The Internet Addiction Scale (IAS) is a self-report instrument based on the seven substance dependence criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th ed., American Psychiatric Association, 1994) and two additional criteria recommended by Griffiths. The IAS was administered to 300 high school students along with the Beck Depression Inventory (BDI) and Submissive Acts Scale (SAS). For test-retest reliability, the IAS was administered a second time 7 days after the first administration. An interitem reliability reduced the initial scale from 31 to 27 items (with Cronbach's alpha of 0.94). The factor analysis suggests the existence mainly of one factor in the IAS. Correlation analyses indicated that BDI and SAS were significantly correlated positively with the IAS. One-week test-retest correlation for the IAS was highly significant. According to these results, the psychometric properties of the IAS are promising.

Spectral analysis (SA) of blood pressure (BP) and heart rate (HR) fluctuations has been proposed as a unique approach to obtain a deeper insight into cardiovascular regulatory mechanisms in health and disease. A number of studies performed over the last 15 years have shown that autonomic influences are involved in the modulation of fast BP and HR fluctuations (with a period <1 min), particularly at frequencies between 0.2 and 0.4 Hz [high frequency (HF) region or respiratory frequency] and around 0.1 Hz [mid frequency (MF) region]. In patients with secondary or primary autonomic dysfunction, SA of BP and HR signals recorded at rest or during orthostatic challenge in a laboratory environment have shown the occurrence of a reduction in the power of MF and/or HF, BP and HR components. Such a reduction is associated or may even precede the clinical manifestation of autonomic neuropathy. However, the above results collected in standardized laboratory conditions cannot reflect the features of neural cardiovascular control during daily life in ambulant individuals with autonomic failure. To investigate this issue, SA techniques have been applied to 24 h beat-to-beat intra-arterial and non-invasive finger BP recordings obtained in elderly subjects and in pure autonomic failure patients, respectively. In these conditions, HR powers displayed a reduction over a wide range of frequencies (from 0.5 to below 0.01 Hz). Conversely, BP powers underwent a complex rearrangement characterized by a reduction in the power around 0.1 Hz and by an increase in the powers at the respiratory frequency and at frequencies below 0.01 Hz. Dynamic quantification of the sensitivity of the baroreceptor-heart rate reflex by combined analysis of systolic BP and pulse interval (i.e. the interval between consecutive systolic peaks) powers around 0.1 Hz (alpha technique) has shown that in elderly subjects, and even more so in pure autonomic failure patients, baroreflex sensitivity is markedly reduced over the 24 h, and is no longer characterized by its physiological day-night modulation. In conclusion, although in some instances SA of cardiovascular signals may fail to fully reflect the features of autonomic cardiovascular control, the evidence discussed clearly demonstrates that this approach represents a promising tool for a dynamic assessment of the early impairment of neural circulatory control in autonomic failure. This is particularly the case when these analyses are performed on 24 h continuous BP and HR recordings in ambulant subjects.

Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (n=43) and stable angina (SA) (n=15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (P<0.01). UA biopsy samples showed numerous DR+ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-alpha, IL-6, IFN-gamma, and iNOS genes (P<0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-alpha, IL-6, and iNOS, and, to a lesser extent, of IFN-gamma genes, but did not affect the number of DR+ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina.

The innate immune response is, in the first place, elicited at the site of infection. Thus, the host response can be different among the infected cells and the cells surrounding them. Effector-triggered immunity (ETI), a form of innate immunity in plants, is triggered by specific recognition between pathogen effectors and their corresponding plant cytosolic immune receptors, resulting in rapid localized cell death known as hypersensitive response (HR). HR cell death is usually limited to a few cells at the infection site, and is surrounded by a few layers of cells massively expressing defense genes such as Pathogenesis-Related Gene 1 (PR1). This virtually concentric pattern of the cellular responses in ETI is proposed to be regulated by a concentration gradient of salicylic acid (SA), a phytohormone accumulated around the infection site. Recent studies demonstrated that jasmonic acid (JA), another phytohormone known to be mutually antagonistic to SA in many cases, is also accumulated in and required for ETI, suggesting that ETI is a unique case. However, the molecular basis for this uniqueness remained largely to be solved. Here, we found that, using intravital time-lapse imaging, the JA signaling pathway is activated in the cells surrounding the central SA-active cells around the infection sites in Arabidopsis thaliana. This distinct spatial organization explains how these two phythormone pathways in a mutually antagonistic relationship can be activated simultaneously during ETI. Our results re-emphasize that the spatial consideration is a key strategy to gain mechanistic insights into the apparently complex signaling cross-talk in immunity.

OBJECTIVE

We have reported that indoxyl sulfate (IS), a uremic toxin, accelerates proximal tubular cell senescence. Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been reported to induce endothelial cell senescence. This study aimed to determine whether IS induces endothelial cell senescence in comparison with ADMA, and to investigate its molecular mechanism.

METHODS

Human umbilical vein endothelial cells (HUVECs) were incubated with IS (250 μM) and/or ADMA (10 μM). These concentrations were comparable with their mean serum levels in hemodialysis patients. Cell senescence was evaluated by measuring senescence-associated beta-galactosidase (SA-β-gal) activity. N-acetylcysteine, an antioxidant, and pifithrin alpha p-nitro, a p53 inhibitor, were used to determine the role of reactive oxygen species (ROS) and p53 in the induction of cell senescence.

RESULTS

Both IS and ADMA significantly increased SA-β-gal activity in HUVECs. Further, some additional increase in SA-β-gal activity was observed when IS and ADMA were co-incubated. Preincubation of N-acetylcysteine or pifithrin alpha p-nitro significantly inhibited SA-β-gal activity induced by IS and ADMA in HUVECs. Thus, both IS and ADMA induced endothelial senescence through ROS and p53.

CONCLUSIONS

IS induces endothelial cell senescence by increasing ROS production and p53 activity, like ADMA.

BACKGROUND

Natural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity.

OBJECTIVE

In vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human T(H)2 cells was performed.

METHODS

The functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells.

RESULTS

The synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-alpha, and IL-6 by CD14(+) cells and IFN-alpha and CXCL10 by blood dendritic cell antigen (BDCA)-4(+) plasmacytoid dendritic cells. A nuclear factor kappaB-dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific T(H)2 cells toward the T(H)1/T(H)0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors.

CONCLUSIONS

Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific T(H)2 cells to a T(H)1/T(H)0 phenotype.

CONCLUSIONS

Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.

OBJECTIVE

To assess the relationship between insulin resistance and baroreflex gain (BRS) in the context of the metabolic syndrome.

METHODS

Observational population study.

METHODS

We studied the healthy population of a small Mediterranean island (Linosa, about 0.5 square miles, 450 inhabitants) where genetic, psychosocial and behavioral bias is likely to be minimal for historical and social reasons.

METHODS

Baroreflex gain (BRS, by the frequency domain alpha index) and indices of autonomic regulation of the sino-atrial (SA) node derived from spectral analysis of RR interval variability were obtained, together with metabolic and behavioral indicators in the 144 participating subjects (age range 20-82 years). Carotid artery thickness (CCA) was also obtained with computer-aided ultrasound techniques. Insulin resistance was estimated by the homeostasis model assessment (HOMA), and subjects divided in tertiles accordingly.

RESULTS

BRS appeared to be reduced progressively with increasing levels of HOMA (respectively, 21.0 +/- 2.6, 17.7 +/- 1.7, 15.7 +/- 1.9 ms/mmHg, P < 0.03), while spectral indices of autonomic SA regulation appeared to be only insignificantly affected. Conversely, CCA was significantly increased with increasing HOMA (P < 0.024). Furthermore, BRS appeared to be significantly correlated with various elements of the metabolic syndrome, with CCA and abdominal obesity showing the strongest link.

CONCLUSIONS

In an otherwise healthy population, BRS, but not spectrally derived indices of SA node autonomic regulation, are progressively reduced with increasing severity of insulin resistance, possibly as a consequence of attendant carotid artery thickening.

A cryptically I-active sialylglycoprotein (glycoprotein 2) isolated from bovine erythrocyte membranes as Sendai virus receptor (Suzuki, Y., Suzuki, T. and Matsumoto, M. (1983) J. Biochem. 93, 1621-1633) contains N-glycolylneuraminic acid (NeuGc) as its predominate sialic acid and exhibits poor receptor activity for a variety of influenza viruses. Enzymatic modification of asialoglycoprotein-2 to contain N-acetylneuraminic acid (NeuAc) in the NeuAc alpha 2-3Gal and NeuAc alpha 2-6Gal sequences using specific sialyltransferase resulted in the appearance of receptor activity toward human influenza viruses A and B. The biological responsiveness chicken erythrocytes treated with sialidase and then reconstituted with derivatized glycoprotein 2 showed considerable recovery to influenza virus hemagglutinin-mediated agglutination, low-pH fusion and hemolysis. Specific hemagglutination inhibition activity of derivatized glycoprotein 2 was 5-16-times higher than that of human glycophorin. A/PR/8/34 (H1N1) virus preferentially recognized derivatized glycoprotein 2 containing NeuAc alpha 2-3Gal sequence over that containing NeuAc alpha 2-6Gal while the specificity of A/Aichi/2/68 (H3N2) for the sialyl linkages was reversed. B/Lee virus recognized both sequences almost equally. The biological responsiveness to the viruses of the erythrocytes labeled with the derivatized glycoprotein 2 containing NeuGc was considerably lower than that of derivatized glycoprotein 2 containing NeuAc. The results demonstrate that the hemagglutinins of human isolates of influenza viruses A and B differ in the recognition of microdomains (NeuAc, NeuGc) of the receptors for binding and fusion activities in viral penetration and the sequence to which sialic acid (SA) is attached (SA alpha 2-3Gal, SA alpha 2-6Gal). Inner I-active neolacto-series type II sugar chains may be important in revealing the receptor activity toward the hemagglutinin of both human influenza viruses A and B.

A 70-year-old woman underwent right hemicolectomy and six carcinomas were recognized in the resected colon. These carcinomas were considered to be of a cell lineage common to serrated adenoma (SA) and hyperplastic (metaplastic) polyp (H/MP), because of the occurrence of multiple SAs and H/MPs around the carcinomas, as well as the co-existence of SA and H/MP areas within the carcinomas. These carcinomas had the following common histological and immunohistochemical features: a serrated structure resembling SA; a lace-like structure; infiltrative growth within the muscularis propria, with dedifferentiation at the invasive front; and immunohistochemical expression of pS2 and human gastric mucin. Based on these features, a new subtype of carcinoma is proposed, with a cell lineage common to SA and H/MP. It would also seem that p53 is involved in the serrated adenoma-carcinoma sequence.

OBJECTIVE

The use of an alpha emitter for radioimmunotherapy has potential advantages compared with beta emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of short-lived alpha emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretargeted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the alpha emitter, (213)Bi-labeled biotin.

METHODS

Biotinidase-resistant 7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-biotin was radiolabeled with (205,206)Bi or (213)Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 micro g) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored.

RESULTS

Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted. At therapeutically effective doses renal toxicity was observed.

CONCLUSIONS

(213)Bi-DOTA-biotin, directed by the Pretarget method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.

The thin layer chromatogram binding assay was used to study the reaction of several natural-monoclonal autoantibodies which recognize sialic acid-dependent antigens of human erythrocytes. Immunostaining of gangliosides derived from human and bovine erythrocytes was achieved with four autoantibodies designated anti-Pr2, anti-Gd, Sa and Fl, each of which has a different haemagglutination pattern with untreated and proteinase-treated erythrocytes and with cells of I and i antigen types. From the chromatogram binding patterns of anti-Pr2 with gangliosides of the neolacto and the ganglio series, it is deduced that this antibody reacts best with N-acetylneuraminic acid when it is alpha 2-3- or alpha 2-6-linked to a terminal Gal(beta 1-4)Glc/GlcNAc GlcNAc sequence and to a lesser extent when it is alpha 2-3-linked to a terminal Gal(beta 1-3)GalNAc sequence or to an internal galactose and when it is alpha 2-8-linked to another, internal N-acetylneuraminic acid residue. The other three antibodies differ from anti-Pr2 in their lack of reaction with glycolipids of the ganglio series. They react with the NeuAc(alpha 2-3)Gal(beta 1-4)Glc/GlcNAc sequence as found in GM3 and in glycolipids of the neolacto series, but show a preference for the latter, longer sequences. Thus all four antibodies react with sialylated oligosaccharides containing i type (linear) and I type (branched) neolacto backbones. Fl antibody differs from the other three in its stronger reaction with branched neolacto sequences in accordance with its stronger agglutination of erythrocytes of I rather than i type. The four antibodies show a specificity for N-acetyl- rather than N-glycolyl-neuraminic acid.

Intracellular reactive oxygen species (ROS) were attenuated by the expression of peroxiredoxin II (Prx II). Cellular senescence as judged by senescence-associated (SA)-beta-galactosidase (Gal) positive cell formation was increased in Prx II-deficient mouse embryonic fibroblast (MEF). Ras expression was increased following passages. The level of Ras expression was higher in Prx II-/- MEF than wild type MEF. ERK activity was also augmented by the deletion of Prx II. SA-beta-Gal-positive cell formation was reduced by PD98059, ERK inhibitor. Activated nuclear transcription factor, nuclear factor-kappaB (NFkappaB) by the deletion of Prx II was inhibited by the treatment with PD98059. In contrast, no changes in SA-beta-Gal-positive cell formation were detected by NFkappaB inhibitor, N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK). Collectively, results suggest that Prx II deletion activate Ras-ERK-NFkappaB pathways and cellular senescence in Prx II-/- MEF cells was mediated by ERK activation but not by NFkappaB activation.

The pharmacokinetics of vincristine (VCR) after an intravenous bolus dose of 2 mg were studied in patients with cancer with and without a concomitant treatment with the calcium-entry blocker nifedipine (NIF). VCR concentrations were determined by a sensitive radioimmunoassay. Pharmacokinetic data were analyzed by a nonlinear weighted least-square regression program (SAS-NLIN). A tri-exponential model fitted the raw data better than a bi-exponential model in five of 14 (35%) patients treated with VCR alone and in seven of 12 (58%) patients treated with VCR plus NIF (P = NS). The T1/2 alpha was shorter in NIF-treated patients, whereas the T1/2 gamma was longer in the NIF-treated group. The NIF-treated group showed an increase in the AUC O-infinity and AUC 1 to 96 hours, and a decrease in the AUC 0 to 1 hour. Total plasma clearance of VCR and 7-day urinary excretion of VCR was reduced in the NIF-treated patients. These data suggest that, when VCR is administered to NIF-treated patients with cancer, there is a decrease in VCR clearance from the body. Theoretically, a greater cytotoxicity may be anticipated.

OBJECTIVE

Sleep apnoea (SA) is a common problem among congestive heart failure (CHF) patients. Evidence has shown that cardiac resynchronization therapy (CRT) reduces morbidity and mortality associated with CHF. The aim of this paper was to review studies evaluating the reduction of the Apnoea-Hypopnoea Index (AHI) in patients with SA after treatment with CRT and to perform a meta-analysis to estimate the true effect of CRT on SA.

RESULTS

A systematic electronic literature search was conducted in Medline and Embase to identify studies reporting on the effects of CRT on SA. A hand search of five major cardiology societies was performed to identify any unpublished studies through structured abstracts submitted to conference proceedings. To be eligible for inclusion, studies had to include a comparison of CRT vs. no pacing and use AHI as an outcome. Non-English studies were excluded. Nine manuscripts and five abstracts were identified for review. Six manuscripts and three abstracts were included in meta-analysis, which included 170 patients. After treatment with CRT, a significant reduction in AHI was found in patients with central sleep apnoea (CSA) with a mean reduction of -13.05 (CI -16.74 to -9.36; P < 0.00001) but not in patients with obstructive sleep apnoea (13.32; CI -9.04 to 2.39; P = 0.25).

CONCLUSIONS

Cardiac resynchronization therapy reduces the severity of SA. Major effects are seen in patients with CSA. The presence of SA may be an additional consideration when deciding on which heart failure patients will receive CRT.

The point estimate of sample coefficient alpha may provide a misleading impression of the reliability of the test score. Because sample coefficient alpha is consistently biased downward, it is more likely to yield a misleading impression of poor reliability. The magnitude of the bias is greatest precisely when the variability of sample alpha is greatest (small population reliability and small sample size). Taking into account the variability of sample alpha with an interval estimator may lead to retaining reliable tests that would be otherwise rejected. Here, the authors performed simulation studies to investigate the behavior of asymptotically distribution-free (ADF) versus normal-theory interval estimators of coefficient alpha under varied conditions. Normal-theory intervals were found to be less accurate when item skewness >1 or excess kurtosis >1. For sample sizes over 100 observations, ADF intervals are preferable, regardless of item skewness and kurtosis. A formula for computing ADF confidence intervals for coefficient alpha for tests of any size is provided, along with its implementation as an SAS macro.

Mycoplasma hyorhinis has been shown to induce the secretion of tumor necrosis factor alpha (TNF-alpha) from monocytes. To identify the molecules responsible for this activity, we separated sonicated M. hyorhinis lysate material by centrifugation at 100,000 x g into soluble (S) and particulate (P) fractions. The fractions were assayed for TNF-alpha-inducing activity by the L929 bioassay. Both the soluble and particulate fractions were able to induce TNF-alpha in roughly equal amounts. The optimum dose for both fractions was 1 micrograms/ml. Proteinase K treatment of either fraction eliminated the activity, suggesting that a protein component is involved in induction. Phase partitioning into Triton X-114 aqueous (A) and detergent (D) phases showed that the soluble fraction was composed of 80% aqueous-phase proteins, while the particulate fraction was>> 75% detergent-phase proteins. All four fractions (SA, SD, PA, and PD) were able to induce TNF-alpha release. Treatment with NaIO4 to remove carbohydrate reduced the inducing activity of the SA phase by 80%, whereas that of the other fractions was unaffected by this treatment. The M(r)S of the inducing activity were determined by the monocyte Western (immunoblot) technique. The SA phase activity was associated with a single periodate-sensitive peak of 69 to 75 kDa. The two detergent phases had similar profiles of inducing activity, containing four peaks of activity. These peaks corresponded to 48 to 52, 43 to 45, 39 to 40, and 31 to 32 kDa. The PA fraction also contained four peaks of activity, 69 to 75, 55 to 57, 48 to 52, and 39 to 40 kDa. Thus, both a protein and glycan moiety from M. hyorhinis are capable of inducing TNF-alpha release from human monocytes.

Since the discovery of soluble amyloid-beta (sA beta), it became clear that the same amino acid sequence can have both a fibrillar or a soluble state. In this work, we describe the isolation of two different species derived from synthetic A beta(1-40) differing in their conformational and fibrillogenesis properties. The separation was performed taking advantage of the fact that only one species is sedimentable by centrifugation after 2 weeks of incubation at 1 mg/ml. One species is highly amyloidogenic (A beta ac) and has an antiparallel beta-sheet structure and the other one is poorly amyloidogenic (A beta nac) and contains mainly random coil or alpha-helix structure. Chemical changes were not detected in the primary structure of both species and the differences in the physical properties and very likely in biological behaviour are thought to have a conformational basis. We propose that the transformation of the non-amyloidogenic into the amyloidogenic conformation could be the fundamental event in the pathological polymerization of sA beta and in the development of Alzheimer's disease.

OBJECTIVE

This study aimed to assess the reliability of a number of self report questionnaires for epidemiological investigations of adolescents' mental health in Cape Town, South Africa. The scales used were: the Short Mood and Feelings Questionnaire (SMFQ), Zung Self-rating Anxiety Scale (SAS), Self-esteem Questionnaire (SEQ), Harvard Trauma Questionnaire (HTQ) and Multi-Dimensional Scale of Perceived Social Support (MSPSS).

METHODS

The self-report questionnaire (available in Afrikaans, English and isiXhosa) was administered to 237 grade 8 students (14-15 years) on 2 occasions in metropolitan Cape Town high schools. The mean interval between first and second administration of the questionnaire was 8.3 days. Test-retest reliability was assessed using Cohen's kappa and observed agreement. Pearson's correlation coefficients were used to assess consistency across total scores between occasion 1 and occasion 2. Cronbach's alpha was used to assess the internal consistency of each scale.

RESULTS

All items had at least fair test-retest reliability (kappa>> 0.20) apart from two items on the Self-rating Anxiety Scale and one item on the Harvard Trauma questionnaire. Test-retest reliability was strong for the HTQ (Pearson's correlation coefficient >0.75), moderate for the SAS, SEQ and MSPSS (0.50-0.74) and weak for the SMFQ (0.25-0.49). Cronbach's alpha for all scales was acceptable (>0.60). Analysis by the different language versions (Afrikaans/English and isi-Xhosa/ English) of the questionnaire indicated good internal consistency for most measures for all three languages.

CONCLUSIONS

The results indicate that many of these instruments may be used reliably in South Africa to assess adolescent mental health and that the different language versions of the instruments used in the questionnaire are generally reliable for use in South African schools. However, some caution is required with the use of the SAS and SEQ in different language groups.

Posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD) are frequently comorbid among veteran and community samples. Several studies have demonstrated significant comorbidity between trauma, PTSD, and social anxiety (SA), and a growing number of studies have explored the nature of this association. Although a diagnosis of either PTSD or SAD alone can result in significant impairment in social and occupational functioning, these difficulties are often magnified in persons suffering from both disorders. This review describes the current state-of-the-art regarding the co-occurrence of trauma, PTSD, and SA. First, we provide an overview of empirical data on the prevalence of co-occurring trauma, PTSD, and SAD. Second, we describe possible explanatory models of the co-occurrence, with a specific focus on the shared vulnerability model. Third, we review the available empirical data addressing the postulates of this model, including both genetic and psychological vulnerabilities. Fourth, we describe additional factors-guilt, shame, and depressive symptoms-that may help to explain the co-occurrence of PTSD and SA. A better understanding of this complex relationship will improve the efficacy of treatment for individuals suffering from both disorders. We conclude with key areas for future research.

Estimation of the energy from a given Boltzmann sample is straightforward since one just has to average the contribution of the individual configurations. On the other hand, calculation of the absolute entropy, S (hence the absolute free energy F) is difficult because it depends on the entire (unknown) ensemble. We have developed a new method called "the hypothetical scanning molecular dynamics" (HSMD) for calculating the absolute S from a given sample (generated by any simulation technique). In other words, S (like the energy) is "written" on the sample configurations, where HSMD provides a prescription of how to "read" it. In practice, each sample conformation, i, is reconstructed with transition probabilities, and their product leads to the probability of i, hence to the entropy. HSMD is an exact method where all interactions are considered, and the only approximation is due to insufficient sampling. In previous studies HSMD (and HS Monte CarloHSMC) has been extended systematically to systems of increasing complexity, where the most recent is the seven-residue mobile loop, 304-310 (Gly-His-Gly-Ala-Gly-Gly-Ser) of the enzyme porcine pancreatic alpha-amylase modeled by the AMBER force field and AMBER with the implicit solvation GB/SA (paper I, Cheluvaraja, S.; Meirovitch, H. J. Chem. Theory Comput. 2008, 4, 192). In the present paper we make a step further and extend HSMD to the same loop capped with TIP3P explicit water at 300 K. As in paper I, we are mainly interested in entropy and free energy differences between the free and bound microstates of the loop, which are obtained from two separate MD samples of these microstates. The contribution of the loop to S and F is calculated by HSMD and that of water by a particular thermodynamic integration procedure. As expected, the free microstate is more stable than the bound microstate by a total free energy difference, Ffree-Fbound=-4.8+/-1, as compared to -25.5 kcal/mol obtained with GB/SA. We find that relatively large systematic errors in the loop entropies, Sfree(loop) and Sbound(loop) are cancelled in their difference which is thus obtained efficiently and with high accuracy, i.e., with a statistical error of 0.1 kcal/mol. This cancellation, which has been observed in previous HSMD studies, is in accord with theoretical arguments given in paper I.

These studies were designed to determine the role of endogenous gastric mucosal prostaglandins (PG) in maintaining mucosal integrity. Vagally denervated, separated pouches of gastric fundic mucosa in unanesthetized dogs were irrigated with either acetylsalicylic acid (ASA) or salicylic acid (SA) (0, 2.5, 5.0, 10.0, 20.0, and 40.0 mM) in 150 mM HCl. Transmucosal potential difference (PD) and net H+, Na+, and K+ flux were measured. Mucosal ex vivo generation of 6-oxo-PGF1 alpha, PGE2, and PGF2 alpha was measured by radioimmunoassay in mucosal biopsies taken after exposure to each agent. No difference in PD or net H+, Na+, or K+ flux was observed between pouch irrigation with ASA or SA at 2.5-20.0 mM concentrations. Net H+ and Na+ flux was significantly greater (P less than 0.01) after irrigation with 40 mM SA than with 40 mM ASA. No significant reduction in gastric mucosal ex vivo generation of 6-oxo-PGF1 alpha (range, 65-98 ng.g-.min-1), PGE2 (range, 250-326 ng.g-1.min-1), or PGF2 alpha (range, 115-156 ng.g-1.min-1) was observed after pouch irrigation with all concentrations of SA. In comparison, gastric mucosal ex vivo generation of 6-oxo-PGF1 alpha (range, 75-2 ng.g-1.min-1), PGE2 (range, 22-3 ng.g-1.min-1), and PGF2 alpha (range, 40-2 ng.g-1.min-1) was significantly reduced after irrigation with all concentrations of ASA. From these data, we conclude that the activity of endogenous gastric prostacyclin, PGE2 alpha, and PGF2 alpha is not a prerequisite for mucosal integrity as measured by PD and net cationic flux.

Isolated, polarized, proximal tubule cells of Rana pipiens were voltage clamped and examined for both single-channel and whole cell currents. Barium-sensitive whole cell conductances were calculated from the difference in slopes of the current-voltage relations before and after 5 mM external barium. In 11 voltage-clamped cells with high K in the pipette (and cell), isosmotic addition of 40 mM glucose to the bathing solution increased cell volume by 23 +/- 4% within 2-3 min and increased barium-sensitive conductance by 40 +/- 10% from 0.5 to 0.7 nS (P < 0.005, with each cell as its own control). Isosmotic addition of nonmetabolizable methyl-alpha-D-glucopyranoside, which enters with Na across the apical membrane, produced a similar increase in barium-sensitive conductance (30 +/- 13%). In contrast, 3-O-methyl-D-glucopyranose, which is not cotransported with Na, did not alter either cell volume or barium-sensitive conductance. Isosmotic addition of 40 mM phenylalanine (Phe) increased cell volume by 21 +/- 3% and increased barium-sensitive conductance by 36 +/- 19% from 1.1 to 1.5 nS (P < 0.005, with each cell as its own control; n = 8). All K channels observed at the basolateral membrane of these amphibian cells were found to be activated by pipette suction (stretch) and inhibited by 5 mM external barium (outside-out patches). Hence, stretch-activated (SA) K channels must be mediating the macroscopic increase in whole cell K conductance (GK) after isosmotic addition of glucose and Phe. The process does not seem to involve changes in ATP, because Phe increased GK even more when cytosolic ATP was maintained at high levels (10(-4) M extracellular ouabain and 5 mM intracellular ATP). It is also unlikely that changes in cell pH or calcium mediate the increase in GK, because the bulk composition of the cell is "clamped" by the pipette solution in these experiments (1-micron tip patch pipettes). Consequently, the substrate-induced increase in GK probably arises from a swelling-associated deformation of the submembane cytoskeleton or a direct change in membrane tension. In either case, SA channels would play a physiological role in proximal tubule K homeostasis during sugar and amino acid reabsorption in the proximal tubule of the kidney.

The purpose of this study was to evaluate the expressions and the roles of proteins involved in cell cycle regulation and DNA repair in cis-diamminedichloroplatinum (II) (cisplatin or CDDP)-induced acute renal failure (ARF). Treatment with CDDP (6 mg/kg, iv) induced tubular damage and increased serum creatinine (Scr) and the number of TUNEL-positive cells in the outer stripe of the outer medulla in rats, which reached peak levels at 5 days after CDDP. The expressions of cyclin-dependent kinase inhibitors (p21 and p27), cyclin B1, cyclin D1, PCNA, GADD 45, and GADD 153 were significantly increased in the outer medulla, reaching peak levels at 3 days after CDDP. Increments of p27 and PCNA were observed in the same nuclei. Sodium arsenite (SA), a heavy metal, attenuated tubular damage and increased Scr- and TUNEL-positive cells at 5 days after CDDP. SA augmented CDDP-induced increment of p27 but suppressed the increased expression of cyclin B1 and cyclin D1 at 3 days after CDDP. SA-induced attenuation of nephrotoxicity was associated with enhanced expression of proliferating cell nuclear antigen (PCNA) and growth-arrest and DNA damage (GADD) 153 in damaged tubular cells. Our findings indicated that (1) proteins related to cell cycle regulation and DNA repair are induced in CDDP nephrotoxicity, (2) the SA-induced attenuation of CDDP nephrotoxicity is associated with increased expression of p27 and decreased expression of cyclin B1 and cyclin D1, they all induce cell cycle arrest at G1/S and G2/M, and (3) enhanced expression of DNA repair-related proteins is also associated with attenuation of CDDP-nephrotoxicity.

Apigenin is a representative dietary flavone (2-phenyl-4H-1-benzopyran-4-one) inhibiting cancer cell growth both in cell culture systems and in vivo. The prooxidant potential of apigenin was confirmed by the observations using flowcytometric and immunoblotting techniques that the intracellular accumulations of reactive oxygen species (ROS) and protein carbonyls were detected in the cells treated with apigenin in a dose-dependent manner. Conversely, chrysin (5,7-dihydroxyflavone) did not show any prooxidant effect. A structure-activity relationship data thus indicated that a 4'-monohydroxyl group, which can be oxidized to semiquinone radical but not up to quinone-like metabolite, is essential for prooxidant effect. When HL-60 cells were treated with not only a heme synthesis inhibitor succinyl acetone (SA) but also myeloperoxidase (MPO) inhibitors, the ROS level enhanced by apigenin was significantly reduced. The gathered data suggested that peroxidase-catalyzed production of apigenin B-ring phenoxyl radicals might be responsible for the prooxidant effect. This is supported by the observation that MPO is able to catalyze production of apigenin phenoxyl radicals, detected by an electron spin resonance-spin trapping technique. We also reveal that both SA and alpha-tocopherol enhance cellular susceptibility to apoptosis-inducing stimuli by apigenin. In conclusion, the prooxidant effect of apigenin is likely to oxidize a variety of thiols through the formation of phenoxyl radicals and thus seems to play a significant role in the abortive apoptotic pathway switching to necrotic cell death.