Obese children show hyperactivation to food pictures in brain networks linked to motivation, reward and cognitive control.

OBJECTIVE: To investigate the neural mechanisms of food motivation in children and adolescents, and examine brain activation differences between healthy weight (HW) and obese participants. SUBJECTS: Ten HW children (ages 11-16; BMI < 85%ile) and 10 obese children (ages 10-17; BMI >95%ile) matched for age, gender and years of education. MEASUREMENTS: Functional magnetic resonance imaging (fMRI) scans were conducted twice: when participants were hungry (pre-meal) and immediately after a standardized meal (post-meal). During the fMRI scans, the participants passively viewed blocked images of food, non-food (animals) and blurred baseline control. RESULTS: Both groups of children showed brain activation to food images in the limbic and paralimbic regions (PFC/OFC). The obese group showed significantly greater activation to food pictures in the PFC (pre-meal) and OFC (post-meal) than the HW group. In addition, the obese group showed less post-meal reduction of activation (vs pre-meal) in the PFC, limbic and the reward-processing regions, including the nucleus accumbens. CONCLUSION: Limbic and paralimbic activation in high food motivation states was noted in both groups of participants. However, obese children were hyper-responsive to food stimuli as compared with HW children. In addition, unlike HW children, brain activations in response to food stimuli in obese children failed to diminish significantly after eating. This study provides initial evidence that obesity, even among children, is associated with abnormalities in neural networks involved in food motivation, and that the origins of neural circuitry dysfunction associated with obesity may begin early in life.

Pharmacokinetics and metabolism of a cysteinyl leukotriene-1 receptor antagonist from the heterocyclic chromanol series in rats: in vitro-in vivo correlation, gender-related differences, isoform identification, and comparison with metabolism in human hepatic tissue.

CP-199,331 is a potent antagonist of the cysteinyl leukotriene-1 (LT(1)) receptor, targeted for the treatment of asthma. The pharmacokinetic/metabolism properties of CP-199,331 were studied in rats and compared with those in human liver microsomes/hepatocytes. In vitro biotransformation of CP-199,331 in rat and human hepatocytes was similar, consisting primarily of CP-199,331 O-demethylation. Marked sex-related differences in plasma clearance (CL(p)) of CP-199,331 were observed in rats: 51 and 1.2 ml/min/kg in males and females, respectively. This difference in CL(p) was attributed to gender differences in metabolizing capacity because V(max) and K(m) values for CP-199,331 metabolism were 30-fold higher and 8-fold lower, respectively, in male rat liver microsomes compared with female microsomes. Scale-up of the in vitro microsomal data predicted hepatic clearance (CL(h)) of 64 and 2.5 ml/min/kg in male and female rats, respectively. These values were in close agreement with the in vivo CL(p), suggesting that CP-199,331 CL(p) in male and female rats was entirely due to hepatic metabolism. Studies with rat recombinant cytochromes P450 and anti-rat cytochrome P450 (CYP) antibodies revealed the involvement of male rat-specific CYP2C11 in the metabolism of CP-199,331. In contrast, CP-199,331 metabolism in human liver microsomes was principally mediated by CYP3A4. The projected human clearance in liver microsomes and hepatocytes varied 6-fold from low to moderate, depending on CYP3A4 activity. Considering that O-demethylation is the major route of elimination in humans, the in vivo clearance of CP-199,331 may exhibit moderate variability, depending on CYP3A4 abundance in the human population.

Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists.

A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).

Angiographic quantification of diffuse coronary artery disease: reliability and prognostic value for bypass operations.

OBJECTIVES: Diffuse distal coronary disease is thought to worsen the outcome of coronary bypass operations, but it is not easily quantified. The present study seeks to show that distal coronary diffuseness can be assessed by a structured reading of the coronary angiogram and that the resulting measure predicts operative mortality. METHODS: Sequential survivors (n = 100) and nonsurvivors (n = 34) of nonemergency bypass operations were studied retrospectively. Angiograms were read as follows: (1) Coronary branches at risk were identified; (2) the amount of myocardium supplied by each branch was estimated in steps of 0.5 such that the entire left ventricle added to 8 segments; (3) distal disease severity in each branch was rated on a 5-point scale; and (4) a distal coronary diffuseness score was determined by summing (severity rating x segments supplied) for all branches. Reliability was assessed by correlating the results of blinded re-readings of the same angiograms by the same and different investigators. The score's association with mortality was determined by means of logistic regression. RESULTS: A distal coronary diffuseness score could be determined from all angiograms. Interobserver and intraobserver reliabilities were high, with r values of 0.81 and 0.83, respectively (P <.001). The score was 1 of 3 significant independent predictors of operative mortality, along with nonelective and repeat operations. CONCLUSION: Diffuse distal coronary disease can be quantified by a structured reading of the coronary angiogram and is a powerful independent predictor of surgical death. Inclusion of a standardized measure of this risk factor would improve statistical models of operative risk.

Discovery of CP-199,330 and CP-199,331: two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity.

CP-199,330 (3) and CP-199,331 (4) are cysLT1 receptor antagonists that are equipotent to marketed cysLT1 receptor antagonists zafirlukast and pranlukast, show good pharmacokinetics in rats and monkeys, and are devoid of liver toxicity in monkeys as seen in CP-85,958 (1).

trans-3-Benzyl-4-hydroxy-7-chromanylbenzoic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor.

The SAR of a series of 2-(7-chromanyl)benzoic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in the benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chromanol substituent were potent LTB4 receptor antagonists, the increased lipophilicity imparted by the additional phenyl substituent led to decreased potency in the presence of plasma proteins. From among the potent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development.

Synthetic approaches to 2-(4-hydroxy-7-chromanyl)benzoic acids as antagonists of leukotriene B4.

Structural modification of 1 led to a series of 2-(4-hydroxy-7-chromanyl)benzoic acid LTB4 antagonists exemplified by 2 and 3. The use of an organostannane biaryl coupling, a non steroselective reduction and a chromatographic resolution limited the utility of this synthetic route. To address these issues, a new synthetic route was developed utilizing a palladium catalyzed coupling of aryl oxazolines in tandem with a stereospecific enone reduction as key synthetic steps. Resolution was achieved by fractional crystallization of a (S)-(-)-alpha-methylbenzylamine salt.

Development of new chromanol antagonists of leukotriene D4.

By addressing the issues of potency and metabolism in 3, a new series of LTD4 antagonists represented by (+)-26 was developed which is equipotent to clinical LTD4 antagonists Zafirlukast (1) and Pranlukast (2).

N-carbamoyl analogs of Zafirlukast: potent receptor antagonists of leukotriene D4.

Exploration of the indole nitrogen region of Zafirlukast (1) has uncovered a potent series of cysteinyl leukotriene D4 (LTD4) antagonists. These studies showed that a variety of functionality could be incorporated in this region of the molecule without sacrificing potency. Efforts to exploit this site in order to improve oral efficacy are discussed.

Development of 2,2-dimethylchromanol cysteinyl LT1 receptor antagonists.

A new series of cysLT1 receptor antagonists represented by CP-288,886 (7) and CP-265,298 (8) were developed which are equipotent to clinical cysLT1 receptor antagonists Zafirlukast (1) and Pranlukast (2).

Biarylcarboxylic acids and -amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret.

In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 microM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).

Radiation risk to patients from percutaneous transluminal coronary angioplasty.

OBJECTIVES: This retrospective study sought to estimate patient radiation exposure during percutaneous transluminal coronary angioplasty, the corresponding organ doses and the resulting cancer mortality risk. Patient demographic data were also examined. BACKGROUND: Coronary angioplasty is commonly used as an intervention for coronary atherosclerosis, and repeated application in the same patient is now common. The combined use of fluoroscopy and cineradiography in this complicated, delicate and, hence, lengthy procedure induced us to investigate the patient radiation exposures and resulting risks. METHODS: All complete records for angioplasty procedures performed over a 3-year period were entered into a data base. The data comprised 1,893 procedures performed in a total of 1,503 patients, of whom 21% had two or more procedures in the 3-year period. Fluoroscopy time was converted to entrance exposures, assuming a rate of 520 muC kg-1 min-1 (2.0 R min-1). Cineradiographic film lengths were determined for a smaller number of procedures (200) and converted to exposures at 7.7 muC kg-1 frame-1 (30 mR frame-1). In addition, fluoroscopy and cineradiographic times and, hence, exposures for 91 diagnostic angiograms performed in these patients were obtained. Exposures were converted to organ doses using the Monte Carlo results of the Rosenstein group and then to cancer mortality risks using the latest rates of the International Commission on Radiological Protection. RESULTS: The mean age was 56.0 years; men constituted 77.5% of the patients. Radiation doses varied considerably owing to a large spread in exposure times (e.g., fluoroscopy time per angioplasty case averaged 19 min but for some cases exceeded 1 h). The average patient skin entrance exposure per angioplasty procedure was 32.0 mC kg-1 (124 R), of which 69.7% was from cineradiography. The resulting cancer mortality risk per angioplasty procedure is approximately 8 x 10(-4). CONCLUSIONS: The skin exposures estimated for angioplasty are on average higher than for other X-ray procedures. The cancer mortality risk does not exceed the mortality risk of bypass surgery. Good professional practice requires maximization of the benefit/risk ratio through quality assurance in all aspects of the procedure.

Acquired postoperative coronary arteriovenous fistula.

A patient is described who underwent closed mitral valvotomy and presented 21 years later with left ventricular failure. Coronary angiography revealed a coronary artery to pulmonary vein arteriovenous fistula. This is the first report of an acquired fistula of this type developing secondary to trauma associated with cardiac surgery. Diagnosis and treatment implications are discussed.

Pelvic fracture as an indicator of increased risk of thoracic aortic rupture.

Thoracic aortic rupture is a lethal injury associated with severe blunt trauma. Survival is directly related to early diagnosis and operative treatment. Establishing the diagnosis requires a high index of suspicion, recognition of radiologic evidence of mediastinal bleeding, and identification of injuries frequently associated with aortic rupture. A retrospective review of blunt trauma patients at the Washington Hospital Center Trauma Unit and data from the Major Trauma Outcome Study identified a two- to fivefold increase in the incidence of aortic injury among patients with pelvic fracture. Twenty to forty-five per cent of patients with aortic rupture had associated pelvic fracture. Our study documents that pelvic fracture is as reliable an indicator of associated aortic rupture as many currently accepted injuries. Its presence should raise suspicion for aortic injury.

Crohn's disease angiographically mimicking vascular malformation or neoplasm.

We report a young woman with lower gastrointestinal bleeding in whom, angiographically and surgically, the offending cecal lesion appeared to be a vascular malformation or neoplasm. Pathologically, Crohn's disease associated with extremely prominent vascularity was discovered to be responsible for this unusual appearance and the bleeding.

Late reassessment of percutaneous transluminal coronary angioplasty results: clinical, exercise and angiographic follow-up.

One hundred and forty-five patients underwent percutaneous transluminal coronary angioplasty (PTCA) in the authors' hospital between 1981 and 1983. Four have since died and all but one of the remainder were accounted for at follow-up 41 +/- 12 months later. Recurrence of angina was present in 28% of patients having successful PTCA versus 33% of patients with surgery for failed PTCA. Use of antianginal drugs and return to work was similar in the two groups. Mean treadmill time, peak heart rate, incidence of treadmill angina and exercise thallium-201 defects were not different in the two groups. Late follow-up coronary angiography in 60 patients who had successful PTCA showed a significant decrease in mean stenosis of the dilated segment from 31 to 23%. Of 25 patients who had late angiography after failed PTCA, three had satisfactory patency of the dilated segment. New significant coronary stenosis was seen in only 17% of patients not having coronary bypass surgery.

Percutaneous embolotherapy in life-threatening hemoptysis.

Percutaneous embolization of the bronchial arteries to control massive or recurrent hemoptysis has become an accepted procedure, especially in treating patients with chronic pulmonary disease who are poor candidates for lung resection. Nonbronchial systemic collateral arteries and pulmonary arteries may contribute significantly to pulmonary hemorrhage, but embolization of these vessels has not been stressed in recent literature. When embolization of the bronchial artery fails to control hemoptysis, nonbronchial systemic collateral arteries should be embolized. If no systemic collaterals are present, then embolization of segmental pulmonary arteries may prove helpful.

The rapid evolution of a large mycotic aneurysm of the abdominal aorta.

Computed tomography (CT) and ultrasonography (US) have been shown to be effective, noninvasive methods for the detection of established mycotic aortic aneurysms. We report a patient in whom CT and US were performed immediately before and after the development of a large mycotic abdominal aortic aneurysm, providing a unique opportunity to observe its rapid evolution.