(J Vase Surg 2009;50:1378-90.)”
“Objective: To further document the experienced burden in patients with peripheral arterial disease (PAD), we compared the health status of patients with PAD and chronic heart failure (CHF). As a secondary aim, we studied clinical and socio-demographic correlates of health status in both conditions.

Methods: We conducted a cross-sectional observational study in four outpatient clinics in the Southern part of The Netherlands, with subjects consisting of ambulatory (346 PAD and

188 CHF) patients. All patients completed the Short-Form 12 to assess their physical and mental health status. Information about socio-demographic, clinical risk factors, and disease severity indices was obtained from patients’ medical records. Propensity methodology was applied to enhance comparability between both medical conditions.

Results. Bcl-2 inhibitor Type of medical condition explained differences in health status (F = 33.1, P < .0001, Effect Size = 0.27). Impaired physical health status was more often reported in PAD patients (48.4%) compared with CHF patients see more (17.4%, Odds Ratio [OR] = 4.4, 95% Confidence Interval [CI] 2.3-8.8, P < .0001); impaired mental health status was more noted in CHP patients (43.5% vs. 22.0%,

OR = 1.7, 95% CI 1.2-2.6, P = .002). In PAD, younger age (P = .002), low education (P = .02), cardiac history (P =.02), diabetes mellitus (P = .03), and a lower ankle brachial index (P = .003) were associated with worse Emricasan supplier physical health status; younger age (P = .01) and living without partner (P = .01) were associated with lower mental health status scores. In CHF, patients with comorbid diabetes mellitus (P < .001) and females (P = .001) reported worse physical health, whereas no clinical or socio-demographics were associated with mental health status.

Conclusions: By contrasting PAD patients’ health status with another chronic disabling condition, the impact of PAD on patients’ physical health status became evident; whereas mental health status was more affected in CHF, patients with PAD reported a greater

physical burden as compared with CHF patients. PAD patients who were younger, lower-educated, without a partner or had a cardiac history especially reported a higher disease burden. Clinicians need to be aware of these differences in order to develop tailor-made disease management programs for different groups of cardiovascular patients. (J Vasc Surg 2009;50:1391-8.)”
“Objective: Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis.

The HE possesses receptor binding and receptor destroying enzyme (RDE) activity and is probably involved in the infection process.

The recombinant HE protein (recHE 4) was expressed in insect cells (Sf9) using the baculovirus expression vector system. Both the transmembrane region and the cytoplasmic tail were deleted, and a C-terminal

His(6)-tag was attached to facilitate identification and purification of the recHE 4 protein. As determined by Western analysis learn more the recHE 4 was secreted at 20 degrees C and not at 28 degrees C. By testing three HE constructs differing in their promoter and secretion signal sequences it was clear that the HE’s own secretion signal sequence is more important than the promoter with respect to the amount of secreted recHE CB-5083 molecular weight 4 obtained under the conditions used. A one-step purification by nickel-affinity chromatography resulted in a highly purified recHE 4, identified

by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis. Also, the recHE 4 is glycosylated and contains disulfide bridges within the molecule. Functional studies including the verification of the receptor destroying enzyme (RDE) activity as well as the binding to Atlantic salmon erythrocytes (hemagglutination) indicate that the recHE 4 has similar functions as its native counterpart.

In conclusion, insect cells secrete a functional form of the ISAV 4 HE. This is suitable for further analyses on its function and immunogenicity. (c) 2008 Elsevier Inc. All rights reserved.”
“The mammalian brain commonly uses structural proximity to reflect proximity in stimulus and perceptual space. Objects or object features that are near each other in eFT-508 research buy physical structure or perception are also near each other in the brain. This generates sensory maps. The topography of olfactory connectivity implies a rudimentary map in the olfactory

epithelium, a more intricate map in the olfactory bulb, but no ordered topography is evident in piriform cortex. Currently, we are largely unable to link the ordered topography in epithelium and bulb to meaningful olfactory axes within a strong predictive framework. We argue that the path to uncovering such a predictive framework depends on systematically characterizing olfactory perception, and we describe initial efforts in this direction.”
“Curiosity is a cornerstone of cognition that has the potential to lead to innovations and increase the behavioral repertoire of individuals. A defining characteristic of curiosity is inquisitiveness directed toward novel objects. Species differences in innovative behavior and inquisitiveness have been linked to social complexity and neocortical size [18]. In this study, we observed behavioral actions among nine socially reared and socially housed capuchin monkeys in response to an unfamiliar object, a paradigm widely employed as a means to assess curiosity.

“
“Oxidative and cytotoxic damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Recent studies have indicated that sonic hedgehog

(Shh) signaling could protect neurons against oxidative stress by increasing superoxide dismutase 1 (SOD1) activity. Glioma-associated oncogene homolog 1 (Gli1) and patched-1 (Ptch1) are both components and transcriptional targets of the Shh pathway. Here, we designed this study to determine the effect of inhibition of Shh pathway on the development of cerebral ischemia injury. Male. Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion Selleckchem Liproxstatin 1 (pMCAO). Cyclopamine (0.18 mg/kg), the classical inhibitor of Shh signaling, was stereotactic injected into the lateral cerebral ventricle immediately after pMCAO. At 24 h neurological deficit was evaluated using a modified six point scale; brain water content was measured: infarct size was analyzed with 2,3,5-triphenyltetrazolium learn more chloride (Tit). Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), Western Blotting and activity assay were used to analyze the

expression of Gli1. Ptch1 and SOD1. Compared with Vehicle group, cyclopamine down-regulated Gli1, Ptch1 and SOD1 in pMCAO-affected brain tissue (P<0.05), and increased infarct volume (P<0.05), brain water content (P<0.05) and behavioral deficits (P<0.05). Collectively, the present results suggest that inhibition of Shh signaling pathway exacerbated rat ischemic damage caused by pMCAO, which may be correlated with down-regulated expression of Gli1, Ptch1 and SOD1. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Background Although methamphetamine

abuse has been associated with cognitive deficits, few studies have investigated the acute effects of the drug on complex cognitive performance. This study evaluated the acute effects of intranasal methamphetamine on a computerized task measuring metacognition of agency.

Procedure Ten nontreatment seeking methamphetamine abusers (2F, 8M) completed this four-session, within-participant, double-blind laboratory study; during each session, participants many received one of four doses (0, 12, 25, or 50 mg/70 kg) and completed the metacognition of agency task. In this task, participants were instructed to “”catch”" falling targets with a mouse and then provide metacognitive judgments about their feelings of control.

Results Following placebo, judgments of agency were greater under optimal task conditions compared with less than optimal task conditions. Relative to placebo, the 12-mg dose improved task performance, increased judgments of agency under the optimal condition, and decreased judgments of agency under the less than optimal condition. By contrast, the larger doses (25 and 50 mg) increased judgments of agency only under the optimal condition but disrupted performance under the less than optimal condition.

Serum lipids, vitamin B12, folic acid, pHcy and acute phase protein levels were measured in all cases. MTHFR C677T gene polymorphisms were determined, and IMT of main carotid artery were evaluated ultrasonographically in all subjects. Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity score and Bath Ankylosing Spondylitis Metrology Index were used to assess disease activity and spinal mobility. Fifty AS patients (mean age of 36.6 +/- A 4.79 years) and 50 control subjects (36.34 +/- A 4.72 years) were included in the study. Plasma homocysteine levels of AS patients and

control group were also similar (14.26 +/- A 9.96 vs. 11.81 +/- A 5.53 mu mol/L). Hyperhomocysteinemia Rabusertib was present in 11 subjects in patient group (22.0 %), while it was seen in 5 subjects in the control group (10.0 %). The MTHFR C677T genotype distribution was as follows: CC 31 (62 %), CT 14 (28 %), TT 5 (10 %) in AS patients. The BGJ398 solubility dmso mean carotid IMT values

were also found to be similar between the groups. The most important factor influencing pHcy level was found as MTHFR 677TT genotype. We indicated no difference of atherosclerosis indices revealed by IMT values and pHcy levels AS patients and control subjects. But an association between MTHFR 677 gene polymorphism and pHcy levels was concluded, which may suggest that MTHFR 677 TT polymorphism may be a potential prognostic factor for cardiovascular disease in patients with AS.”
“Several studies of rheumatoid arthritis (RA) incidence and prevalence indicate that occurrence of the disease varies significantly among different populations. We aimed to estimate the prevalence and incidence of RA in South Korea. We used

Korean National Health Insurance (NHI) claims data to estimate the prevalence of RA in 2007-2009 and the incidence of RA in 2008. On the basis of our PF299804 cell line previous validation study, the presence of RA was defined by the diagnostic code for RA with biologic or non-biologic disease-modifying anti-rheumatic drugs in the same claim in each year. To estimate the incidence of RA, we identified cases of RA in 2008 and set the 12-month period prior to 2008 as a disease-free period. Among the incident case of 2008, only patients who continued treatment in 2009 were defined as true incident case of RA in 2008. The corresponding prevalence estimates were 0.26 % (95 % CI 0.25-0.27) in 2006, 0.27 % (95 % CI 0.26-0.28) in 2007, and 0.27 % (95 % CI 0.26-0.28) in 2008. The incidence of RA in 2008 was estimated at 42/100,000 (95 % CI 29.3-54.7) in the general population of South Korea. Data gathered nationwide through the NHI yielded estimates of RA prevalence and incidence in South Korea. This study is the first report of nationwide prevalence and incidence of South Korea and those are comparable to values for other countries in Asia.

Furthermore, we show that receptors formed by alpha 4 beta 3 subunits alone also show high GABA sensitivity and that saturating GABA responses of alpha 4 beta 3 receptors are increased to the same extent by etomidate, propofol, and THDOC as are alpha 4 beta 3 delta receptors. Therefore, both alpha 4 beta 3 and alpha 4 beta 3 delta receptors show low GABA efficacy, and GABA is also a partial agonist on certain binary alpha beta receptor subtypes. Increasing GABA efficacy on alpha 4/6 beta Z-DEVD-FMK datasheet 3 delta and alpha 4 beta 3 receptors is likely to make an important contribution to the anesthetic effects of etomidate, propofol

and the neurosteroid THDOC. (C) 2008 Elsevier Ltd. All rights reserved.”
“Repeated intermittent exposure to psychostimulants can lead to long-lasting sensitization CDK inhibitor of the drugs’ behavioral and biochemical effects. Such findings have figured importantly in recent theories of drug addiction

proposing that sensitized nucleus accumbens (NAcc) dopamine (DA) overflow in particular acts in concert with other alterations in the neurochemistry of this nucleus to promote drug seeking and self-administration. Yet, experiments in rodents, non-human primates and humans have not always detected behavioral or biochemical sensitization following drug exposure, bringing into doubt the utility of this In an effort to reconcile apparent discrepancies in the literature, this review assesses conditions model. that might affect the expression of sensitization during testing. Specifically, the role played by conditioned cues is reviewed. A number of reports strongly support a potent and critical role for conditioned stimuli in the expression of sensitization. Findings suggest that stimuli associated either with the presence or absence of drug can respectively facilitate or inhibit sensitized responding. It is concluded that the presence or

absence of such stimuli during testing for sensitization in animal and human studies could significantly affect the results Selleck C188-9 obtained. It is necessary to consider this possibility especially when interpreting the results of studies that fail to observe sensitized responding. (c) 2008 Elsevier Ltd. All rights reserved.”
“Penicillin, an open-channel blocker of GABA(A) receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and context-dependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABAA receptors expressed in HEK293T cells.

Our sample consisted

of 288 schizophrenia and 288 control subjects. All recruits were Han Chinese drawn from the city of Shanghai.

Results: No individual SNP nor any haplotype was associated with schizophrenia in our study.

Conclusion: These results suggest that the five SNPs within the GRIK4 gene are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population. (c) 2008 Elsevier Inc. All rights reserved.”
“The maintenance of self-tolerance is an integral part of the immune surveillance process, in which cytokines act as master regulators of a complex network involving multiple cell types. On such cytokines, transforming growth factor-beta (TGF-beta) exerts a suppressive control over immune reactivity, which so far appears to be mostly confined to the T-cell compartment. Recently, dendritic cells (DCs) PRT062607 cell line have been found to be both an early source and a target of TGF-beta actions. In these cells, autocrine, paracrine and T-cell-derived TGF-beta activates the tolerogenic pathway of tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) -

resulting in a burst of regulatory kynurenines that contribute to establishing a state of ‘infectious tolerance’. Current molecular insights suggest a synergistic potential for MX69 TGF-beta and IDO in physiologically or therapeutically opposing human pathologies sustained by over-reacting immune responses.”
“Transforming growth factor beta (TGF-beta) physiologically induces Epstein-Barr virus (EBV) lytic infection by activating the expression of EBV’s latent-lytic switch BZLF1 gene. Liang et al. (J. Biol. Chem. 277:23345-23357, 2002) previously identified a Smad-binding element (SBE) within the BZLF1 promoter, Zp; however, it accounts for only 20 to 30% of TGF-beta-mediated activation of transcription

from Zp. Here, we identified additional factors responsible for the rest of this activation. The incubation Lonafarnib cost of EBV-positive MutuI cells with a TGF-beta neutralizing antibody or inhibitors of the TGF-beta type I receptor (T beta RI) or Smad3 eliminated the TGF-beta-induced reactivation of EBV. The coexpression of Smad2, Smad3, and Smad4 together with a constitutively active form of T beta RI induced 15- to 25-fold transcription from Zp in gastric carcinoma AGS cells. By electrophoretic mobility shift assays, we identified four additional Smad-binding elements, named SBE2 to SBE5. Substitution mutations in individual SBEs reduced Smad-mediated activation of Zp by 20 to 60%; together, these mutations essentially eliminated it. Chromatin immunoprecipitation assays confirmed that Smad4 newly bound the Zp region of the EBV genome following the incubation of MutuI cells with TGF-beta. SBE2 overlaps the ZEB-binding ZV silencing element of Zp.

Findings: Follicular fluid and serum were collected at the time of follicular aspiration in in vitro fertilisation without (Natural cycle IVF, n = 24) and with (conventional gonadotropin stimulated IVF, n = 31) gonadotropin stimulation.

The concentration of the extra-ovarian hormones prolactin and cortisol were analysed by immunoassays.

Results: Median serum prolactin and cortisol concentrations were 12.3 ng/mL and 399 nmol/L without versus 32.2 ng/mL and 623 nmol/L with gonadotropin stimulation. The corresponding concentrations in follicular fluid were 20.6 ng/mL and 445 nmol/L versus 28.8 ng/ml and 456 nmol/L for prolactin and cortisol. As a consequence, mean follicular fluid: serum ratios were significantly reduced under gonadotropin RepSox chemical structure stimulation (prolactin p = 0.0138, cortisol p = 0.0001). As an enhanced blood-follicular permeability and transportation, induced by gonadotropin stimulation, would result in increased instead of decreased follicular fluid: serum ratios as found in this study, it can be assumed that this does not affect extra-ovarian protein and steroid hormones as illustrated by prolactin and cortisol.

Conclusions: The model of serum follicular fluid: serum ratio of hormones, produced outside the ovaries, did Copanlisib concentration not reveal

a gonadotropin induced increased blood-follicular transportation click here capacity. Therefore it can be assumed that the effect of gonadotropins on follicular endocrine function is not due to an increased ovarian permeability of extra-ovarian hormones.”
“Background: Oocyte-specific genes play critical

roles in oogenesis, folliculogenesis and early embryonic development. The objectives of this study were to characterize the expression of a novel oocyte-specific gene encoding an F-box protein during ovarian development in rainbow trout, and identify its potential interacting partners in rainbow trout oocytes.

Methods: Through analysis of expressed sequence tags (ESTs) from a rainbow trout oocyte cDNA library, a novel transcript represented by ESTs only from the oocyte library was identified. The complete cDNA sequence for the novel gene (named fbxoo) was obtained by assembling sequences from an EST clone and a 5′RACE product. The expression and localization of fbxoo mRNA and protein in ovaries of different developmental stages were analyzed by quantitative real time PCR, immunoblotting, in situ hybridization and immunohistochemistry. Identification of Fbxoo binding proteins was performed by yeast two-hybrid screening.

Results: fbxoo mRNA is specifically expressed in mature oocytes as revealed by tissue distribution analysis. The fbxoo cDNA sequence is 1,996 bp in length containing an open reading frame, which encodes a predicted protein of 514 amino acids.

Results. There were 4905 attendees in Europe4, 1094 in Estonia, 1221 in The Netherlands and 2825 in Chile. In the algorithm four variables were fixed characteristics (sex, age, lifetime depression screen, family history of psychological difficulties); three current status (Short Form 12 physical health subscale

and mental health subscale scores, and unsupported difficulties in paid and/or unpaid work); one concerned country; and one time of follow-up. The overall C-index in Europe4 was 0.752 [95% confidence interval (CI) 0.724-0.780]. The effect selleck screening library size for difference in predicted log odds between developing and not developing anxiety was 0.972 (95% CI 0.837-1.107). The validation of predictA resulted in C-indices of 0.731 (95% CI 0.654-0.809) in Estonia, 0.811 (95% CI 0.736-0.886) in The Netherlands and 0.707 (95% CI 0.671-0.742) in Chile.

Conclusions. PredictA accurately predicts the risk of anxiety syndromes. The algorithm is strikingly

similar to the predictD algorithm for major depression, suggesting considerable overlap in the concepts of anxiety and depression.”
“Purpose: We investigated trends in urinary diversion use and surgeon characteristics in the performance of incontinent and continent urinary diversion see more using American Board of Urology data.

Materials and Methods: Annualized case log data for urinary diversion were obtained from the American Board of Urology for urologists who certified or recertified from 2002 to 2010. We evaluated the association between surgeon characteristics and the performance of any urinary diversion or the type of urinary diversion.

Results: Of the 5,096 certifying or recertifying urologist case logs examined 1,868 (37%) urologists performed any urinary diversion. The median number of urinary diversions was

4 per year (IQR 2, 6) and 222 urologists (4%) performed 10 or more per year. On multivariate analysis younger urologists, those self-identified as oncologists or female urologists, those who certified in more recent years and those in larger practice areas or outside the Northeast region of the United States were more likely to perform any urinary diversion. Only 9% of the total cohort (471 urologists) performed any continent urinary diversion. The likelihood of performing any continent urinary diversion Selleckchem ISRIB increased with the number of urinary diversions (p < 0.0001). As urinary diversion volume increased, the proportion representing continent urinary diversion also increased (p < 0.0005). Surgeons in private practice settings and those in the Northeast were less likely to perform continent urinary diversion.

Conclusions: Few urologists perform any urinary diversion. Continent urinary diversion is most frequently done by high volume surgeons. The type of urinary diversion that a patient receives may depend in part on surgeon characteristics.”
“Background.

tabaci heat shock protein 70 (HSP70) specifically responded to the presence of the monopartite TYLCV and the bipartite Squash leaf curl virus. Immunocapture PCR, protein coimmunoprecipitation, and virus overlay protein binding assays showed in vitro interaction between TYLCV and HSP70. Fluorescence in situ hybridization and immunolocalization this website showed colocalization of TYLCV and the bipartite Watermelon chlorotic stunt virus virions and HSP70 within midgut epithelial cells. Finally, membrane feeding of whiteflies with anti-HSP70 antibodies and TYLCV virions showed an increase in TYLCV transmission, suggesting an inhibitory role for HSP70 in virus transmission, a role that might be related to

protection against begomoviruses while translocating in the whitefly.”
“The concept of ‘depressive realism’, that depression leads to more accurate perception of causal control, has been influential in the field of depression research, but remains controversial. Recent work testing contingency learning has suggested that contextual processing might determine realism-like effects. Serotonin (5-hydroxytryptamine, (5-HT)), which is implicated in the pathophysiology of depression, might also influence contextual processing. selleck chemicals Using acute tryptophan depletion (ATD), we tested the hypothesis that dysfunctional serotoninergic neurotransmission

influences contingency judgements in dysphoric subjects via an effect on contextual processing.

We employed a novel contingency learning task to obtain separate measures (ratings) of the causal effect of partcipants’ responses and efficacy of the background context over an outcome. Participants, without a history of depression, completed this task on and off ATD in a double-blind, placebo-controlled, within-subjects design.

As with other work on contingency learning, the effects of ATD were related to baseline mood levels. Although no overall effects of ATD were observed, the subgroup of participants with low Beck depression inventory (BDI) scores Selleckchem PKC412 showed reduced ratings of contextual control and improved accuracy of

contingency judgements under positive contingencies following ATD, compared to placebo. High BDI participants demonstrated low accuracy in contingency judgements, regardless of serotoninergic status.

No effect of ATD on contingency judgements was observed in the group as a whole, but effects were observed in a subgroup of participants with low BDI scores. We discuss these data in light of the context processing hypothesis, and prior research on 5-HT and depressive realism.”
“Background and Purpose: Peptide analog of thymulin (PAT) has been shown to have anti-hyperalgesic and anti-inflammatory properties in animal models of inflammation. Recent reports suggest that the peripheral cholinergic system has an anti-inflammatory role mediated by alpha 7-nicotinic acetylcholine receptor (alpha 7-nAChR).

Importantly, sorafenib also modulated phospho-Erk, Bim, Bax and Mcl-1 levels in samples procured from patients in an ongoing Phase I clinical trial of sorafenib in AML. Combination of sorafenib with cytarabine or the novel small molecule Bcl-2 inhibitor ABT-737 synergistically induced cell death in AML cell lines. Our results strongly suggest potential activity of sorafenib as a novel mechanism-based therapeutic agent in AML.”
“Sodium-coupled neutral amino-acid transporter member 2 (SNAT2) belongs to the family of neutral amino-acid transporters. SNAT2 is encoded by the gene SIc38a2, whose expression was reported

to increase in vitro in fibroblasts, endothelial and renal cells exposed to a hypertonic medium. SNAT2 tonicity-induced expression brings about cellular accumulation of amino-acid, which contributes to osmoadaptation to hypertonicity. Since brain osmoadaptation is observed AZD2281 cost in relationship to neurological disorders CHIR-99021 in vitro resulting from pathological osmotic imbalances in blood plasma, we have investigated, through immunocytochemistry, SNAT2 expression in brain of rats subjected to systemic hypertonicity. Following prolonged systemic hypertonicity (24 h), small, strongly immunolabeled elements were observed that were not present in sham-treated animals. They were evenly distributed in the gray matter, with a lower density in the forebrain and a higher

density in the brain stem. However the highest density by far was observed in white matter, where they were frequently aligned in chain-like rows. These observations suggested an oligodendrocyte location that was further established by double immunofluorescent labeling, using the oligodendrocyte phenotypic markers

2’3′-cyclic nucleotide 3′ phosphodiesterase and carbonic anhydrase II. SNAT2-positive elements were found associated with oligodendrocyte cell bodies, while oligodendrocyte processes were devoid of labeling. A quantitative analysis performed in the cerebral cortex MEK162 molecular weight indicated that virtually all SNAT2-positive elements were associated with oligodendrocyte cell bodies and conversely that the overwhelming majority of oligodendrocytes showed SNAT2 immunolabeling. The tonicity-induced expression of SNAT2 was not observed following acute systemic hypertonicity (6 h). Our results suggest that the osmoadaptation of brain oligodendrocytes to hypertonicity relies upon amino-acid accumulation through the tonicity-induced expression of SNAT2. The possible significance of these findings in relationship to the selective loss of oligodendrocytes observed in osmotic demyelination syndrome is discussed. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Mcl-1 is an antiapoptotic Bcl-2 family member, whose degradation is supposedly required for the induction of apoptosis. However, histone deacetylase inhibitors (HDACi) induce apoptosis primarily through the Bak/Mcl-1/Noxa and Bim pathways without decreasing Mcl-1.