Serum palmitoleate acts as a lipokine in subjects at high cardiometabolic risk.

BACKGROUND AND AIM: Clinical data on the role as a lipokine of de novo lipogenesis-derived palmitoleic acid (C16:1n-7cis) in serum non-esterified fatty acids (palmitoleate) are scarce. We aimed to assess whether palmitoleate relates to cardiometabolic risk. METHODS AND RESULTS: In this cross-sectional study we included 358 individuals aged 30-65-years at high cardiovascular risk. We tested the association of palmitoleate (determined by gas chromatography) with metabolic syndrome (MS) and its components (defined by ATPIII criteria), fatty liver index (a surrogate of non-alcoholic fatty liver disease [NAFLD]), and subclinical atherosclerosis (determined as ultrasound-measured carotid intima-media thickness and arterial stiffness). Palmitoleate concentration was higher in women compared with men (median ± range interquartile, 1.36 ± 0.96 vs. 0.97 ± 0.77 µmol/L respectively, P < 0.001). In both genders palmitoleate concentration was associated with a higher prevalence of MS: men, odds ratio [OR: 1.12 (95%CI: 1.03; 1.23, P = 0.010)]; women [OR: 1.07 (95%CI: 1.03; 1.13, P = 0.005)], and all of its components except low HDL-cholesterol and hypertriglyceridemia. Palmitoleate was also associated with increased risk of NAFLD in both men [OR: 1.12 (95%CI: 1.03; 1.29, P = 0.031)] and women [OR: 1.11 (95%CI: 1.05; 1.19, P = 0.001)]. No associations with subclinical atherosclerosis were detected. CONCLUSIONS: Our observational data supports a relationship between de novo lipogenesis-derived circulating palmitoleic acid (palmitoleate) and increased cardiometabolic risk.

FABP4 plasma concentrations are determined by acquired metabolic derangements rather than genetic determinants.

BACKGROUND AND AIMS: Circulating FABP4 is strongly associated with metabolic and cardiovascular risk (CVR) and has been proposed as a new risk biomarker. Several FABP4 gene polymorphisms have been associated with protein expression in vitro and metabolic and vascular alterations in vivo. The aim of this study is to evaluate the impact of FABP4 polymorphisms on FABP4 plasma levels and subclinical arteriosclerosis in patients with obesity, metabolic syndrome (MS) or type 2 diabetes (T2DM). METHODS AND RESULTS: We studied 440 individuals with obesity, MS, T2DM or other cardiovascular risk conditions who attended the vascular medicine and metabolism unit of our hospital. Anamnesis, physical examination and anthropometry data were recorded. Standard biochemical parameters were determined. Plasma FABP4 concentrations were measured. Carotid intima-media thickness (cIMT) was assessed using ultrasonography. The following FABP4 gene single-nucleotide polymorphisms (SNPs) were analyzed: rs3834363, rs16909233, rs1054135, rs77878271, rs10808846 and rs8192688. None of the studied gene allele variants were hyper-represented in patients grouped according the presence of metabolic alterations nor were they associated with the FABP4 concentration. The FABP4 gene variants did not determine cIMT differences between the groups. In a multivariate analysis, gender and BMI, but not gene variants, significantly determined plasma FABP4 concentrations. CONCLUSIONS: In clinical settings, the circulating FABP4 levels are determined by the acquired metabolic derangements and not genetic variation.

Circulating FABP4 is a marker of metabolic and cardiovascular risk in SLE patients.

The aim of this study is to determine if circulating fatty acid-binding protein 4 (FABP4) plasma levels are a possible marker of metabolic risk in SLE patients. Circulating levels of adipose FABP4 are associated with adiposity, insulin resistance (IR), metabolic syndrome, diabetes and cardiovascular diseases. Patients affected by systemic lupus erythematosus (SLE) show an accelerated atherosclerosis that cannot be entirely explained by traditional cardiovascular risk factors. Sixty consecutive patients with SLE and 34 non-SLE age-matched controls were recruited for the study. Total plasma lipids and circulating FABP4 were determined. Subclinical atherosclerosis was evaluated by measuring carotid intimae-media thickness (c-IMT) by sonography, and the distribution of lipoprotein subclasses was analysed by nuclear magnetic resonance (NMR) spectroscopy. In the SLE group, FABP4 was associated with IR, atherogenic dyslipidaemia, as measured by NMR, and the presence of subclinical atherosclerosis. In multivariate analyses FABP4 was associated with increased c-IMT independent of the inflammatory state of the patient. In sum, circulating FABP4 is involved in the metabolic disturbances of SLE affecting lipid metabolism and IR, and it could be a biomarker of atherosclerosis in this population.

Subclinical atherosclerosis determinants in morbid obesity.

BACKGROUND AND AIMS: Obesity is associated with increased cardiovascular risk. However, the impact of morbid obesity on vascular structure and function is not well understood. This study was designed to appraise subclinical atherosclerosis markers, including carotid intima media thickness (cIMT), endothelial function, and arterial wall stiffness, and their determinants, in morbidly obese patients. METHODS AND RESULTS: In this cross-sectional study 194 overweight and obese patients were distributed in morbid-obese patients (MOP, n = 110), obese (OP, n = 84) and overweight patients (OwP, n = 33) groups. Demography, anthropometry, clinical and standard biochemical data were recorded. cIMT, endothelial function, defined as the small artery reactivity index (saRHI), and artery wall rigidity, studied by the augmentation index, were determined. More than 50% of the MOP, OP and OwP had a cIMT above the 75th percentile per age and gender. No differences in cIMT or saRHI were observed, although overweight and obese patients (OOP) had higher arterial rigidity compared with the morbid-obese patients. In a multivariate regression test, while cholesterol was the main determinant of cIMT in overweight and obese patients, glucose metabolism was the determinant in MOP. CONCLUSION: More than half of the population have a cIMT above general population ranges. OwP, OP and MOP have similar cIMT and saRHI. However, OOP have greater arterial wall rigidity. Dysglycemia is the main factor associated with subclinical atherosclerosis in MOP.

Effects of therapeutic lifestyle changes on peripheral artery tonometry in patients with abdominal obesity.

BACKGROUND AND AIMS: Abdominal obesity (AO) is associated with endothelial function (EF) alteration and increased global cardiovascular (CV) risk. Therapeutic lifestyle changes (TLSC) reduce CV risk, but the impact on EF assessed by peripheral artery tonometry (PAT) is unknown. In this study, we aimed to prospectively assess the effects of TLSC on EF measured by PAT in increased CV risk patients with AO. METHODS AND RESULTS: 150 patients with AO and moderate CV risk were randomized to groups receiving a one-year intervention of either conventional medical care (control group, CG) or an intensive TLSC program (intervention group, IG). Vascular studies (EF by PAT, intima-media thickness (IMT)) and lifestyle (LS) assessment were performed before and after intervention. The PAT ratio improved in the IG and worsened in the CG. The global CV risk was reduced (P = 0.017) in the IG due to a significant decrease in systolic blood pressure (P < 0.001), increase in HDL cholesterol and ApolipoproteinA1 (P = 0.013). More individuals in the IG than in the CG quit smoking (P = 0.001) and increased their physical activity (P = 0.014). The improvement in at least two LS components was associated with a PAT ratio increase (2.44 IC: 95% 0.99-6.00, P = 0.051). The PAT ratio increase determined less IMT progression (-1.1 IC: 95% 0.91-1.00, P = 0.053). CONCLUSIONS: Good adherence to a TLSC program reduces global CV risk and determines PAT ratio improvement. The PAT ratio increase is the main determinant of lower IMT progression.

Ultrasound identification of landmarks preceding lumbar puncture: a pilot study.

AIM: To assess the utility of bedside ultrasound performed by an emergency physician in adults undergoing diagnostic lumbar puncture. METHOD: Ultrasound was used as the primary means of determining the site of skin puncture, angle of needle advancement and depth needed to access the subarachnoid space. RESULTS: Cerebrospinal fluid was obtained from 36 of 39 patients (92.3%) in the first interspinous space attempted. CONCLUSIONS: The ultrasonographically measured depth of the dura mater correlates strongly with the final needle depth.

Stereoscopic digital mammogram: Usefulness in daily practice.

OBJECTIVES: To assess the benefit of stereoscopic digital mammography in daily practice. METHODS: Stereoscopic digital (SD) mammography allows a fused 3D view of mammogram. A 4-degree cranio-caudal (CC) angle view matched with a regular CC view allows generating a stereoscopic view. Three breast radiologists reviewed retrospectively 1110 stereoscopic digital mammograms (1075 women) performed between November 2011 and February 2013 with the following sequence: each evaluated firstly conventional mammogram alone, and then integrated SD mammograms. The benefit was quoted in 3-grade scale: 0 for no benefit, 1 moderate and 2 excellent. The concordance between radiologists was evaluated by the W Randall coefficient. Subgroup analysis according to the BI-RADS classification, breast density and type of abnormalities were performed by calculating odds-ratio. RESULTS: The readers had the same opinion regarding the value of stereoscopic digital mammograms in 87% of cases (962/1110). Benefit was null, moderate and excellent in 8, 52 and 26% respectively. The concordance of radiologists was excellent with a W coefficient above 0.89. CONCLUSIONS: SD mammogram improved interpretation of abnormal mammograms. This potentially interesting and promising complementary tool might be beneficial in daily breast imaging practice.

Ultrasound features of retroareolar breast carcinoma.

PURPOSE: The goal of this study was to report the ultrasound features of retroareolar breast carcinoma (RABC). MATERIALS AND METHODS: The ultrasound examinations of the breast of 53 women with RABC were reviewed. They had a mean age of 67.2 years±13.4 (standard deviation [SD]) (range: 46-85 years). RABC were defined as carcinomas located less than 2cm from the nipple on mammogram. RESULTS: Among the 53 RABC, 42 (42/53; 79%) were invasive ductal carcinomas, 6 (6/53; 11%) were invasive lobular carcinomas, 4 (4/53; 8%) were ductal carcinomas in situ and 1 (1/53; 2%) was intracystic papillary carcinoma. The mean size of RABCs was 22.5mm±8.2 (SD) (range: 7.2-54.8mm). RABCs presented as a mass (53/53; 100%) with an irregular shape (44/53; 83%), a non-parallel orientation (37/53; 70%), non-circumscribed margins (50/53; 94%), a hypoechoic echotexture (46/53; 87%,) posterior attenuation (45/53; 85%) and increased vascularity (37/53; 70%) on Doppler ultrasound. CONCLUSION: On ultrasound, RABC have a presentation similar to that of breast carcinoma in other locations.

Double-echo gradient chemical shift MR imaging fails to differentiate minimal fat renal angiomyolipomas from other homogeneous solid renal tumors.

OBJECTIVES: The purpose of this retrospective study was to evaluate the diagnostic performance of double-echo gradient chemical shift (GRE) magnetic resonance (MR) imaging for the differentiation of angiomyolipomas with minimal fat (mfAML) from other homogeneous solid renal tumors. METHODS: Between 2005 and 2010 in two institutions, all histologically proven homogenous solid renal tumors imaged with computed tomography and MR imaging, including GRE sequences, have been retrospectively selected. A total of 118 patients (mean age: 61 years; range: 20-87) with 119 tumors were included. Two readers measured independently the signal intensity (SI) on GRE images and calculated SI index (SII) and tumor-to-spleen ratio (TSR) on in-phase and opposed-phase images. Intra- and interreader agreement was obtained. Cut-off values were derived from the receiver operating characteristic (ROC) curve analysis. RESULTS: Twelve mfAMLs in 11 patients were identified (mean size: 2.8cm; range: 1.2-3.5), and 107 non-AML tumors (3.2cm; 1-7.8) in 107 patients. The intraobserver reproducibility of SII and TSR was excellent with an intraclass correlation coefficient equal to 0.99 [0.98-0.99]. The coefficient of correlation between the readers was 0.99. The mean values of TSR for mfAMLs and non-mfAMLs were -7.0±22.8 versus -8.2±21.2 for reader 1 and -6.7±22.8 versus -8.4±20.9 for reader 2 respectively. No significant difference was noticed between the two groups for SII (p=0.98) and TSR (p=0.86). Only 1 out of 12 mfAMLs and 11 of 107 non-AML tumors presented with a TSR inferior to -30% (p=0.83). CONCLUSION: In a routine practice, GRE sequences cannot be a confident tool to differentiate renal mfAMLs from other homogeneous solid renal tumors.

Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function.

BACKGROUND: A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level. OBJECTIVE: We aimed to study the impact of a lower level of PA on cardiovascular health. DESIGN: Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed. RESULTS: After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P<0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r=0.341, P=0.022), GPx (r=0.303, P=0.047) and decreases in RHR (r=-0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21-4.01), decrease in RHR (1.91, 95%CI: 1.01-4.98), and an increase in GPx (2.61, 95%CI: 1.16-5.01). CONCLUSION: In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity.

Protein structure-based design, synthesis, and biological evaluation of 5-thia-2,6-diamino-4(3H)-oxopyrimidines: potent inhibitors of glycinamide ribonucleotide transformylase with potent cell growth inhibition.

The design, synthesis, biochemical, and biological evaluation of a novel series of 5-thia-2,6-diamino-4(3H)-oxopyrimidine inhibitors of glycinamide ribonucleotide transformylase (GART) are described. The compounds were designed using the X-ray crystal structure of human GART. The monocyclic 5-thiapyrimidinones were synthesized by coupling an alkyl thiol with 5-bromo-2, 6-diamino-4(3H)-pyrimidinone, 20. The bicyclic compounds were prepared in both racemic and diastereomerically pure forms using two distinct synthetic routes. The compounds were found to have human GART KiS ranging from 30 microM to 2 nM. The compounds inhibited the growth of both L1210 and CCRF-CEM cells in culture with potencies down to the low nanomolar range and were found to be selective for the de novo purine biosynthesis pathway. The most potent inhibitors had 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene ring to give compounds 10, 18, and 19 resulted in inhibitors with significantly decreased mFBP affinity.

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics.

The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The ketomethylene-containing inhibitors typically display slightly reduced 3CP inhibition activity relative to the corresponding peptide-derived molecules, but they also exhibit significantly improved antiviral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which function as potent antirhinoviral agents (EC90 = <1 microM) against multiple virus serotypes in cell culture.

Substituted benzamide inhibitors of human rhinovirus 3C protease: structure-based design, synthesis, and biological evaluation.

A series of nonpeptide benzamide-containing inhibitors of human rhinovirus (HRV) 3C protease was identified using structure-based design. The design, synthesis, and biological evaluation of these inhibitors are reported. A Michael acceptor was combined with a benzamide core mimicking the P1 recognition element of the natural 3CP substrate. alpha,beta-Unsaturated cinnamate esters irreversibly inhibited the 3CP and displayed antiviral activity (EC(50) 0.60 microM, HRV-16 infected H1-HeLa cells). On the basis of cocrystal structure information, a library of substituted benzamide derivatives was prepared using parallel synthesis on solid support. A 1.9 A cocrystal structure of a benzamide inhibitor in complex with the 3CP revealed a binding mode similar to that initially modeled wherein covalent attachment of the nucleophilic cysteine residue is observed. Unsaturated ketones displayed potent reversible inhibition but were inactive in the cellular antiviral assay and were found to react with nucleophilic thiols such as DTT.

Design, synthesis, and evaluation of nonpeptidic inhibitors of human rhinovirus 3C protease.

The design, synthesis, and biological evaluation of reversible, nonpeptidic inhibitors of human rhinovirus (HRV) 3C protease (3CP) are reported. A novel series of 2,3-dioxindoles (isatins) were designed that utilized a combination of protein structure-based drug design, molecular modeling, and structure-activity relationship (SAR). The C-2 carbonyl of isatin was envisioned to react in the active site of HRV 3CP with the cysteine responsible for catalytic proteolysis, thus forming a stabilized transition state mimic. Molecular-modeling experiments using the apo crystal structure of human rhinovirus-serotype 14 (HRV-14) 3CP and a peptide substrate model allowed us to design recognition features into the P1 and P2 subsites, respectively, from the 5- and 1-positions of isatin. Attempts to optimize recognition properties in the P1 subsite using SAR at the 5-position were performed. In addition, a series of ab initio calculations were carried out on several 5-substituted isatins to investigate the stability of sulfide adducts at C-3. The inhibitors were prepared by general synthetic methods, starting with commercially available 5-substituted isatins in nearly every case. All compounds were tested for inhibition of purified HRV-14 3CP. Compounds 8, 14, and 19 were found to have excellent selectivity for HRV-14 3CP compared to other proteolytic enzymes, including chymotrypsin and cathepsin B. Selected compounds were assayed for antiviral activity against HRV-14-infected HI-HeLa cells. A 2.8 A cocrystal structure of derivative 19 covalently bound to human rhinovirus-serotype 2 (HRV-2) 3CP was solved and revealed that the isatin was situated in essentially the same conformation as modeled.

Tripeptide aldehyde inhibitors of human rhinovirus 3C protease: design, synthesis, biological evaluation, and cocrystal structure solution of P1 glutamine isosteric replacements.

The investigation of tripeptide aldehydes as reversible covalent inhibitors of human rhinovirus (HRV) 3C protease (3CP) is reported. Molecular models based on the apo crystal structure of HRV-14 3CP and other trypsin-like serine proteases were constructed to approximate the binding of peptide substrates, generate transition state models of P1-P1' amide cleavage, and propose novel tripeptide aldehydes. Glutaminal derivatives have limitations since they exist predominantly in the cyclic hemiaminal form. Therefore, several isosteric replacements for the P1 carboxamide side chain were designed and incorporated into the tripeptide aldehydes. These compounds were found to be potent inhibitors of purified HRV-14 3CP with Kis ranging from 0.005 to 0.64 microM. Several have low micromolar antiviral activity when tested against HRV-14-infected H1-HeLa cells. The N-acetyl derivative 3 was also shown to be active against HRV serotypes 2, 16, and 89. High-resolution cocrystal structures of HRV-2 3CP, covalently bound to compounds 3, 15, and 16, were solved. These cocrystal structures were analyzed and compared with our original HRV-14 3CP-substrate and inhibitor models.

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structure-activity studies.

The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties and are shown to irreversibly bind to HRV serotype 14 3CP with inhibition activities (kobs/[I]) ranging from 100 to 600 000 M-1 s-1. These inhibitors are also shown to exhibit antiviral activity when tested against HRV-14-infected H1-HeLa cells with EC50's approaching 0.50 microM. Extensive structure-activity relationships developed by Michael acceptor alteration are reported along with the evaluation of several compounds against HRV serotypes other than 14. A 2.0 A crystal structure of a peptide-derived inhibitor complexed with HRV-2 3CP is also detailed.

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure-activity studies.

The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (kobs/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 microM. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (kobs/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 microM). A 1.9 A crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements.

The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.

Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder.

BACKGROUND: To determine in open trials the therapeutic benefit of a nutritional supplement for bipolar disorder. METHOD: The sample consisted of 11 patients with DSM-IV-diagnosed bipolar disorder aged 19 to 46 years, who were taking a mean of 2.7 psychotropic medications each at study entry. Three additional patients dropped out prematurely. The intervention is a broad-based nutritional supplement of dietary nutrients, primarily chelated trace minerals and vitamins, administered in high doses. At study entry and periodically thereafter, patients were assessed with the Hamilton Rating Scale for Depression (HAM-D), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS). RESULTS: For those who completed the minimum 6-month open trial, symptom reduction ranged from 55% to 66% on the outcome measures; need for psychotropic medications decreased by more than 50%. Paired t tests revealed treatment benefit on all measures for patients completing the trial: HAM-D mean score at entry = 19.0, mean score at last visit = 5.4, t = 5.59, df = 9, p < 01; BPRS mean score at entry = 35.3, mean score at last visit = 7.4, t = 2.57, df = 9, p <.05; YMRS mean score at entry = 15.1, mean score at last visit = 6.0, t = 4.11, df = 9, p < .01. The effect size for the intervention was large (> .80) for each measure. The number of psychotropic medications decreased significantly to a mean +/- SD of 1.0+/-1.1 (t = 3.54, df = 10, p < .01). In some cases, the supplement replaced psychotropic medications and the patients remained well. The only reported side effect (i.e., nausea) was infrequent, minor, and transitory. CONCLUSION: Some cases of bipolar illness may be ameliorated by nutritional supplementation. A randomized, placebo-controlled trial in adults with bipolar I disorder is currently underway, as well as open trials in children.

Psychosocial assessment in the general pediatric population: a multiple-gated screening and identification procedure.

This article describes a screening and assessment procedure to identify the need for psychologic and psychiatric services within the general pediatric population. This procedure is additionally designed to facilitate timely and focused treatment planning. It begins with a brief, user friendly instrument, the Pediatric Symptom Checklist (PSC), to routinely screen all pediatric patients. The procedure continues by asking parents of children who are identified as meeting cutoff criteria (on the PSC) or at-risk for psychosocial problems to complete a more sophisticated instrument, the Child Behavior Checklist. Using the PSC and the Child Behavior Checklist in this multiple-gated manner allows for screening and then identification of problem child behaviors, providing data necessary to complete an initial treatment plan. The procedure is proposed as an efficient means of routinely screening for, and then identifying, child psychosocial problems in general pediatric populations.