascicle to the suprascapular nerve after its infraclavicular relocation. This new intraplexal nerve transfer could be applied in patients with isolated injury of the upper trunk and concomitant lesion of the extraplexal nerve donors usually used for reinnervation of the suprascapular nerve.

Lower cytokine secretion ex vivo by natural killer T cells in HIV-infected individuals is associated with higher CD161 expression

Objective: Natural killer T (NKT) cells are efficiently targeted by HIV and severely reduced in numbers in the circulation of infected individuals. The functional capacity of the remaining NKT cells in HIV-infected individuals is poorly characterized. This study measured NKT cell cytokine production directly ex vivo and compared these responses with both the disease status and NKT subset distribution of individual patients. Methods: NKT cell frequencies, subsets, and ex-vivo effector functions were measured in the peripheral blood mononuclear cells of HIV-infected patients and healthy controls by flow cytometry. We measured cytokines from NKT cells after stimulation with either a-galactosyl ceramide-loaded CD1d dimers (DimerX-alpha GalCer) or phorbol myristate acetate and ionomycin. Results: The frequencies of NKT cells secreting interferon-gamma and tumor necrosis factor-alpha were significantly lower in HIV-infected patients than healthy controls after DimerX-alpha GalCer treatment, but responses were similar after treatment with phorbol myristate acetate and ionomycin. The magnitude of the interferon-gamma response to DimerX-alpha GalCer correlated inversely with the number of years of infection. Both interferon-gamma and tumor necrosis factor-alpha production in response to DimerX-alpha GalCer correlated inversely with CD161 expression. Conclusion: The ex-vivo Th1 responses of circulating NKT cells to CD1d-glycolipid complexes are impaired in HIV-infected patients. NKT cell functions may be progressively lost over time in HIV infection, and CD161 is implicated in the regulation of NKT cell responsiveness. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Study of the discovery potential of light custodians in a clean decay channel at the LHC

Models of warped extra dimensions with custodial symmetry usually predict the existence of a light Kaluza-Klein fermion arising as a partner of the right-handed top quark, sometimes called light custodians which we will denote (b) over tilde (R). The production of these particles at the LHC can give rise to multi-W events which could be observed in same-sign dilepton channels, but its mass reconstruction is challenging. In this paper we study the possibility of finding a signal for the pair production of this new particle at the LHC focusing on a rarer, but cleaner decay mode of a light custodian into a Z boson and a b-quark. In this mode it would be possible to reconstruct the light custodian mass. In addition to the dominant standard model QCD production processes, we include the contribution of a Kaluza-Klein gluon first mode. We find that (b) over tilde (R) stands out from the background as a peak in the bZ invariant mass. However, when taking into account only the electronic and muonic decay modes of the Z boson and b-tagging efficiencies, the LHC will have access only to the very light range of masses, m((b) over tilde) = O(500) GeV.

HANDEDNESS INFLUENCES PASSIVE SHOULDER RANGE OF MOTION IN NONATHLETE ADULT WOMEN

Objective: The Purpose of this study was to determine whether handedness influences bilateral shoulder range of motion in nonathlete adult women. Methods: This was an observational Study. Shoulder range of motion (flexion, abduction, horizontal adduction, extension, external and internal rotation) was passively and bilaterally measured in 50 female, right-handed, and healthy university students, ranging from 20 to 29 years of age, who were not practicing repetitive activities with the upper limbs at the time Of this study. The assessment was performed with a universal goniometer, twice for each subject by the same examiner. irst and second measurements were correlated using the intraclass correlation coefficient, which was high for all movements and ranged from 0.80 to 0.97. The Student t test and Wilcoxon test were used to compare the range of motion between the dominant and nondominant shoulders and the mean differences between the 2 sides. The effect of size vias alpha = .05. Results: There is statistically significance difference between the 2 sides when the rotational range of motion is compared the dominant shoulder presented increased external rotation (mean, 4.74 degrees; 95% confidence interval, 1.61-7.87) and decreased internal rotation (mean, 3.52 degrees; 95% confidence interval, 1.64-5.4) compared to the opposite Shoulder. Conclusion: Dominance should be considered when shoulder rotation is evaluated even in nonathlete adult women. (J Manipulative Physiol Ther 2009;32:149-153)