BACKGROUND

We previously developed questionnaires based on contemporary theories to measure physical activity determinants among youth [Motl et al., Prev Med 2000; 31:584-94]. The present study examined the factorial invariance and latent mean structure of unidimensional models fit to the questionnaires measuring attitude, subjective norm, perceived behavioral control, and self-efficacy about physical activity among black and white adolescent girls.

METHODS

Black (n = 896) and white (n = 823) girls in the 8th grade completed the questionnaires measuring attitude, subjective norm, perceived behavioral control, and self-efficacy about physical activity. The responses were subjected to analyses of factorial invariance and latent mean structure using confirmatory factor analysis with full-information maximum likelihood estimation in AMOS 4.0.

RESULTS

The unidimensional models of the four questionnaires generally demonstrated invariance of the factor structure, factor loadings, and factor variance across race but not invariance of the variance-covariance matrices or item uniquenesses. The analyses of latent mean structure demonstrated that white girls had higher latent mean scores on the measures of attitude and self-efficacy than black girls; there were similar, but smaller, differences between white and black girls on the measures of subjective norm and perceived behavioral control.

CONCLUSIONS

The questionnaires can be employed in interventions to test the mediating influences of attitude, subjective norm, perceived behavioral control, and self-efficacy on participation in physical activity by black and white adolescent girls.

Although many TATA-less promoters transcribed by RNA polymerase II initiate transcription at multiple sites, the regulation of multiple start site utilization is not understood. Beginning with the prediction that multiple start site promoters may share regulatory features and using the P-glycoprotein promoter (which can utilize either a single or multiple transcription start site(s)) as a model, several promoters with analogous transcription windows were grouped and searched for the presence of a common DNA element. A downstream protein-binding sequence, MED-1 (Multiple start site Element Downstream), was found in the majority of promoters analyzed. Mutation of this element within the P-glycoprotein promoter reduced transcription by selectively decreasing utilization of downstream start sites. We propose that a new class of RNA polymerase II promoters, those that can utilize a distinctive window of multiple start sites, is defined by the presence of a downstream MED-1 element.

Combined MRI and 3D spectroscopic imaging (MRI/3D-MRSI) was used to study the metabolic effects of hormone-deprivation therapy in 65 prostate cancer patients, who underwent either short, intermediate, or long-term therapy, compared to 30 untreated control patients. There was a significant time-dependent loss of the prostatic metabolites choline, creatine, citrate, and polyamines during hormone-deprivation therapy, resulting in the complete loss of all observable metabolites (total metabolic atrophy) in 25% of patients on long-term therapy. The amount and time-course of metabolite loss during therapy significantly differed for healthy and malignant tissues. Citrate levels decreased faster than choline and creatine levels during therapy, resulting in an increase in the mean (choline + creatine)/citrate ratio with duration of therapy. Due to a loss of all MRSI detectable citrate, this ratio could not be used to identify cancer in 69% of patients on long-term therapy. In the absence of citrate, however, residual prostate cancer could still be detected by elevated choline levels (choline/creatine ratio>> or =1.5), or the presence of only choline in the proton spectrum. The loss of citrate and the presence of total metabolic atrophy correlated roughly with decreasing serum prostatic specific antigen levels with increasing therapy. In summary, MRI/3D-MRSI provided both a measure of residual cancer and a time-course of metabolic response following hormone-deprivation therapy. Magn Reson Med 46:49-57, 2001.

We used the rhesus macaque model of heterosexual human immunodeficiency virus (HIV) transmission to test the hypothesis that in vitro measures of macrophage tropism predict the ability of a primate lentivirus to initiate a systemic infection after intravaginal inoculation. A single atraumatic intravaginal inoculation with a T-cell-tropic molecular clone of simian immunodeficiency virus (SIV), SIVmac239, or a dualtropic recombinant molecular clone of SIV, SIVmac239/1A11/239, or uncloned dualtropic SIVmac251 or uncloned dualtropic simian/human immunodeficiency virus (SHIV) 89.6-PD produced systemic infection in all rhesus macaques tested. However, vaginal inoculation with a dualtropic molecular clone of SIV, SIVmac1A11, resulted in transient viremia in one of two rhesus macaques. It has previously been shown that 12 intravaginal inoculations with SIVmac1A11 resulted in infection of one of five rhesus macaques (M. L. Marthas, C. J. Miller, S. Sutjipto, J. Higgins, J. Torten, B. L. Lohman, R. E. Unger, H. Kiyono, J. R. McGhee, P. A. Marx, and N. C. Pedersen, J. Med. Primatol. 21:99-107, 1992). In addition, SHIV HXBc2, which replicates in monkey macrophages, does not infect rhesus macaques following multiple vaginal inoculations, while T-cell-tropic SHIV 89.6 does (Y. Lu, P. B. Brosio, M. Lafaile, J. Li, R. G. Collman, J. Sodroski, and C. J. Miller, J. Virol. 70:3045-3050, 1996). These results demonstrate that in vitro measures of macrophage tropism do not predict if a SIV or SHIV will produce systemic infection after intravaginal inoculation of rhesus macaques. However, we did find that the level to which these viruses replicate in vivo after intravenous inoculation predicts the outcome of intravaginal inoculation with each virus.

Recent in vitro studies have suggested a role for sialylation in chemokine receptor binding to its ligand (Bannert, N., S. Craig, M. Farzan, D. Sogah, N.V. Santo, H. Choe, and J. Sodroski. 2001. J. Exp. Med. 194:1661-1673). This prompted us to investigate chemokine-induced leukocyte adhesion in inflamed cremaster muscle venules of alpha2,3 sialyltransferase (ST3Gal-IV)-deficient mice. We found a marked reduction in leukocyte adhesion to inflamed microvessels upon injection of the CXCR2 ligands CXCL1 (keratinocyte-derived chemokine) or CXCL8 (interleukin 8). In addition, extravasation of ST3Gal-IV(-/-) neutrophils into thioglycollate-pretreated peritoneal cavities was significantly decreased. In vitro assays revealed that CXCL8 binding to isolated ST3Gal-IV(-/-) neutrophils was markedly impaired. Furthermore, CXCL1-mediated adhesion of ST3Gal-IV(-/-) leukocytes at physiological flow conditions, as well as transendothelial migration of ST3Gal-IV(-/-) leukocytes in response to CXCL1, was significantly reduced. In human neutrophils, enzymatic desialylation decreased binding of CXCR2 ligands to the neutrophil surface and diminished neutrophil degranulation in response to these chemokines. In addition, binding of alpha2,3-linked sialic acid-specific Maackia amurensis lectin II to purified CXCR2 from neuraminidase-treated CXCR2-transfected HEK293 cells was markedly impaired. Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo.

Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as the chondrodysplasias. One such disorder, multiple epiphyseal dysplasia (MED), is characterized by mild dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the disease mechanisms that underpin the pathophysiology of MED we generated a murine model of epiphyseal dysplasia by knocking-in a matn3 mutation. Mice that are homozygous for the mutation develop a progressive dysplasia and have short-limbed dwarfism that is consistent in severity with the relevant human phenotype. Mutant matrilin-3 is retained within the rough endoplasmic reticulum of chondrocytes and is associated with an unfolded protein response. Eventually, there is reduced proliferation and spatially dysregulated apoptosis of chondrocytes in the cartilage growth plate, which is likely to be the cause of disrupted linear bone growth and the resulting short-limbed dwarfism in the mutant mice.

BACKGROUND

Despite the initial encouraging outcome in developing CBT for bipolar affective disorder [Arch. Gen. Psychiatry 2002 (in press); Psychol. Med. 31 (2001) 459-467], very little is known about whether there are any differences in dysfunctional attitudes between unipolar and bipolar patients. Both the behavioural activation system theory [J. Pers. Soc. Psychol. 67 (1994) 488-498; Major Theories of Personality Disorder, Guilford Press, New York, 1996; Psychol. Bull. 117 (1995) 434-449] and the cognitive model for bipolar affective disorder [Cognitive Therapy for Bipolar Disorder: A Therapist's Guide to Concepts, Methods and Practise, Wiley, New York, 1999] postulate high goal striving as a risk factor for bipolar disorder. However, the existing subscales in the dysfunctional attitude scale (DAS) were derived from patients and relatives of patients suffering from unipolar depression, patients with a mixed psychiatric diagnosis or normal controls. None of the existing subscales reflects high goal striving beliefs. Using a sample of bipolar patients may yield different factors.

METHODS

A total of 143 bipolar 1 patients filled in the short version of DAS 24. Principal component analysis was carried out to derive factors. The scores of these factors were compared with those of 109 unipolar patients to investigate if these factors distinguish bipolar patients from unipolar patients.

RESULTS

Three factors were derived: factor 1 'Goal-attainment' accounted for 25.0% of the total variance. Factor 2 'Dependency' accounted for 11.0% of the total variance. Factor 3 'Achievement' accounted for 8.2% of the total variance. However, factor 1 appeared to consist of items that made a coherent theoretical construct. No significant differences were found when the validation sample was compared with 109 patients suffering from unipolar depression in any of the three factors. When subjects who were likely to be in a major depressive episode were excluded, the scores of bipolar patients (n=49) were significantly higher than euthymic unipolar patients (n=25) in factor 1 'Goal attainment'. Goal-attainment also correlated with the number of past hospitalisations due to manic episodes and to bipolar episodes as a whole.

CONCLUSIONS

The Goal-attainment subscale captures the risky attitudes described by the behavioural activation system theory and the cognitive model for bipolar affective disorder. It is postulated that these beliefs may interact with the illness and predispose bipolar patients to have a more severe course of the illness.

Pharmacological approaches are available to medically-managed patients with symptomatic BPH before surgical intervention is required. These include daily treatment with alpha-blockers and 5-alpha-reductase inhibitors alone or in combination. These medical approaches have two major problems. First, treatments are chronic and must be taken daily. Second, there are significant financial costs and quality of life issues for such chronic treatments. Is it possible to develop effective acute therapy for symptomatic BPH without the long-term androgen deprivation-induced side effects? Two seminal but rarely cited studies of Walsh [Peters, Walsh: N Engl J Med 317:599-604, 1987] and Coffey et al. [Sufrin et al.: Invest Urol 13:418-423, 1976], combined with the growing understanding of the stem cell organization of the prostate stromal (S) and epithelial (E) compartments and their reciprocal paracrine and autocrine interactions provides the rationale for an acute approach.The Walsh study documents that: (1) androgen deprivation disrupts the reciprocal interaction between the prostate S and E thereby decreasing the weight of both compartments and (2) once BPH develops, androgen deprivation does not decrease the number of stem cell units in either the S or E compartments since subsequent androgen restoration fully restores the enlarged gland. The Coffey study documents that acute androgen deprivation sensitizes S-E interactions to radiation induced disruptions so that following radiation, androgen restoration does not induce full gland regrowth. Therefore, effective therapy for symptomatic BPH should be achievable by acute treatment with reversible androgen deprivation for a limited period followed by a single dose of conformal external beam radiation before allowing the man to recovery his normal serum testosterone.

Cysteine-rich repeated units of 40-70 amino acids are building blocks of many mammalian proteins, including 12 proteins of the complement system. Human complement arranged motifs, designated short consensus repeats (SCRs), which constitute the entire extracellular portion of this protein. Klickstein et al. [Klickstein, L. B., Bartow, T. J., Miletic, V., Rabson, L. D., Smith, J. A. & Fearon, D. T. (1988) J. Exp. Med. 168, 1699-1717 (abstr.)] localized a C4b binding domain to SCR-1 and/or SCR-2 and a C3b binding domain to SCR-8 and/or SCR-9. These SCRs bind different ligands, although SCR-1 and SCR-8 are 55% homologous and SCR-2 and SCR-9 are 70% homologous. To examine if one or two SCRs are required for ligand binding and to define sites within the SCRs that determine specificity of binding, mutagenesis analysis of a truncated, secreted form of CR1, called CR1-4 by Hourcade et al. [Hourcade, D., Meisner, D. R., Atkinson, J. P. & Holers, V. M. (1988) J. Exp. Med. 168, 1255-1270], was undertaken. The latter, composed of the first eight and one-half amino-terminal SCRs of CR1, efficiently bound C4b but not iC3. SCR-1 and SCR-2 were necessary for this interaction. Analysis of the mutant CR1-4 proteins, in which amino acids in SCR-1 and SCR-2 were substituted a few at a time with the homologous amino acids of SCR-8 and SCR-9, led to the identification of one amino acid in SCR-1 and three amino acids in SCR-2 important for C4b binding. Furthermore, five amino acids at the end of SCR-9, if placed in the homologous positions of SCR-2, conferred iC3 binding and are likely essential for ligand binding activity of SCR-8 and SCR-9. This iC3 binding occurred only if SCR-1 was present, indicating that two contiguous SCRs are necessary for this interaction. These results provide identification of amino acids within SCRs that are important for ligand binding.

An assay for the separation and detection of lipid hydroperoxides and hydrogen peroxide in biological samples using HPLC and isoluminol chemiluminescence was recently described (Y. Yamamoto, M. H. Brodsky, J. C. Baker, and B. N. Ames (1987) Anal. Biochem. 160, 7-13; Y. Yamamoto and B. N. Ames (1987) Free Rad. Biol. Med. 3, 359-361). In this paper the application of this assay to the analysis of human blood plasma is described in detail, and three compounds producing chemiluminescence that were observed in the initial studies in plasma extracted with methanol and hexane are further characterized. It is shown that various lipid hydroperoxides added to plasma are detected by the assay. In contrast, hydrogen peroxide added to plasma is rapidly degraded by endogenous catalase. Hydrogen peroxide and a second, minor compound producing chemiluminescence, which appear in the assay of the methanol and the hexane extract of plasma, respectively, appear to be generated during analysis and are not likely to be present in plasma. The third compound yielding a chemiluminescence peak, which is extracted into the hexane phase of plasma and was earlier assigned to cholesterol ester hydroperoxide, is shown to be neither a cholesterol ester nor a hydroperoxide, but the hydroquinone ubiquinol-10. As the chemiluminescence response of hydroperoxides, but not of hydroquinones, is eliminated by reducing reagents such as sodium borohydride or triphenylphosphine, such reduction should be used to confirm that any chemiluminescence producing lipid observed in the assay is a hydroperoxide, not a hydroquinone. We conclude that isolated human plasma from healthy subjects is very unlikely to contain hydrogen peroxide in concentrations greater than about 0.25 microM and does not contain lipid hydroperoxides in concentrations greater than 0.03 microM. The method described, when used with appropriate precautions, is a convenient and very sensitive assay for lipid hydroperoxides in biological tissues.

OBJECTIVE

The aim of this study was to compare the efficacy and the complications associated with the use of two new bioactive meshes, Surgisis Gold 8-ply mesh, a product obtained by the processing of porcine small intestine sub-mucosa (Cook Surgical, Bloomington, IN, USA), and Alloderm, processed cadaveric human acellular dermis (Life Cell Corporation, Branchburg, NJ, USA), for ventral herniorrhaphy.

BACKGROUND

Ventral hernia repair in potentially contaminated or potentially infected fields limit the use of synthetic mesh products. In this scenario, biosynthetic mesh products that are absorbed and/or replaced with the body's own tissue reduce the incidence of post-operative chronic wound complications (Franklin et al. in Hernia 8(3):186-189, 2004; Franklin et al. in Hernia 6(4):171-174, 2002; Hirsch in J Am Coll Surg 198(2):324-328, 2004; Holton et al. in J Long Term Eff Med Implants 15(5):547-558, 2005; Buinewicz and Rosen in Ann Plast Surg 52(2):188-194, 2004). Rapid revascularization, repopulation, and remodeling of the matrix occur on contact with the patient's own tissue. Only limited, and mostly preliminary data, is available on the use of these types of mesh and concerning the potential complications associated with the use of these types of meshes. We publish our experience with the use of these mesh products, along with their associated complications. Furthermore, we have also provided suggestions for improvements in the mesh designs.

METHODS

Between June 2002 and March 2005, 74 patients underwent ventral hernia repair using biosynthetic or natural tissue mesh. The first 41 procedures were performed using Surgisis Gold 8-ply mesh formed from porcine small intestine sub-mucosa, and the remaining 33 patients had ventral hernia repair with Alloderm. The patients had their first follow-up 7-10 days after discharge from the hospital. They were again seen at 6 weeks, or, if needed, earlier, and, thereafter, as needed. Patients who reported any complications to the office were followed up immediately within 1-2 days. Any signs of wound infection, diastasis, hernia recurrence, changes in bowel habits, and seroma formation were evaluated.

RESULTS

Non-perforated Surgisis mesh resulted in significant seroma formation in 10/11 patients. The seroma complication was reduced, but not eliminated, with the use of the perforated Surgisis mesh (3/30 patients). Explanted material revealed separated layers of un-incorporated middle layers of the 8-ply Surgisis mesh. Three of the patients had the mesh placed in a contaminated field with no resultant sequela, and there were no hernia recurrences. Patients also had a significant degree of discomfort and pain during the immediate post-operative period. The use of the Alloderm mesh resulted in eight hernia recurrences. Fifteen of the Alloderm patients (15/33) developed a diastasis or bulging at the repair site. Seroma formation was only a problem in two patients.

CONCLUSIONS

Seroma formation was a major problem with the non-perforated Surgisis mesh repair, as was the post-operative pain. On the other hand, post-operative diastasis and hernia recurrence were a major problem with the Alloderm mesh. Further design improvements are required in both forms of these new mesh products. Surgeons should be aware of these potential complications prior to the selection of either of these products and the patient should be informed and educated accordingly.

BACKGROUND

Growing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25-33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written.

OBJECTIVE

The aim of this paper is to review and evaluate research on LITS and to identify, describe and discuss commonalities and differences between LITS and daily smokers.

METHODS

The primary databases used to search for publications were Pub Med (National Library of Medicine) and SCOPUS (Elsevier).

RESULTS

LITS inhale smoke and have post-smoking blood nicotine concentrations that are broadly equivalent to those found in daily smokers. However, LITS differ from daily smokers with regard to cigarette consumption and frequency of cigarette use, sociodemographic and socioeconomic characteristics, motives, personality traits, dependence, withdrawal and craving, response to smoking-related cues, quitting perception, past-smoking status, and initiation.

CONCLUSIONS

In contrast to daily smokers, LITS show few or no signs of dependence as currently defined by DSM-IV criteria, appear to exercise more self-control, seem to be less impulsive, and their smoking experience is primarily associated with positive rather than negative reinforcement. Conclusions drawn from the reviewed literature highlight the multivariate factors that must be taken into account when defining LITS and emphasize the importance of further research on this increasing fraction of smokers. The potential implications of increased LITS prevalence on smoking-related disease risks remain to be thoroughly investigated.

The PMM2 gene, which is defective in CDG-Ia, was cloned three years ago [Matthijs et al., 1997b]. Several publications list PMM2 mutations [Matthijs et al., 1997b, 1998; Kjaergaard et al., 1998, 1999; Bjursell et al., 1998, 2000; Imtiaz et al., 2000] and a few mutations have appeared in case reports or abstracts [Crosby et al., 1999; Kondo et al., 1999; Krasnewich et al., 1999; Mizugishi et al., 1999; Vuillaumier-Barrot et al., 1999, 2000b]. However, the number of molecularly characterized cases is steadily increasing and many new mutations may never make it to the literature. Therefore, we decided to collate data from six research and diagnostic laboratories that have committed themselves to a systematic search for PMM2 mutations. In total we list 58 different mutations found in 249 patients from 23 countries. We have also collected demographic data and registered the number of deceased patients. The documentation of the genotype-phenotype correlation is certainly valuable, but is out of the scope of this molecular update. The list of mutations will also be available online (URL: http://www.kuleuven. ac.be/med/cdg) and investigators are invited to submit new data to this PMM2 mutation database.

HIV-1 transcription is activated by HIV-1 Tat protein, which recruits cyclin-dependent kinase 9 (CDK9)/cyclin T1 and other host transcriptional coactivators to the HIV-1 promoter. Tat itself is phosphorylated by CDK2, and inhibition of CDK2 by small interfering RNA, the iron chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), and the iron chelator deferasirox (ICL670) inhibits HIV-1 transcription. Here we have analyzed a group of novel di-2-pyridylketone thiosemicarbazone- and 2-benzoylpyridine thiosemicarbazone-based iron chelators that exhibit marked anticancer activity in vitro and in vivo (Proc Natl Acad Sci USA 103:7670-7675, 2006; J Med Chem 50:3716-3729, 2007). Several of these iron chelators, in particular 2-benzoylpyridine 4-allyl-3-thiosemicarbazone (Bp4aT) and 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), inhibited HIV-1 transcription and replication at much lower concentrations than did 311 and ICL670. Neither Bp4aT nor Bp4eT were toxic after a 24-h incubation. However, longer incubations for 48 h or 72 h resulted in cytotoxicity. Analysis of the molecular mechanism of HIV-1 inhibition showed that the novel iron chelators inhibited basal HIV-1 transcription, but not the nuclear factor-κB-dependent transcription or transcription from an HIV-1 promoter with inactivated SP1 sites. The chelators inhibited the activities of CDK2 and CDK9/cyclin T1, suggesting that inhibition of CDK9 may contribute to the inhibition of HIV-1 transcription. Our study suggests the potential usefulness of Bp4aT or Bp4eT in antiretroviral regimens, particularly where resistance to standard treatment occurs.

Receptors in rat brain membranes which specifically bind 3H-diazepam were characterized pharmacologically using reference substances representing several pharmacological classes of drugs. Of 28 benzodiazepines tested, several "classical" ones (diazepam, clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam and chlorazepate) with known clinical efficacy, as well as three newer "triazolo" benzodiazepines (estazolam, U 35,005, U 31,957), one new "imidazolo" benzodiazepine, U 31,219, and one new 2-carbamoylmethylene-benzodiazepine, displaced 3H-diazepam binding at low concentrations (Ki=1--60 nM). For these benzodiazepines there was a stastically significant correlation between Ki values for displacement and ED50 (or MED) values in several pharmacological tests predictive of anxiolytic activity in man. More than 100 nonbenzodiazepines, representing 22 distinct pharmacological classes as well as 14 presumed neurotransmitters in the CNS, including 4 peptides, were much weaker as 3H-diazepam displacers (K2 greater than 0.1 nM). These results suggest that in vitro 3H-diazepam binding represents the physiologically relevant binding to hitherto unknown receptors in the CNS.

OBJECTIVE

The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.

METHODS

We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.

RESULTS

We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.

CONCLUSIONS

These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.

OBJECTIVE

To assess the sensitivity of two bilateral cochlear implant users to interaural level and time differences (ILDs and ITDs) for various signals presented through the auxiliary inputs of clinical sound processors that discard fine timing information and only preserve envelope cues.

METHODS

In a lateralization discrimination experiment, the just noticeable difference (JND) for ILDs and envelope ITDs was measured by means of an adaptive 2-AFC method. Different stimuli were used, including click trains at varying repetition rates, a speech fragment, and noise bursts. For one cochlear implant listener and one stimulus, the sensitivity to envelope ITDs was also determined with the method of constant stimuli. The dependency of ILD-JNDs on the interaural place difference was studied with stimulation at single electrode pairs by using sinusoidal input signals in combination with appropriate single-channel processor fittings. In a lateralization position experiment, subjects were required to use a visual pointer on a computer screen to indicate in-the-head positions for blocks of stimuli containing either ILD or ITD cues. All stimuli were loudness balanced (before applying ILD) and fed directly into the auxiliary inputs of the BTE processors (TEMPO+, Med-El Corp.). The automatic gain control and the processors' microphones were deactivated.

RESULTS

Both cochlear implant listeners were highly sensitive to ILDs in all broadband stimuli used; JNDs approached those of normal-hearing listeners. Pitch-matched single electrode pairs showed significantly lower ILD-JNDs than pitch-mismatched electrode pairs. Envelope ITD-JNDs of cochlear implant listeners obtained with the adaptive method were substantially higher and showed a higher test-retest variability than waveform ITD-JNDs of normal-hearing control listeners and envelope ITD-JNDs of normal-hearing listeners reported in the literature for comparable signals. The envelope ITD-JNDs for the click trains were significantly lower than for the speech token or the noise bursts. The best envelope ITD-JND measured was ca. 250 mus for the click train at 100 cycles per sec. Direct measurement of the psychometric function for envelope ITD by the method of constant stimuli showed discrimination above chance level down to 150 micros. The lateralization position experiment showed that both ILDs and envelope ITDs can lead to monotonic changes in lateral percept.

CONCLUSIONS

The two cochlear implant users tested showed strong effects of ILDs in various broadband stimuli with respect to JNDs as well as lateralization position. The high dependency of ILD-JNDs on the interaural pitch difference suggests the potential importance of pitch-matched assignment of electrodes in the two ears by the speech processors. Envelope ITDs appear to be more ambiguous cues than ILDs, as reflected by the higher and more variable JNDs compared with normal-hearing listeners. The envelope ITD-JNDs of cochlear implant listeners depended on the stimulus.

A Rho-kinase inhibitor increases corpus cavernosum (CC) pressure in an in vivo rat model (Chitaley, K., Wingard, C. J., Webb, R. C., Branam, H., Stopper, V. S., Lewis, R. W., and Mills, T. M. (2001) Nat. Med. 7, 119-122) suggesting that Rho-mediated Ca(2+) sensitization of CC smooth muscle maintains the flaccid (contracted) state. We directly demonstrate Ca(2+) sensitization of permeabilized rabbit and human CC and identify a highly expressed molecular component of this pathway. Ca(2+) sensitization of force induced by endothelin or GTPgammaS was significantly greater in CC than in rabbit ileum smooth muscle and was accompanied by a 17-fold higher RhoA content. Pull-down assays with the RhoA binding domain of mDia showed the high RhoA content of CC to be available for activation by GTPgammaS. Ca(2+) sensitization induced by endothelin, phenylephrine, or GTPgammaS was completely relaxed by the Rho kinase inhibitor Y-27632. Human and rabbit CC both express the phosphatase inhibitor CPI-17, the myosin phosphatase regulatory (MYPT-1) and catalytic (PP1delta) subunits, and two isoforms of Rho kinase. We suggest that high expression of RhoA contributes, through RhoA-mediated Ca(2+) sensitization, to the flaccid state of CC that can be reversed by a water-soluble, orally active Rho kinase inhibitor suitable for therapy of erectile dysfunction.

OBJECTIVE

The purpose of these guidelines is to offer to the nuclear medicine team a framework that could prove helpful in daily practice. These guidelines contain information related to the indications, acquisition, processing and interpretation of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in paediatric oncology. The Oncology Committee of the European Association of Nuclear Medicine (EANM) has published excellent procedure guidelines on tumour imaging with (18)F-FDG PET (Bombardieri et al., Eur J Nucl Med Mol Imaging 30:BP115-24, 2003). These guidelines, published by the EANM Paediatric Committee, do not intend to compete with the existing guidelines, but rather aim at providing additional information on issues particularly relevant to PET imaging of children with cancer.

CONCLUSIONS

The guidelines summarize the views of the Paediatric Committee of the European Association of Nuclear Medicine. They should be taken in the context of "good practice" of nuclear medicine and of any national rules, which may apply to nuclear medicine examinations. The recommendations of these guidelines cannot be applied to all patients in all practice settings. The guidelines should not be deemed inclusive of all proper procedures or exclusive of other procedures reasonably directed to obtaining the same results.

Cartilage oligomeric matrix protein (COMP) is a large extracellular pentameric glycoprotein found in the territorial matrix surrounding chondrocytes. More than 60 unique COMP mutations have been identified as causing two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED/EDM1). Recent studies demonstrate that calcium-binding and calcium induced protein folding differ between wild type and mutant COMP proteins and abnormal processing of the mutant COMP protein causes the characteristic large lamellar appearing rough endoplasimic reticulum (rER) cisternae phenotype observed in PSACH and EDMI growth plate chondrocytes. To understand the cellular events leading to this intracellular phenotype, PSACH chondrocytes with a G427E, D469del and D511Y mutations were grown in 3-D culture to produce cartilage nodules. Each nodule was assessed for the appearance and accumulation of cartilage-specific proteins within the rER and for matrix protein synthesis. All three COMP mutations were associated with accumulation of COMP in the rER cisternae by 4 weeks in culture, and by 8 weeks the majority of chondrocytes had the characteristic cellular phenotype. Mutations in COMP also affect the secretion of type IX collagen and matrilin-3 (MATN3) but not the secretion of aggrecan and type II collagen. COMP, type IX collagen and MATN3 were dramatically reduced in the PSACH matrices, and the distribution of these proteins in the matrix was diffuse. Ultrastructural analysis shows that the type II collagen present in the PSACH matrix does not form organized fibril bundles and, overall, the matrix is disorganized. The combined absence of COMP, type IX collagen and MATN3 causes dramatic changes in the matrix and suggests that these proteins play important roles in matrix assembly.

The spatial distributions of functional activation of rat somatosensory cortex by forepaw stimulation were quantitatively compared using blood oxygen level dependent (BOLD) signal and signal weighted by cerebral blood volume (CBV). The BOLD contrast to noise (CNR) distribution showed a significant dorsal shift with respect to the CBV method at fields strengths of 2 T (0.69 +/- 0.09 mm) and 4.7 T (0.44 +/- 0.15 mm). These shifts were attributed to the gradient of resting state blood volume across somatosensory cortex and the different CNR characteristics of the two image methods. The underlying principles suggest that the CBV method has a more uniform sensitivity to percent changes in functional indicators (blood volume or deoxygenated hemoglobin) across regions of variable resting state CBV. Magn Reson Med 42:591-598, 1999.

Amelioration of experimental autoimmune encephalomyelitis (EAE) by blockade of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), has been recently demonstrated [Nat. Med. 6 (2000) 67; Nat. Med. 6 (2000) 62]. However, the mechanisms underlying regulation of the extracellular glutamate concentration in EAE are unclear. To address this, we examined the expression of three distinct Na(+)-dependent glutamate transporters (GLT-1, GLAST and EAAC1) in the spinal cord of the Lewis rat EAE. EAE induced a dramatic increase in EAAC1 protein and mRNA levels, which corresponded closely with the course of neurological symptoms. In contrast, the levels of GLT-1 and GLAST protein were down-regulated in the spinal cord at the peak of disease symptoms, and no recovery was observed after remission. Furthermore, these changes in GLT-1, GLAST and EAAC1 expression were suppressed by treatment with NBQX. These results suggest that AMPA receptor activation precedes the altered expression of glutamate transporters, and that the dysregulation of extracellular glutamate concentration might play a critical role in pathological changes and neuronal dysfunction in EAE.

On 30 June 1997 the Council of Ministers approved the Directive on the Health Protection of Individuals in relation to Medical Exposures (MED) (97/43/EURATOM). This MED must be implemented in national law no later than 13 May 2000, repealing at that time Directive 84/466/EURATOM, the so-called 'Patient Directive'. It complements the Basic Safety Standards Directive of 1996 (96/29/EURATOM) as regards medical exposures, which comes into force at the same date. The MED considerably extends the scope of application from exposures of patients to all exposures directly or indirectly related to medical uses of ionising radiation. The MED reaffirms the objectives of the 1984 Directive--to aim at optimum diagnostic efficacy at reasonable dose to the patient and to reduce the number of unnecessary and inadequate exposures--but also strengthens most of its requirements as a result of the experience gained with its implementation and, at the same time, adds new provisions considered important taking into account scientific and technical evolution in the radiological field. In particular those exposures where there is no direct health benefit for the person undergoing the exposure and exposures at great risk are given special attention. With the aim of facilitating the implementation of the MED in national legislation the European Commission, with the help of the group of experts established under article 31 of the EURATOM Treaty, will produce technical guidelines with further explanation on some of the requirements of the MED.

Background. Heparin, used clinically as an anticoagulant, also has anti-inflammatory properties. The purpose of this systematic review was to provide a comprehensive review regarding the efficacy and safety of heparin and its derivatives as anti-inflammatory agents. Methods. We searched the following databases up to March 2012: Pub Med, Scopus, Web of Science, Ovid, Elsevier, and Google Scholar using combination of Mesh terms. Randomized Clinical Trials (RCTs) and trials with quasi-experimental design in clinical setting published in English were included. Quality assessments of RCTs were performed using Jadad score and Consolidated Standards of Reporting Trials (CONSORT) checklist. Results. A total of 280 relevant studies were reviewed and 57 studies met the inclusion criteria. Among them 48 studies were RCTs. About 65% of articles had score of 3 and higher according to Jadad score. Twelve studies had a quality score>> 40% according to CONSORT items. Asthma (n = 7), inflammatory bowel disease (n = 5), cardiopulmonary bypass (n = 8), and cataract surgery (n = 6) were the most studied disease condition. Forty studies use unfractionated heparin (UFH) for intervention; the remaining studies use low molecular weight heparin (LMWH). Conclusion. Despite the conflicting results, heparin seems to be a safe and effective anti-inflammatory agent; although it is shown that heparin can decrease the level of inflammatory biomarkers and improves patient conditions, still more data from larger rigorously designed studies are needed to support use of heparin as an anti-inflammatory agent in clinical setting. However, because of the association between inflammation, atherogenesis, thrombogenesis, and cell proliferation, heparin and related compounds with pleiotropic effects may have greater therapeutic efficacy than compounds acting against a single target.