Do community-level predictors of pneumococcal carriage continue to play a role in the conjugate vaccine era?

This paper examined whether previously identified community-level factors (high proportion of crowded households and/or persons below the poverty level) remained associated with childhood pneumococcal carriage in the heptavalent pneumococcal conjugate vaccine (PCV7) era. Using logistic regression, individual factors were used to develop base models to which community-level factors were added to evaluate impact on pneumococcal carriage within two paediatric study cohorts from Massachusetts (urban Boston, outside Boston). Six years after introduction of universal childhood PCV7 vaccination, we found no consistent evidence that census tract characteristics (e.g. population size and density, age and race distribution, percent participating in group childcare, parental education, percent lacking in-unit plumbing, poverty, and community stability) affected odds of pneumococcal carriage when added to individual predictors (e.g. younger age, current respiratory tract infections, and attendance in group childcare). How community-level factors influence pneumococcal carriage continues to change in the era of increasing immunization coverage.

Photodynamic therapy for the treatment of vertebral metastases in a rat model of human breast carcinoma.

The feasibility and efficacy of photodynamic therapy (PDT) for the treatment of vertebral metastases using a minimally invasive surgical technique adapted from vertebroplasty was evaluated in a rodent model. Initial validation included photosensitizer (benzoporphyrin-derivative monoacid-ring A) drug uptake studies and in vitro confirmation of PDT efficacy. Intracardiac injection of human MT-1 breast cancer cells was performed in athymic rats. In 63 rats that developed vertebral metastases 21 days post-inoculation, single treatment of PDT was performed using a parapedicular approach placing an optical fiber adjacent to targeted vertebrae. Two milligrams per kilogram of photosensitizer drug was administered intravenously followed by 150 mW of 690 nm light illumination at varying drug-light intervals and light energies. Histologic and immunohistochemical analysis was performed assessing treatment effect. Local tumor viability and growth was quantified by bioluminescence imaging pre and 48 h post-treatment. PDT demonstrated an ablative effect on vertebral metastases (light energies 25-150 J). The effect varied in proportion to light energy with the greatest anti-tumor effect observed at 150 J using a 3 h drug-light interval. 9/22 rodents in the 3 h drug-light interval developed hindlimb paralysis following treatment, consistent with drug uptake studies demonstrating an increase in spinal cord uptake 3h following drug administration. The observations of paralysis following treatment highlight the importance of closely defining the therapeutic window of treatment in safety and efficacy.

Mechanisms of impaired growth hormone secretion in genetically obese Zucker rats: roles of growth hormone-releasing factor and somatostatin.

GH secretion is markedly blunted in obesity; however, the mechanism(s) mediating this response remains to be elucidated. In the present study we examined the involvement of the two hypothalamic GH-regulatory hormones, GH-releasing factor (GRF) and somatostatin (SRIF), using the genetically obese male Zucker rat. Spontaneous GH, insulin, and glucose secretory profiles obtained from free moving, chronically cannulated rats revealed a marked suppression in amplitude and duration of GH pulses in obese Zucker rats compared to their lean littermates (mean 6-h plasma GH level, 3.9 +/- 0.4 vs. 21.5 +/- 3.8 ng/ml; P less than 0.001). Obese rats also exhibited significant hyperinsulinemia in the presence of normoglycemia. The plasma GH response to an iv bolus of 1 microgram rat GRF-(1-29)NH2, administered during peak and trough periods of the GH rhythm, was significantly attenuated in obese rats at peak (137.4 +/- 26.1 vs. 266.9 +/- 40.7 ng/ml; P less than 0.02), although not at trough, times. Passive immunization of obese rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values; the mean 6-h plasma GH level of obese rats given SRIF antiserum was not significantly different from that of obese rats administered normal sheep serum. Both pituitary wet weight and pituitary GH content and concentration were reduced in the obese group. Measurement of hypothalamic GRF immunoreactivity revealed a significant (P less than 0.05) reduction in the mediobasal hypothalamic GRF content in obese rats (503.2 +/- 60.1 pg/fragment) compared to that in lean controls (678.1 +/- 50.2 pg/fragment), although no significant difference was observed in hypothalamic SRIF concentration. Peripheral SRIF immunoreactive levels were significantly (P less than 0.01) elevated in both the pancreas and stomach of obese rats. These results demonstrate that the genetically obese Zucker rat exhibits 1) marked impairment in both spontaneous and GRF-induced GH release, which cannot be reversed by SRIF immunoneutralization, 2) significant reduction in pituitary GH concentration, 3) depressed hypothalamic GRF content, and 4) elevated gastric and pancreatic, but not hypothalamic, SRIF levels. The findings suggest that the defect in pituitary GH secretion observed in the genetically obese Zucker rat is due, at least partially, to insufficient stimulation by hypothalamic GRF, and that SRIF does not play a significant role.

Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation.

Neuropeptide Y (NPY) is a potent orexigenic agent capable of producing hyperphagia and obesity. NPY-containing neurons project from the hypothalmic arcuate nucleus to the paraventricular nucleus, an area known to be sensitive to the orexigenic effects of NPY. In this study we investigated the possibility that preproNPY messenger RNA (mRNA) content may be altered in obese Zucker rats compared to that of their lean littermates. Total RNA was isolated from hypothalamic dissections from male and female, obese and lean Zucker rats. RNA was also isolated from dissections of: olfactory bulb, entorhinal cortex, hippocampus, and striatum of female obese and lean rats. PreproNPY mRNA content was determined by solution hybridization-RNase protection analysis. The results revealed a 2- to 3-fold increase in preproNPY mRNA levels in the hypothalamus of obese animals compared to lean. The increase was observed in both sexes and was specific to the hypothalamus. In situ hybridization localized this increase to the arcuate nucleus. An additional RNase protection study was pursued to investigate the effects of 72 h food deprivation on hypothalamic preproNPY mRNA levels in lean and obese animals. Lean animals displayed an approximate 2-fold increase in preproNPY mRNA content, whereas obese animals showed no significant increase after food deprivation. These data are consistent with the hypothesis that NPY projections within the hypothalamus are involved in regulating feeding behavior and weight gain, and that disturbed regulation of hypothalamic NPY expression may play a role in the etiology of obesity in the genetically obese Zucker rat.

Growth hormone and prolactin secretion in genetically obese Zucker rats.

GH and PRL levels were measured by RIA in plasma samples taken from genetically obese and nonobese rats over a 6-h period at consecutive 15-min intervals. The mean GH level was 204 ng/ml for lean animals and 48 ng/ml for obese rats; the difference is significant (t = 5.8; P less than 0.01). For the group of 5 lean rats, there were 10 GH peaks that exceeded the upper limit of the assay (800 ng/ml), whereas for the group of 6 obese rats, there were only 2 peaks that exceeded the upper limit. In some of the obese rats, peaks of very small amplitude were present. No differences were seen in PRL levels. The mean plasma PRL level was 3.6 ng/ml for lean animals and 3.3 ng/ml for obese rats. Abnormalities in GH in obese rats may be related to an imbalance between hypothalamic releasing and inhibiting factors or a defect in the pituitary.

Hormonal control of growth in the genetically obese Zucker rat. I. Linear growth, plasma insulin-like growth factor-I (IGF-I) and IGF-binding proteins.

The genetically obese Zucker rat is a widely used model of early-onset obesity. Like obese children, these obese rats are hyperinsulinemic and have low GH secretion. However, data on linear growth and insulin-like growth factor-I (IGF-I) levels in this model are scanty and contradictory. In the present study, we investigated linear growth and its hormonal control in Zucker rats (male and female) from 4-20 weeks of age. In the obese animals, compared to their lean littermates, the naso-anal length was normal or slightly greater, whereas the tails and femurs were shorter. The plasma concentration of IGF-I increased between 4-20 weeks of age, and IGF-I levels were normal or slightly higher in the obese animals. The serum level of IGF-binding protein-3 (IGFBP-3) measured by Western ligand blotting was not significantly different in lean vs. obese rats. To assess the IGF-I response to GH, bovine GH was administered (250 micrograms/100 g BW, ip, daily for 3 days) to 16- to 20-week-old female Zucker rats; plasma IGF-I concentrations increased more in the obese (percent increase over baseline, 347 +/- 44% vs. 194 +/- 31%; P < 0.01). These results show that despite low GH secretion, genetically obese Zucker rats have 1) normal linear (nasoanal) growth, 2) normal or increased circulating levels of IGF-I and IGFBP-3, and 3) increased plasma IGF-I responses to exogenous GH. These results suggest that the GH-independent growth in this model could result from direct effects of hyperinsulinism on circulating IGF-I and IGFBP-3 levels and/or indirect effects through increased GH receptor function.

Long descending projections of the hypothalamus in the pigeon, Columba livia.

An autoradiographic analysis was performed on the descending projections of nucleus periventricularis magnocellularis (PVM) of the hypothalamus in the pigeon. A PVM-medullospinal pathway was observed coursing posteriorly through the lateral hypothalamus, ventrolateral midbrain tegmentum, and into the spinal lemniscus (ls) in the ventrolateral pons and medulla. In the pons, some fibers course dorsomedially from ls and terminate at the lateral border of the locus coeruleus. At medullary levels, fibers from ls sweep dorsomedially in the plexus of Horsley and project to certain regions of the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (NX). Specifically, PVM fibers project heavily into NTS subnuclei medialis superficialis, medialis ventralis, and lateralis (sulcalis) dorsalis as well as into the ventral parvocellular subnucleus of NX. Fibers in ls were traced caudally into the lateral funiculus as far as upper cervical levels of the spinal cord. Although autoradiographs of lower cervical or thoracic spinal cord sections were not available, PVM fibers do descend to thoracic spinal cord levels, as evidenced by the retrograde transport of horseradish peroxidase. In addition to the medullospinal pathway, the autoradiographs demonstrated PVM projections to septum, diencephalon, and midbrain. Labeled PVM fibers are found in the lateral septal nucleus, nucleus of the anterior pallial commisure, dorsomedial thalamic nucleus, dorsolateral anterior thalamic nucleus (pars ventralis), median eminence, medial and lateral hypothalamus, medial mammillary area, and nucleus intercollicularis and central gray of the midbrain. The projection of fibers to medullospinal regions and median eminence suggests that PVM is homologous to the mammalian paraventricular nucleus. These projections to specific subnuclei of NTS and NX denote hypothalamic control over certain autonomic functions.

The localization of vasotocin and neurophysin neurons in the diencephalon of the pigeon, Columba livia.

Vasotocin (VT)- and neurophysin (NP)-synthesizing neurons were demonstrated by immunocytochemistry in the diencephalon of the pigeon, Columba livia. Three diencephalic regions contain VT-NP cells: (1) periventricular preoptic area and hypothalamus, including nucleus periventricularis magnocellularis (PVM); (2) lateral preoptic area and hypothalamus; and (3) dorsal diencephalon. The immunoreactive cells in each of these three regions were divided into groups based on cytology and topography. No differences were found in the location of VT and NP cell groups. The periventricular region contains three continuous cell groups (P1-P3) extending from the posteroventral preoptic area to the anterodorsal hypothalamus and PVM. The lateral region has two cell groups composed of medium- to large-sized cells associated with the quintofrontal tract (L1) or with the optic tract (L2), while a third group (L3) lies between these two cell groups. Two accessory cell groups reside in the dorsolateral hypothalamus; L4 contains scattered cells of varied size, whereas L5 has small- to medium-sized cells clumped together. The dorsal diencephalic cell groups are found in the following locations: (1) lateral and dorsal to the lateral forebrain bundle (DD1); (2) in the area ventral to the dorsomedial anterior thalamic nucleus and dorsolateral to PVM (DD2); and (3) at the dorsolateral border of nucleus rotundus (DD3). To avoid potentially inaccurate mammalian homologies, the cell group nomenclature denotes topographic position. Nevertheless, the presence of VT-NP cells in PVM and projections to the brainstem and spinal cord suggest a homology between PVM and some of the parvocellular subnuclei of the mammalian paraventricular nucleus.

Analysis of the interaction of naltrexone with eating following adrenergic and cholinergic stimulation of the hypothalamus.

The anoretic potency of the narcotic antagonist drug nalthrexone, was investigated against eating elicited by the perifornical hypothalamic injection of 24.0 nmol of norepinephrine or 6.0 nmol of carbachol. Although eating following administration of norepinephrine was not significantly affected by pretreatment with naltrexone, carbachol-induced eating and drinking were dramatically attenuated by doses of naltrexone as small as 0.25 mg/kg. These data suggest the existence of an opiate link in these cholinergically-mediated behaviors.

Imidazole-5-acrylic acids: potent nonpeptide angiotensin II receptor antagonists designed using a novel peptide pharmacophore model.

A series of novel nonpeptide angiotensin II receptor antagonists containing a substituted (E)-acrylic acid has been developed. The overlay of 1, an imidazole-5-acetic acid found in the patent literature, on a novel pharmacophore model of AII suggested that extension of the acid side chain and attachment of a second aryl residue to mimic the C-terminal phenylalanine region of AII would lead to increased activity. A study of extended acid side chains at C-5 of the imidazole nucleus led to the discovery of the (E)-acrylic acid 5 as a promising starting point for further exploration. As predicted by the modeling, substitution of a benzyl group on the acrylic acid side chain to mimic the phenylalanine gave increased potency. An extensive study of the SAR of the newly introduced aromatic ring revealed that electron-rich heteroaryl rings provided improved activity, most notably in the in vivo rat models. Compound 40, (E)-3-[2-butyl-1- [(2-chlorophenyl)methyl]imidazol-5-yl]-2-[(2-thienyl)methyl]-2- propenoic acid, has been shown to be a potent, competitive, and orally active small molecule AT-1 receptor antagonist. It exhibits a 2 orders of magnitude increase in binding affinity and a 10-fold improvement in in vivo potency as compared to compound 1 and represents an important milestone in the development of even more potent nonpeptide angiotensin II receptor antagonists.

Some benzyl-substituted imidazoles, triazoles, tetrazoles, pyridinethiones, and structural relatives as multisubstrate inhibitors of dopamine beta-hydroxylase. 4. Structure-activity relationships at the copper binding site.

Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1) by examining the effects upon in vitro inhibitory potencies resulting from structural changes at the copper-binding region of inhibitor. Attempts were made to determine replacement groups for the thione sulfur atom of the prototypical inhibitor 1-(4-hydroxybenzyl)imidazole-2-thione described previously. The synthesis and evaluation of oxygen and nitrogen analogues of the soft thione group demonstrated the sulfur atom to be necessary for optimal activity. An additional series of imidazole-2-thione relatives was prepared in an effort to probe the relationship between the pKa of the ligand group and inhibitory potency. In vitro inhibitory potency was shown not to correlate with ligand pKa over a range of approximately 10 pKa units, and a rationale for this is advanced. Additional ligand modifications were prepared in order to explore bulk tolerance at the enzyme oxygen binding site and to determine the effects of substituting a six-membered ligand group for the five-membered imidazole-2-thione ligand.

Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids.

The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem. 1992, 35, 3858). Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II. Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity. SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency. Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented. The parent diacid analog, SK&F 108566 or (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazole-5-yl]-2-[(2- thienyl)methyl]propenoic acid, is currently in clinical development for the treatment of hypertension.

Pediatric residency training in an era of managed care: an introduction to proceedings of a national conference.

On May 4, 1996, a conference sponsored jointly by the Division of Medicine of the Health Resources and Services Administration and the Ambulatory Pediatric Association brought together pediatric educators from academic medical centers and managed care organizations to address the challenges and opportunities for pediatric residency training, given current trends toward increasing managed care for children. This supplement is designed to bring the issues discussed there to a broader audience of pediatricians and educators. The contributions are written by the participants of that conference, with invited commentaries to add additional perspectives on each topic. The papers were reviewed by an editorial board of leaders in pediatric education with experience in relevant areas. This introduction describes the impetus for the conference and highlights a number of critical issues facing pediatric postgraduate training that are presented in greater depth in the contributions that follow. Finally, this paper summarizes the recommendations of the conference for meeting the challenges of training pediatricians in these areas.

Pediatric education and managed care: a literature review.

Managed care is becoming the dominant form of health care delivery and financing in the United States, necessitating changes in pediatric education. This transition is redefining the questions of what needs to be taught, who should be teaching it, where it should be taught, and how to pay for this education. We performed a literature review and examined reports from policy and professional groups to seek answers to these questions. We have identified curricular, administrative, and financial challenges to pediatric education in managed care. Although road maps for innovation have been described, there is a deficiency of research and information in key areas of pediatric education in the managed care environment.

Fever in pediatric primary care: occurrence, management, and outcomes.

OBJECTIVE: To describe the epidemiology, management, and outcomes of children with fever in pediatric primary care practice. PATIENTS: A cohort of 20 585 children 3 to 36 months of age cared for in 11 pediatric offices of a health maintenance organization between 1991 and 1994. METHODS: Using automated medical records we identified all office visits with temperatures >/=38 degrees C for a random sample of 5000 children, and analyzed diagnoses conferred, laboratory tests performed, and antibiotics prescribed. We also determined the frequency of in-person and telephone follow-up after initial visits for fever. Finally, we reviewed hospital claims data for the entire cohort of 20 585 to identify cases of meningitis, meningococcal sepsis, and death from infection. RESULTS: Among 3819 initial visits of an illness episode, 41% of children had no diagnosed bacterial or specific viral source. Of these, 13% with a temperature of 38 degrees C to 39 degrees C and 36% with a temperature of >/=39 degrees C received laboratory testing. Almost half (43%) received some documented follow-up care in the subsequent 7 days. Among the 26 970 child-years of observation in the entire cohort, 15 children (56 per 100 000 child-years) were treated for bacterial meningitis or meningococcal sepsis. Five had an office visit for fever in the week before hospitalization, but only 1 had documented fever >/=39 degrees C and received neither laboratory testing for occult bacteremia nor treatment with an antibiotic. CONCLUSION: The majority of febrile children in ambulatory settings were diagnosed with a bacterial infection and treated with an antibiotic. Of highly febrile children without a source, 36% received laboratory testing consistent with published expert recommendations, and short-term follow-up was common. Meningitis or death after an office visit for fever without a source was predictably rare. These data suggest that increased testing and/or treatment of febrile children beyond the rates observed here are unlikely to affect population rates of meningitis substantially.

Quality of care for preschool children with asthma: the role of social factors and practice setting.

OBJECTIVE: To determine whether patient race or source of payment is associated with differences in the quality of inpatient and outpatient treatment for young children with asthma. DESIGN: Structured medical record review. SETTING: Tertiary care pediatric hospital. PATIENTS: We studied 354 patients aged 1 to 6 years discharged with asthma between October 1, 1989 and September 30, 1990. MEASURES: We developed indicators of the quality of asthma care provided before and during hospitalization and planned after discharge. Outpatient indicators were the use of inhaled beta-agonists and the use of preventive anti-inflammatory medications (inhaled steroids or cromolyn sodium) before admission. In-hospital indicators were the intensity of inhaled beta-agonist therapy in the emergency department and length of stay. Planning for post-hospital care was assessed by the prescription of a nebulizer for home use. We examined associations between these indicators and patient race and source of payment, and explored the influence of primary-care practice type on these associations. RESULTS: After adjustment for potential confounders, we found that Hispanic patients were less likely than white patients to have taken inhaled beta-agonists before admission. Both black and Hispanic patients were less likely than white patients to have taken anti-inflammatory medications. When we adjusted for the patients' primary-care practice type, the effect of patient race did not persist for these indicators of outpatient care. We found no differences by patient race in emergency department care or length of hospital stay. However, black and Hispanic patients were much less likely to be prescribed a nebulizer for home use upon discharge. After adjustment for confounders, there were no differences in the quality of asthma care by source of payment. CONCLUSIONS: We found that young children of racial minorities admitted for an asthma exacerbation were less likely to have received maximally effective preventive therapy. We also identified marked differences in the quality of care planned after hospital discharge for black and Hispanic patients, compared with white patients. Particularly in an era of health reform, attention should focus on barriers to high-quality care for underserved children, who are already at high risk for asthma-related morbidity.

Obesity- and sex-related alterations in growth hormone messenger RNA levels.

The secretion of growth hormone (GH) is abnormal in genetically obese Zucker rats. Measurements of pulsatile GH release and circulating GH levels in lean (Fa/?) and obese (fa/fa) rats have shown that both are reduced in the latter. We have studied pituitary GH gene expression in order to understand the role of GH synthesis in this abnormality. Obese animals have lower pituitary GH mRNA levels than lean controls. Within each genotype a sex difference was observed with the female animals having lower GH mRNA levels than the males. It is unlikely that the GH abnormality is due to a generalized pituitary defect because prolactin mRNA levels were the same in all four groups of rats.

Relationship between asthma medication and antibiotic use.

STUDY OBJECTIVES: Increasing morbidity due to asthma and antimicrobial resistance among human pathogens are both major public-health concerns. Numerous studies describe the overuse of antibiotics in general populations and underuse of anti-inflammatory medications by asthmatic patients. However, little is known about the relationship between asthma medication and antibiotic use in asthmatics. Specifically, we tested the hypothesis that higher use of bronchodilator and anti-inflammatory medication by asthmatics, as a marker of problematic asthma, is associated with greater antibiotic use. We also test the hypothesis that physicians who are low prescribers of anti-inflammatory medications are high prescribers of antibiotics. DESIGN: We conducted a retrospective cohort study evaluating asthma medication and antibiotic use by children and adults with asthma and the prescribing of these medications by primary-care physicians. SETTING/PATIENTS: Subjects were continuously enrolled asthma patients aged 6 to 55 years receiving care in an urban, group-model, health maintenance organization. INTERVENTIONS: None. MEASUREMENT AND RESULTS: Main outcome measures were (1) antibiotic use by asthmatics stratified by low, moderate, and high bronchodilator use; (2) antibiotic use by asthmatics stratified by no, intermittent, and long-term anti-inflammatory use; and (3) correlation between physician-level anti-inflammatory agent to bronchodilator ratio (AIF:BD) and their rate of antibiotic prescribing. We found that (1) high bronchodilator users received 1.72 antibiotics per person-year (95% confidence interval [CI], 1.62 to 1.83), whereas low bronchodilator users received 1.23 antibiotics per person-year (95% CI, 1.19 to 1.27; p < 0.0001); (2) long-term users of anti-inflammatory agents received 1.85 antibiotics per person-year (95% CI, 1.76 to 1.95), whereas those not receiving an anti-inflammatory agent received 0.95 antibiotics per person-year (95% CI, 0.90 to 1.00; p < 0.0001); and (3) despite variations in physician AIF:BDs and antibiotic prescribing, respectively, these measures were not correlated. CONCLUSIONS: Antibiotic use and asthma medication use are positively associated in a cohort of asthma patients. Greater effort is needed to define the appropriate role of antibiotics in asthma management.

Developmental aspect of differences in hypothalamic preproneuropeptide y messenger ribonucleic Acid content in lean and genetically obese zucker rats.

The genetically obese Zucker rat is a well characterized model of early onset human obesity. Many of the endocrine and metabolic abnormalities of obese animals are common to other strains of genetically obese animals as well as morbidly obese humans. Neuropeptide Y (NPY), a potent orexigenic agent, was recently found to be elevated in adult obese animals compared to their lean littermates. In this study we first examined hypothalamic expression of preproNPY mRNA, using solution hybridization/ nuclease protection analysis, in phenotypically-matched, i.e. lean or obese, immature (5-week-old) and mature (33-week-old) animals. Although changes were not statistically different, a trend toward decreased hypothalamic preproNPY mRNA levels was detected in both lean and obese mature animals. We next compared hypothalamic preproNPY mRNA levels between age-matched lean and obese animals at 5, 14 and 33 weeks of age and found elevated preproNPY mRNA levels in obese rats at all three ages. These data suggest that increased levels of hypothalamic NPY are an early manifestation of the obese phenotype and may, therefore, contribute to hyperphagia and increased weight gain in obese Zucker rats.