TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study.

Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue [p = 0.003] and/or arthritis [p = 0.002] were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex [p = 0.027], more lesions on MRI [p = 0.01] and higher CRP levels [p = 0.03]. Randomized clinical trials are needed to confirm observations and generate evidence.

Antipredator response diminishes during periods of resource deficit for a large herbivore.

The starvation-predation hypothesis predicts that, during resource shortages, prey forego antipredator behavior and forage as much as possible to avoid starvation, even when risk of predation is high. We tested this hypothesis using GPS locations collected simultaneously from moose (Alces alces) and wolves (Canis lupus) in the Greater Yellowstone Ecosystem of North America. We assessed shifts in the speed, displacement, and habitat selection of moose 24 h following encounter with wolves (0-1,500 m distance). We examined whether the strength of antipredator behaviors would weaken as winter progressed and the nutritional condition of moose declined. Moose responded to wolf encounters by increasing their rate of movement in early winter, but only within 500 m distance. Importantly, these responses attenuated as winter progressed. Moose did not avoid their preferred foraging habitat (riparian areas) following encounters with wolves at any distance, and instead they more strongly selected riparian areas, especially in early winter. Our findings support theoretical predictions that resource deficits should dampen prey antipredator behavior, and suggest that nutritional condition of prey may buffer against run-away risk effects in food webs involving large mammalian predators and prey.

Proyecto Piloto "Familias Hablando Unidas" en Asunción, Paraguay. Una intervención para prevenir el embarazo precoz, enfocado en padres de adolescentes / "Families Speaking Together"-a Pilot Study in Asuncion, Paraguay. An intervention to prevent teenage pregnancy, focusing on parents of teens

Introducción: En Paraguay el 16% de las adolescentes de nivel socioeconómico bajo se embarazan antes de cumplir 20 años de edad. Estos embarazos pueden obstaculizar su desarrollo y su progreso educativo y social. Debido a la naturaleza conservadora de la política paraguaya, la educación sexual integral no se enseña en las escuelas, por lo que se deberían usar estrategias alternativas para reducir los embarazos en la adolescencia. Objetivo: Este estudio evalúa la aceptabilidad y factibilidad de implementar una intervención centrada en los padres, denominada "Familias Hablando Unidas", en Asunción y ofrece recomendaciones para su adaptación. La intervención se modificó para el Paraguay y posteriormente fue implementada en el Bañado Sur, de Asunción. Material y Métodos: Los grupos de discusión se llevaron a cabo con los padres que participaron en la intervención, mientras que las entrevistas individuales se llevaron a cabo con informantes claves y adolescentes cuyos padres participaron en la intervención. Se analizaron los datos para entender las reacciones a la intervención y las posibilidades de adaptación. Resultados: La intervención fue bien recibida en general por todos los interesados, sin embargo, los padres todavía referían dificultad para conversar sobre temas de salud sexual y reproductiva con sus hijos después de la misma. Todos los participantes disfrutaron de las discusiones en la intervención y de los materiales incluidos sobre el amor y las relaciones sanas, temas que los participantes dijeron que no habían sido discutidas con frecuencia. El programa Familias Hablando Unidas podría adaptarse muy bien en el Bañado Sur para fomentar la comunicación entre padres e hijos en cuanto a la salud sexual y reproductiva. La dificultad referida por los padres para enfrentar estos temas, incluso después de la intervención, sugiere que, previamente se debería enfocar en el fortalecimiento de la familia, las habilidades para comunicarse de una manera saludable y en el desarrollo de habilidades para los adolescentes, para que posteriormente, los padres puedan sacar el máximo beneficio del programa Familias Hablando Unidas. Palabras Claves: Embarazo adolescente, intervenciones basadas en la evidencia, comunicación padre-hijo, salud sexual y reproductiva

Introduction: In Paraguay 16% of adolescents of low socioeconomic status become pregnant before they reach 20 years of age. These pregnancies can hinder their educational and social development and progress. Due to the conservative nature of Paraguayan politics, comprehensively sex education is not taught in schools, so alternative strategies to reduce adolescent pregnancies need to be taken. Objetives: This study assesses the acceptability and feasibility of implementing a parent-focused intervention, Families Talking Together, in Asunción and provides recommendations for adaptation. The intervention was modifed for Paraguay and subsequently implemented in the Bañado Sur, Asunción. Methodology: Focus groups were conducted with parents who participated in the intervention while individual interviews were conducted with key informants and adolescents whose parents participated. The data were analyzed to understand reactions to the intervention and possibilities for adaptation. Results: The intervention was generally well received by all parties, however parents still reported struggling to discuss sexual and reproductive health topics with their children after the intervention. All participants enjoyed the discussions in the intervention and accompanying materials regarding love and healthy relationships; these were topics that participants said were not often discussed. Families Talking Together could be further adapted for the Bañado Sur to encourage parent-child communication regarding sexual and reproductive health. Parents' diffculty in addressing these issues even after the intervention suggests that prior programming needs to focus on family strengthening, healthy communication skills and skill-building for adolescents before parents would beneft from the Families Talking Together intervention. Key Words: Adolescent pregnancy, evidence-based interventions, father-son communication, sexual and reproductive health

Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1 ) receptor in assays for antidepressant and anxiolytic drugs.

The phenotype of NK1R-/- mice was compared with that of acute pharmacological blockade of the tachykinin NK1 receptor on sensorimotor function and in assays relevant to depressive illness and anxiety. The dose range for L-760735 and GR205171 that was associated with functional blockade of central NK1 receptors in the target species was established by antagonism of the behavioural effects of intracerebroventricular NK1 agonist challenge in gerbils, mice and rats. The caudal grooming and scratching response to GR73632 was absent in NK1R-/- mice, confirming that the receptor had been genetically ablated. There was no evidence of sedation or motor impairment in NK1R-/- mice or following administration of L-760735 to gerbils, even at doses in excess of those required for central NK1 receptor occupancy. In the resident-intruder and forced swim test, the behaviour of NK1R-/- mice, or animals treated acutely with L-760735 or GR205171, resembled that seen with the clinically used antidepressant drug fluoxetine. However, the effects of GR205171 were not clearly enantioselective in mice. In contrast, although NK1R-/- mice also exhibited an increase in the duration of struggle behaviour in the tail suspension test, this was not observed following pharmacological blockade with L-760735 in gerbils or GR205171 in mice, suggesting that this may reflect a developmental alteration in the knockout mouse. There was no effect of NK1 receptor blockade with L-760735 in guinea-pigs or GR205171 in rats, or deletion of the NK1 receptor in mice, on behaviour in the elevated plus-maze test for anxiolytic activity. These findings extend previous observations on the phenotype of the NK1R-/- mouse and establish a broadly similar profile following acute pharmacological blockade of the receptor. These studies also serve to underscore the limitations of currently available antagonists that are suitable for use in rat and mouse behavioural assays.

Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection.

Replacement of the large hydantoin-indole moiety from our previous work with a variety of smaller heterocyclic analogues gave rise to potent CCR5 antagonists having binding affinity comparable to the hydantoin analogues. The synthesis, SAR, and biological profiles of this class of antagonists are described.

Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection.

A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2: lead optimization affording selective, orally bioavailable compounds with potent anti-HIV activity.

Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 3: a proposed pharmacophore model for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-[4-(substituted)piperidin-1-yl]butanes.

Structure-activity relationship studies directed toward the optimization of (2S)-2-(3-chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[4-(substituted)piperidin-1-yl]butanes as CCR5 antagonists resulted in the synthesis of the spiro-indanone derivative 8c (IC50=5 nM). These and previous results are summarized in a proposed pharmacophore model for this class of CCR5 antagonist.

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes.

(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. part 1: discovery and initial structure-activity relationships for 1 -amino-2-phenyl-4-(piperidin-1-yl)butanes.

Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure-activity relationships for substituted 2-Aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes.

(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).

The evolution of loss of heterozygosity on chromosome 17 during the progression to barrett's adenocarcinoma involves a unique combination of target sites in individual specimens.

We have previously identified thirteen common minimally deleted regions (MRs) on chromosome 17 in twelve Barrett's esophageal adenocarcinoma (BOA) specimens using 41 precisely mapped microsatellite markers (Dunn et al., Oncogene, 17: 987-993, 1999). The aim of the present study has been to identify the earliest sites of loss on this chromosome that arise and persist during the progression to BOA. This has been undertaken by the analysis of multiple carefully microdissected tissue samples from each of five esophagectomy specimens, several of which contained identifiable premalignant tissue. Our data demonstrate a stepwise accumulation of loss in each analyzed specimen, consistent with a single clonal pathway in four specimens and several coexisting pathways in one specimen. Several clonal anomalies (loss preceding heterozygosity and variable intrasample degrees of loss at different markers) were also observed. Within extensively deleted regions of the tumor (seen in three specimens), small deletions were detected in premalignant tissue, predominantly at the site of our identified MRs, and these losses were seen to expand and merge during the progression to BOA. Clonal losses at MRs were first detected in tissue showing early changes histologically, including Barrett's intestinal metaplasia and intermediate-grade dysplasia. Our results provide further support for many of the MRs we have previously identified, thereby adding to evidence for the existence of multiple novel cancer-associated genes on chromosome 17 involved in the development of BOA.

Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice.

The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.

Enteroscopy.

It is now more than 25 years since small bowel enteroscopy (SBE) was first described. For several reasons, this technique developed more slowly than other more usual forms of endoscopy. First, small bowel disease is relatively rare in comparison with other gastrointestinal diseases. Also, there was lack of initial design agreement, and three different types of enteroscopes were developed within a short time of each other, two of which (push-type and sonde) are now available commercially. Finally, commercial interests of the manufacturers of endoscopes were mainly focused on the more conventional, large volume markets. In the last few years, specifically designed modern small bowel enteroscopes have become available and, in centers that have access to them, they have superseded attempts at SBE using adult or pediatric colonoscopes. There are now clear indications for SBE, such as: the investigation of obscure causes of bleeding and anemia; malabsorption; clarification of x-ray abnormalities; and, increasingly, the application of therapeutic endoscopy to lesions within the small bowel. Problem areas remain, but with advancing technology and more professional interest in this area, these will be addressed during the next few years.

The second national hospital costing study: background, results and implications.

The costing of hospital outputs, and especially of acute admitted patients categorised by DRG, has been the focus of considerable attention in the last decade. Many individual hospitals now routinely estimate the costs of their main products, several State and Territory health authorities undertake periodic multi-site studies, and there have been a few one-off national studies. This paper summarises the methods and results of the most recent national study, which measured costs at a sample of public and private hospitals around Australia for the 1996-97 financial year. We briefly describe the main results and note some implications.