Enzyme-altered foci in colons of carcinogen-treated rats.

The distal colon and rectum from male F344 rats treated with 15 mg/kg 1,2-dimethylhydrazine.2HCl (DMH) for 20 weeks were analyzed for focal areas of enzyme alteration. Tissues were embedded in methacrylate at 4 degrees C and cut in 2- to 4-micron serial sections. In DMH-treated rats, 8.8 +/- 2.4 foci/cm2 of examined mucosa were observed at 20 weeks and 7.7 +/- 1.1 foci/cm2 at 31 to 52 weeks, compared with 1.2 +/- 0.6 foci/cm2 in control rats (P = 0.01). The number of foci at 31 to 52 weeks compared with 20 weeks did not change significantly, but the area of altered rectal mucosa increased from 0.22 +/- 0.2% at 20 weeks to 1.47 +/- 0.6% at 31 to 52 weeks (P = 0.051). Most foci had decreased N-acetyl-beta-D-glucosaminidase, alpha-naphthyl butyrate esterase, and mucin in epithelial cells and increased gamma-glutamyl transpeptidase in the stroma. Morphologically, the foci varied from normal to overtly dysplastic. Grossly, tumors were identified in 5 of 20 DMH-treated rats killed at 31 to 52 weeks but not in 12 DMH-treated rats killed at 20 weeks or 30 control rats killed at 20 to 52 weeks. These data suggest but do not establish that enzyme-altered foci are putative preneoplastic lesions in the colon.

Aberrant crypts: putative preneoplastic foci in human colonic mucosa.

Aberrant crypts were identified for the first time in whole-mount preparations of normal-appearing human colonic mucosa after staining with methylene blue. The foci of aberrant crypts varied from single altered glands to plaques of greater than 30 crypts. The mean proportion of colonic mucosa altered and the number of foci with aberrant crypts per cm2 of colonic mucosa were (a) higher in patients with colon cancer than in patients without colon cancer or predisposing conditions and (b) highest in our single case of Gardner's syndrome. Aberrant crypts are postulated to be the earliest identifiable potential precursors of colon cancer. Analysis of aberrant crypts may facilitate the study of the early pathological and molecular changes that precede colon cancer.

Traffic Light: prognosis-based eligibility for clinical trials of hematopoietic SCT in adults with sickle cell anemia.

Estimating prognosis in sickle cell anemia (SCA) assumes greater importance as intensive treatments, such as hematopoietic SCT (HSCT), are being tested. Here we estimate the mortality risk from the walk-PHaSST (Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease) trial of homozygous SCA patients with suspected pulmonary hypertension (19/468 deaths; 10 centers in the US and UK). Parallel investigations were also undertaken in the Cooperative Study of Sickle Cell Disease (CSCCD) and a contemporary urban sickle cell disease population (Case Western Reserve University-University Hospitals (CWRU-UH), Cleveland, OH, USA). One- and two-value positive predictive values for 2-year mortality (from study entry) are calculated using factors that include demographics, laboratory values and clinical evaluations. We define high-, intermediate-, and low-risk SCA as > 15%, 10-15% and < 10% 2-year mortality. In walk-PHaSST, no single factor qualifies as high-risk SCA, although several combinations of two factors (that is, both age > 35 years and history of chronic transfusion) do. Either elevated white blood cell count (> 13.5 × 10(3) cells/mcL, 7/70 deaths) or elevated Tricuspid Regurgitant Jet Velocity (⩾ 3.0 m/s, 8/67 deaths) was individually associated with intermediate-risk disease, as were many two-factor combinations. N-terminal pro-brain natriuretic peptide > 160 ng/L, lactate dehydrogenase > 600 IU/L, history of chronic transfusion, sepsis or age > 35 years are individually associated with low-risk SCA, as are many two-factor combinations. SCA risk was integrated with estimated donor type-associated risk from HSCT to form 'Traffic Light' eligibility criteria for clinical trials of HSCT. This method is adaptable to evolutions in clinical care.

Maternal tobacco smoke exposure and persistent pulmonary hypertension of the newborn.

We propose that in utero exposure to tobacco smoke products places a newborn at risk for persistent pulmonary hypertension of the newborn (PPHN). To test this hypothesis, infants with PPHN were identified. Healthy newborns of similar ethnicity were identified as a comparison group. Cord blood cotinine concentrations and maternal questionnaires were obtained. The number of women exposed to tobacco smoke in each group ascertained by questionnaire was borderline significantly different (38.7% vs. 20.5%; p = 0.080). However, more PPHN infants had detectable cotinine in their cord blood (64.5% vs. 28.2%; p = 0.002), and the median cotinine concentrations were significantly higher (5.2 ng/ml vs. 2 ng/ml; p = 0.051) than the comparison infants. Among infants delivered to nonsmoking women, more PPHN infants had detectable cotinine (50% vs. 19%; p = 0.015), and the cotinine concentrations were higher (3.5 ng/ml vs. 1.65 ng/ml; p = 0.022) than the comparison group. We conclude that active and passive smoking during pregnancy is a risk factor for PPHN. Therefore, we recommend that pregnant women cease smoking and avoid environmental tobacco smoke. Key words. cotinine, newborns, passive, persistent pulmonary hypertension, smoking, tobacco smoke pollution.

Low yield of bacterial stool culture in children with nosocomial diarrhea.

OBJECTIVE: To determine whether bacterial stool cultures (BSC) are useful in initial evaluation of children with symptoms of nosocomial diarrhea. To answer this question we performed a retrospective record review to determine the yield of BSC in children who developed diarrhea after the third hospital day (HD-3). METHODS: The hospital computer record keeping system was utilized to compile the result of BSC collected from children and adolescents ages 0 to 20 years between January 1, 1988, and October 31, 1996. All specimens were analyzed for Salmonella, Shigella, Yersinia and Campylobacter. We reviewed hospital charts of all children who developed a positive BSC beyond HD-3 to determine the time of onset of diarrhea and clinical circumstances. RESULTS: A total of 11 516 BSCs were submitted from 9262 children during the 8 1/2-year period. Five hundred sixty-eight (6.6%) of 9262 children had at least 1 positive BSC. Two thousand five hundred seventy-two children had the first BSC submitted after HD-3 and 13 (0.5%) of these children had a positive result. Chart review of these 13 children demonstrated that 6 had onset of diarrhea during the first 3 hospital days. Therefore only 7 children met our criteria for having nosocomially acquired diarrhea caused by a bacterial pathogen. Children whose first BSC was submitted after HD-3 accounted for 3767 (46%) of the total 8126 inpatient BSCs and in excess of $21000 annually in patient billing charges. CONCLUSION: In the absence of a known exposure the isolation of a bacterial pathogen from the stool of children with onset of diarrhea beyond HD-3 is a rare event. Under most circumstances BSC should not be part of the initial evaluation of children with symptoms of nosocomial diarrhea.

Identification and quantification of ureaplasmas colonizing the respiratory tract and assessment of their role in the development of chronic lung disease in preterm infants.

BACKGROUND: The role of Ureaplasma urealyticum in the development of chronic lung disease (CLD) in preterm infants continues to be disputed. Recently U. urealyticum has been found to consist of two species, U. urealyticum and Ureaplasma parvum, a finding that has not been considered in previous studies of CLD. This study examined the possible relationships between development of CLD and respiratory colonization by these newly redefined species, their concentrations in lower respiratory secretions and the effect of pulmonary surfactant treatment on these relationships in preterm infants with birth weights < 1500 g. METHODS: Endotracheal aspirates (ETA) were collected from intubated infants when airway suctioning was medically required. ETA were stored at -80 degrees C until quantitative cultures for ureaplasmas and Mycoplasma hominis were performed. Culture results were correlated with development of CLD. RESULTS: Of 475 infants (birth weights < 1500 g) admitted during the 2-year study period, 272 were excluded because they were not intubated or were extubated before ETA could be obtained. An additional 28 infants died, were discharged or were transferred before they could be assessed for CLD. From the remaining 175 infants ureaplasmas were isolated from 66 (38%). No statistically significant associations were identified between development of CLD and the Ureaplasma species isolated, or concentration of ureaplasmas in lower respiratory secretions. These findings were not altered by treatment with pulmonary surfactant (Survanta). CONCLUSION: Lower respiratory colonization by ureaplasmas does not appear to be a contributory cause of CLD in preterm infants.

A cost-saving algorithm for children hospitalized for status asthmaticus.

OBJECTIVE: To test the ability of an assessment-driven algorithm for treatment of pediatric status asthmaticus to reduce length and cost of hospitalization. DESIGN: Nonrandomized, prospective, controlled trial. SETTING: Tertiary care children's hospital. PATIENTS: Children aged 1 to 18 years hospitalized for status asthmaticus; 104 were treated using the asthma care algorithm (intervention) and 97 using unstructured standard treatment (control). INTERVENTION: Patients were treated using either an assessment-based algorithm or standard care practices. The algorithm group was treated with standard medications (aerosolized albuterol, systemic corticosteroids, epinephrine, ipratropium) administered at a frequency driven by the patient's clinical condition. Specific criteria were outlined for decreasing or augmenting therapy, transferring to intensive care, and discharging to home. A unique patient record containing assessments, algorithm cues, and a treatment record was used. Intervention group patients were interviewed by telephone 1 week after discharge. MAIN OUTCOME MEASURES: Hospital length of stay, cost per hospitalization, relapse rate, protocol adherence. RESULTS: Average hospital stay for intervention patients was significantly shorter than for control patients (2.0 vs 2.9 days, P<.001). Although intervention patients received fewer aerosolized albuterol doses than controls, there was no difference in short-term relapse rate between groups. The intervention saved more than $700 per patient in hospital charges. Adherence to the protocol was excellent, with only 8 variances per patient stay out of more than 150 opportunities. CONCLUSION: An intensive, assessment-driven algorithm for pediatric status asthmaticus significantly reduces hospital length of stay and costs without increasing morbidity.

The pharmacokinetics of colistin in patients with cystic fibrosis.

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.

Superior visual search in autism.

Children with a diagnosis of autism and normally developing children, matched for age and general ability, were tested on a series of visual search tasks in 2 separate experiments. The children with autism performed better than the normally developing children on difficult visual search tasks. This result occurred regardless of whether the target was uniquely defined by a single feature or a conjunction of features, as long as ceiling effects did not mask the difference. Superior visual search performance in autism can be seen as analogous to other reports of enhanced unique item detection in autism. Unique item detection in autism is discussed in the light of mechanisms proposed to be involved in normal visual search performance.

Placental lesions associated with cerebral palsy and neurologic impairment following term birth.

OBJECTIVE: The aim of this study was to determine the association of placental findings with cerebral palsy and related forms of neurologic impairment (NI) following birth at > or =37 weeks gestation (term). DESIGN: In a retrospective comparison, placentas from 40 term infants with NI ascertained on the basis of clinicopathologic review for medicolegal consultation were compared with placentas from 176 consecutive meconium-stained term infants at low risk for NI. RESULTS: After stratification for severity, 9 lesions were significantly increased in placentas from infants with NI: 5 lesions generally considered to occur within days of the time of labor and delivery (meconium-associated vascular necrosis, severe fetal chorioamnionitis, chorionic vessel thrombi, increased nucleated red blood cells, and findings consistent with abruptio placenta) and 4 lesions generally believed to have their onset long before labor and delivery (diffuse chronic villitis, extensive avascular villi, diffuse chorioamnionic hemosiderosis, and perivillous fibrin). Findings independently associated with NI by logistic regression in this descriptive study were severe fetal chorioamnionitis (odds ratio [OR], 13.2; 95% confidence interval [CI], 1.2-144); extensive avascular villi (OR, 9.0; 95% CI, 1.6-51); and diffuse chorioamnionic hemosiderosis (OR, 74.8; 95% CI, 6.3-894). The risk of NI increased as a function of the number of lesions present (OR, 10.1; 95% CI, 5.1-20 for each additional lesion), particularly when lesions generally considered to occur near the time of labor and those believed to occur well before labor were found in the same placenta (OR, 94.2; 95% CI, 11.9-747). CONCLUSIONS: These findings suggest that placental pathology can contribute to an understanding of the mechanisms that contribute to NI at term.

A randomized trial of the Vein Viewer versus standard technique for placement of peripherally inserted central catheters (PICCs) in neonates.

OBJECTIVE: Peripherally inserted central catheters are important but can be difficult to place in neonates. Therefore, we compared a near-infrared device, the Vein Viewer, to determine if its use would increase successful line placement, with standard techniques. STUDY DESIGN: Randomized controlled trial in preterm and term neonates in a level 3 Neonatal Intensive Care Unit. RESULT: In all, 115 subjects were enrolled with 59 randomized to the Vein Viewer group and 56 to the control group. Overall, use of the Vein Viewer showed a trend to more successful placement 86 versus 75%; unadjusted odds ratio 2.33 (0.90, 6.04; P=0.08). Infants randomized to the Vein Viewer were more mature (30 ± 2 weeks gestational age (GA) versus 28 ± 2 weeks GA; P=0.08). After adjusting for GA, use of the Vein Viewer was significantly more likely to lead to successful line placement (adjusted odds ratio 3.05 (1.10, 1.82)). CONCLUSION: The Vein Viewer improved successful placement with the most benefit seen in infants of greater GA.

Relationships among depressive symptoms, sexually transmitted infections, and pregnancy in African-American adolescent girls.

STUDY OBJECTIVE: To explore relationships among depressive symptoms, sexually transmitted infections (STI), and pregnancy in African-American adolescent girls. DESIGN: Retrospective chart review. SETTING: A hospital-based outpatient practice serving primarily African-American patients. PARTICIPANTS: A total of 126 female patients ages 13-19 years who had ligase chain reaction (LCR) for N. gonorrhoeae and C. trachomatis. METHODS: Charts were reviewed for history of STI, history of pregnancy, LCR results, and a history of depressive symptoms as indicated by standardized provider notes and patient self-administered questionnaire. Data are compared using Fisher's exact test. RESULTS: Mean age was 16.6 years (+/-1.6 years); 19.8% of participants had a history of depressive symptoms, 40.5% had a history of STI, 8.7% had a prior pregnancy, and 18.2% had a positive LCR. Of patients with a history of depressive symptoms, 64% had a history of STI compared to 34.6% of those without depressive symptoms (P = 0.01). A positive LCR was found in 20% of patients with a history of depressive symptoms and 17.8% of patients without (P = 0.78). Of patients with a history of depressive symptoms, 12% had a prior pregnancy compared to 7.9% without such history (P = 0.45). CONCLUSIONS: African-American adolescent females in our clinic with a history of depressive symptoms were more likely to have a history of STI. A greater percentage of patients with a history of depressive symptoms also had prior pregnancies and/or current STI. Sexually active adolescent girls should be screened for depressive symptoms as part of their evaluation for sexual risk behaviors.

Potential pharmacokinetic basis for zolpidem dosing in children with sleep difficulties.

The pharmacokinetics of zolpidem was assessed in this open-label, dose-escalation study in children with insomnia. Twenty-one children, seven per age group (2-6, >6 to 12, >12 to 18 years), received a single dose of zolpidem at one of the three dose levels (0.125, 0.25, or 0.50 mg/kg (20 mg maximum dose)). Multiple pharmacokinetic measures were assessed at nine post-dose intervals and pharmacodynamics was assessed by polysomnography and actigraphy. Significant pharmacokinetic effects by dose were observed only as linear increases in maximum concentration (C(max), P<0.001) and area under the plasma concentration-time curve (AUC, P<0.001). Significant pharmacokinetic effects by age group included an increase in AUC (P=0.02), half-life (P=0.04), and mean residence time (P=0.01), whereas total body clearance decreased (P=0.01) and steady-state volume of distribution was variable. Pharmacodynamic measures were independent of the pharmacokinetic estimates. Overall, zolpidem was well tolerated and a pediatric dose of 0.25 mg/kg is recommended for future efficacy studies.

Aberrant crypt foci and colon tumors in F344 rats have similar increases in proliferative activity.

Increased proliferative activity has been described frequently in the colons of animals treated with colon carcinogens and of patients at increased risk of colon cancer; it has been proposed as an intermediate biomarker of colon cancer. Aberrant crypt foci, microscopic lesions identified in whole-mount preparations of colons, are thought to be putative pre-neoplastic lesions. The present studies were carried out to evaluate the proliferative activity of aberrant crypt foci at several different time periods, and of tumors after a single dose of azoxymethane (AOM) in F344 rats. Rats were injected with 5-bromo-2'-deoxyuridine (BUdR) 1 hr before killing. Aberrant crypt foci and tumors were identified and marked in the whole-mount specimens, embedded in glycol methacrylate, and evaluated for histochemically demonstrable hexosaminidase activity. Hexosaminidase is known to be altered in over 95% of aberrant crypt foci. Serial sections were evaluated for BUdR incorporation immunohistochemically with a monoclonal antibody. The mean proliferative activity of aberrant crypt foci in the distal colons was found to be increased 3- to 4-fold over that of the adjacent normal crypts at every time period analyzed (4 to 36 weeks) and was comparable to that seen in benign and malignant colon tumors in the same animals. The observed increase in proliferative activity further supports the hypothesis that aberrant crypt foci are putative pre-neoplastic lesions. Similar aberrant crypt foci, identified in human colons at increased risk of colon cancer, may provide important biomarkers for this common human cancer.

Lead exposure from blood transfusion to premature infants.

OBJECTIVE: The objective of this study was to determine the exposure of premature infants to lead from blood transfusions. STUDY DESIGN: Blood lead concentrations were determined for 19 very premature infants at the time of admission, at 4 weeks of life, and before and after transfusions and in the donor packed red blood cells of 79 transfusions. RESULTS: The number of transfusions per patient was 4. 2 +/- 2.8 (mean +/- SD) with 15.7 +/- 1.9 mL/kg packed red blood cells for a lead dose of 1.56 +/- 1.77 microg/dL. The total dose of lead from these transfusions over the 4-week period was 4.0 +/- 2.8 microg/kg (range, 0.9-10.6 microg/kg). Increases in post-transfusion blood lead concentration were linear with doses higher than 1.5 microg/dL. Packed red blood cells with a blood lead concentration of > or = 5 microg/dL resulted in an elevated post-transfusion blood lead concentration in some infants. CONCLUSIONS: The lead exposure to these infants through blood transfusion exceeds the acceptable daily intake values for lead and may result in unacceptably high post-transfusion blood lead concentrations. Use of packed red blood cells with lead concentrations <3.3 microg/dL is one cost-effective means to reduce exposure.

In situ localization of enzymes and mucin in normal rat colon embedded in plastic.

Several enzymes were investigated histochemically in the colons of normal male F344 rats in order to understand the function of different types of cells in this tissue. Serial methacrylate-embedded sections (2-4 microns) allowed the precise localizations of several enzymes including acid phosphatase, alkaline phosphatase, gamma-glutamyl transpeptidase, N-acetyl-beta-D-glucosaminidase (hexosaminidase), alpha-naphthyl butyrate esterase and 5'-nucleotidase. Sites reactive with periodic acid-Schiff were also localized. Gradients of enzyme activity were observed between caecum and rectum and/or from the luminal surfaces to the bases of the crypts for hexosaminidase, esterase and gamma-glutamyl transpeptidase. To our knowledge this is the first histochemical demonstration of gamma-glutamyl transpeptidase in normal rat colonic epithelial cells. The utilization of the methacrylate-embedding technique has revealed previously undescribed gradients of enzyme activity and has allowed the localization of enzyme activities not previously reported in normal rat colonic mucosa.

Pediatric renal biopsy: should this procedure be performed in an outpatient setting?

Although several retrospective reports suggest that pediatric outpatient renal biopsies may be done in a safe and cost-effective manner, risk factors and the natural history of major complications following this procedure have not been clearly delineated. In an effort to determine the minimal observation period required to detect major post-renal biopsy complications in children and to establish clinical parameters predictive of these complications, a retrospective review of 177 percutaneous renal biopsies was performed. The overall major complication rate was 3.4%, while the minor complication rate was 14.1%. The mean percentage change in hemoglobin 4-10 h postbiopsy in patients with major bleeding complications was significantly greater than patients with minor bleeding complications. Using a 16% drop in hemoglobin 4-10 h postbiopsy, the sensitivity and specificity of identifying a major bleeding complication was 100% and 98%, respectively, while the positive and negative predictive value was 68% and 100%, respectively. All patients with major complications due to excess sedation or immediate bleeding were diagnosed within 11 h of the biopsy. Automated renal biopsies offered several safety and efficiency advantages compared with non-automated methods. Our results suggest that outpatient pediatric renal biopsies should be encouraged provided certain precautions are taken to reduce the risk of developing major complications.

Colonic aberrant crypts in azoxymethane-treated F344 rats have decreased hexosaminidase activity.

Aberrant crypts, identified with methylene blue staining of unsectioned colon from carcinogen-treated rats on the basis of their increased size, were examined for the altered expression of hexosaminidase activity. Previously we identified enzyme-altered foci with normal morphology in sections of colon from carcinogen-treated rats. A reduction of histochemically demonstrable hexosaminidase activity was the most consistent marker for these foci. Aberrant crypts, marked with permanent ink and embedded in methacrylate, had a marked decrease of hexosaminidase activity compared to the adjacent, normal crypts. Hexosaminidase may be a marker that will aid in the identification of the molecular basis of colon cancer in a manner similar to that of esterase D and retinoblastoma.

The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria.

BACKGROUND: Prader-Willi syndrome (PWS) is a complex, multisystem disorder. Its major clinical features include neonatal hypotonia, developmental delay, short stature, behavioral abnormalities, childhood-onset obesity, hypothalamic hypogonadism, and characteristic appearance. The genetic basis of PWS is also complex. It is caused by absence of expression of the paternally active genes in the PWS critical region on 15q11-q13. In approximately 70% of cases this is the result of deletion of this region from the paternal chromosome 15. In approximately 28%, it is attributable to maternal uniparental disomy (UPD; inheritance of 2 copies of a chromosome from the mother and no copies from the father, as opposed to the normal 1 copy from each parent) of chromosome 15, and in <2%, it is the result of a mutation, deletion, or other defect in the imprinting center. Clinical diagnostic criteria were established by consensus in 1993. Subsequently, definitive molecular genetic testing became available for laboratory diagnosis of PWS. However, identification of appropriate patients for testing remains a challenge for most practitioners because many features of the disorder are nonspecific and others can be subtle or evolve over time. For example, hypotonic infants who are still in the failure to thrive phase of the disorder often do not have sufficient features for recognition of PWS and often are not tested. Initial screening with these diagnostic criteria can increase the yield of molecular testing for older children and adults with nonspecific obesity and mental retardation. Therefore, the purpose of clinical diagnostic criteria has shifted from assisting in making the definitive diagnosis to raising diagnostic suspicion, thereby prompting testing. We conducted a retrospective review of patients with PWS confirmed with genetic testing to assess the validity and sensitivity of clinical diagnostic criteria published before the widespread availability of testing for all affected patients and recommend revised clinical criteria. METHODS: Charts of all 90 patients with laboratory-confirmed PWS were reviewed. For each patient, the presence or absence of the major, minor, and supportive features listed in the published diagnostic criteria was recorded. The sensitivity of each criterion, mean of the total number of major and minor criteria, and mean total score for each patient were calculated. RESULTS: There were 68 patients with a deletion (del 15q11-q13), 21 with maternal UPD of chromosome 15, and 1 with a presumed imprinting defect. Age range at the time of the most recent evaluation was 5 months to 60 years (median: 14.5 years; del median: 14 years; range: 5 months-60 years; UPD median: 18 years; range: 5-42 years). The sensitivities of the major criteria ranged from 49% (characteristic facial features) to 98% (developmental delay). Global developmental delay and neonatal hypotonia were the 2 most consistently positive major criteria and were positive in >97% of the patients. Feeding problems in infancy, excessive weight gain after 1 year, hypogonadism, and hyperphagia were all present in 93% or more of patients. Sensitivities of the minor criteria ranged form 37% (sleep disturbance and apneas) to 93% (speech and articulation defects). Interestingly, the sensitivities of 8 of the minor criteria were higher than the sensitivity of characteristic facial features, which is a major criterion. Fifteen out of 90 patients with molecular diagnosis did not meet the clinical diagnostic criteria retrospectively. CONCLUSION: When definitive diagnostic testing is not available, as was the case for PWS when the 1993 criteria were developed, diagnostic criteria are important to avoid overdiagnosis and to ensure that diagnostic test development is performed on appropriate samples. When diagnostic testing is available, as is now the case for PWS, diagnostic criteria should serve to raise diagnostic suspicion, ensure that all appropriate people are tested, and avoid the expense of testing unnecessarily. Our results indicate that the sensitivities of most of the published criteria are acceptable. However, 16.7% of patients with molecular diagnosis did not meet the 1993 clinical diagnostic criteria retrospectively, suggesting that the published criteria may be too exclusive. A less strict scoring system may ensure that all appropriate people are tested. Accordingly, we suggest revised clinical criteria to help identify the appropriate patients for DNA testing for PWS. The suggested age groupings are based on characteristic phases of the natural history of PWS. Some of the features (eg, neonatal hypotonia, feeding problems in infancy) serve to diagnose the syndrome in the first few years of life, whereas others (eg, excessive eating) are useful during early childhood. Similarly, hypogonadism is most useful during and after adolescence. Some of the features like neonatal hypotonia and infantile feeding problems are less likely to be missed, whereas others such as characteristic facial features and hypogonadism (especially in prepubertal females) may require more careful and/or expert examination. The issue of who should have diagnostic testing is distinct from the determination of features among confirmed patients. Based on the sensitivities of the published criteria and our experience, we suggest testing all newborns/infants with otherwise unexplained hypotonia with poor suck. For children between 2 and 6 years of age, we consider hypotonia with history of poor suck associated with global developmental delay sufficient criteria to prompt testing. Between 6 and 12 years of age, we suggest testing those with hypotonia (or history of hypotonia with poor suck), global developmental delay, and excessive eating with central obesity (if uncontrolled). At the ages of 13 years and above, we recommend testing patients with cognitive impairment, excessive eating with central obesity (if uncontrolled), and hypogonadotropic hypogonadism and/or typical behavior problems (including temper tantrums and obsessive-compulsive features). Thus, we propose a lower threshold to prompt diagnostic DNA testing, leading to a higher likelihood of diagnosis of this disorder in which anticipatory guidance and intervention can significantly influence outcome.