Pharmacokinetics of tildipirosin in porcine plasma, lung tissue, and bronchial fluid and effects of test conditions on in vitro activity against reference strains and field isolates of Actinobacillus pleuropneumoniae.

The pharmacokinetics of tildipirosin (Zuprevo(®) 40 mg/mL solution for injection for pigs), a novel 16-membered-ring macrolide for the treatment for swine respiratory disease (SRD), was investigated in studies collecting blood plasma and postmortem samples of lung tissue and bronchial fluid (BF) from swine. In view of factors influencing the in vitro activity of macrolides, and for the interpretation of tildipirosin pharmacokinetics in relation to minimum inhibitory concentrations (MIC), additional experiments were conducted to study the effects of pH, carbon dioxide-enriched atmosphere, buffers, and serum on tildipirosin MICs for various reference strains and Actinobacillus (A.) pleuropneumoniae field isolates. After single intramuscular (i.m.) injection at 4 mg/kg body weight, maximum plasma concentration (Cmax) was 0.9 µg/mL observed within 23 min (Tmax ). Mean residence time from the time of dosing to the time of last measurable concentration (MRTlast) and terminal half-life (T1/2) both were about 4 days. A dose-response relationship with no significant sex effect is observed for area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUClast) over the range of doses up to 6 mg/kg. However, linear dose proportionality could not be proven with statistical methods. The time-concentration profile of tildipirosin in BF and lung far exceeded that in blood plasma. In lung, tildipirosin concentrations reached 3.1 µg/g at 2 h, peaked at 4.3 µg/g at day 1, and slowly declined to 0.8 µg/g at day 17. In BF, tildipirosin levels were 14.3, 7.0, and 6.5 µg/g at days 5, 10, and 14. T1/2 in lung was ∼7 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination. Culture media pH and carbon dioxide-enriched atmosphere (CO2 -EA) had a marked impact on in vitro activity of tildipirosin in reference strains of various rapidly growing aerobic and fastidious bacteria including Histophilus (H.) somni ATCC 700025 and A. pleuropneumoniae ATCC 27090. For A. pleuropneumoniae ATCC 27090 testing conditions without CO2 -EA resulted in reduced acidification of culture media pH and a reduction in the minimum inhibitory concentrations compared to standard in vitro test conditions by 2 log2 dilution steps (4-fold) from 8 to 2 µg/mL. Supplementary buffering of standard culture media resulted in a reduction in the A. pleuropneumoniae (n = 8) MIC range by 4 log2 dilution steps (16-fold) from 8-16 to 0.5-1 µg/mL. Incremental supplementation of culture media with 50% serum resulted in noticeable shifts to lower minimum or maximum MICs by at least 2 log2 dilution steps (≥4-fold) in all aerobic and fastidious reference strains tested except for Pasteurella (P.) multocida. The MIC of A. pleuropneumoniae ATCC 27090 decreased by 2-4 log2 dilution steps (4 to 16-fold) from 8 to 0.5-2 µg/mL when 50% serum was added to the standard assay. Considering a higher presence of serum and the rather neutral pH conditions maintained in vivo, it is suggested to take the influence of these factors on in vitro activity into account when interpreting tildipirosin MICs for A. pleuropneumoniae in relation to pharmacokinetics.

An assessment of satisfaction with ambulatory child psychiatry consultation services to primary care providers by parents of children with emotional and behavioral needs: the massachusetts child psychiatry access project university of massachusetts parent satisfaction study.

This study evaluated parents' experience with University of Massachusetts (UMass) Child Psychiatry Access Project (MCPAP), a consultation service to primary care providers (PCP), aimed at improving access to child psychiatry. Parent satisfaction questionnaire was sent to families referred to UMass MCPAP by their PCP, asking about their concerns leading to the referral, the satisfaction from the service provided, adequacy of the follow up plan, and outcome. Seventy-nine percent of parents agreed or strongly agreed that the services provided were offered in a timely manner. Fifty percent agreed or strongly agreed that their child's situation improved following their contact with the services. Sixty-nine percent agreed or strongly agreed that the service met their family's need. The results suggest moderate to high parental satisfaction with MCPAP model, but highlight ongoing challenges in making successful referrals for children's mental health services in the community, following MCPAP recommendations.

Pharmacokinetics of tildipirosin in bovine plasma, lung tissue, and bronchial fluid (from live, nonanesthetized cattle).

The pharmacokinetics of tildipirosin (Zuprevo(®) 180 mg/mL solution for injection for cattle), a novel 16-membered macrolide for treatment, control, and prevention of bovine respiratory disease, were investigated in studies collecting blood plasma, lung tissue, and in vivo samples of bronchial fluid (BF) from cattle. After single subcutaneous (s.c.) injection at 4 mg/kg body weight, maximum plasma concentration (C(max)) was 0.7 µg/mL. T(max) was 23 min. Mean residence time from the time of dosing to the time of last measurable concentration (MRT(last)) and terminal half-life (T(1/2) ) was 6 and 9 days, respectively. A strong dose-response relationship with no significant sex effect was shown for both C(max) and area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUC(last) ) over the range of doses up to 6 mg/kg. Absolute bioavailability was 78.9%. The volume of distribution based on the terminal phase (V(z)) was 49.4 L/kg, and the plasma clearance was 144 mL/h/kg. The time-concentration profile of tildipirosin in BF and lung far exceeded those in blood plasma. In lung, tildipirosin concentrations reached 9.2 µg/g at 4 h, peaked at 14.8 µg/g at day 1, and slowly declined to 2.0 µg/g at day 28. In BF, the concentration of tildipirosin reached 1.5 and 3.0 µg/g at 4 and 10 h, maintained a plateau of about 3.5 µg/g between day 1 and 3, and slowly declined to 1.0 at day 21. T(1/2) in lung and BF was approximately 10 and 11 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination.

The wraparound approach in systems of care.

Child and adolescent psychiatrists and general psychiatrists who serve children and adolescents with complex mental health needs, generally find themselves interfacing with multiple child-serving systems, including mental health, child welfare, juvenile justice, developmental disabilities, addictions services, and primary health care. In these systems of care, psychiatrists will likely encounter the term "wraparound," which describes a key intervention ushered in with the system-of-care model of service delivery. This article describes the wraparound approach, which has been at the forefront of mental health service delivery for children and youth with serious emotional disturbance since the mid-1980s. Wraparound is an empirically supported, family-driven, strengths-based planning approach that provides individualized care using an array of formal services and natural supports.

Promoting child social-emotional growth in primary care settings: using a developmental approach.

Clinicians are often faced with meaningful child/family mental health concerns, and yet suggesting a helpful course of action can be very challenging. While pediatricians routinely use a developmental framework to evaluate young children's cognitive, motor, and language skills, this occurs much less frequently for social-emotional development. Only recently have newer models of child development been put forth that emphasize the central role that emotions play in organizing the interactions among cognitive, motor, and language development across the lifespan. We review such a model of social-emotional growth and consider its implications for use in primary care settings.

Soluble polymer-supported chemoenzymatic synthesis of the C(21)-C(27) fragment of the bryostatins.

A chemoenzymatic synthesis of the C(21)-C(27) fragment of the marine macrolide family of bryostatin antibiotics is presented. The approach commences from achiral starting materials and has as its crucial step the enzymatic resolution of a racemic mixture of soluble polymer-supported alcohols (syn-10 and syn-11). The immobilized lipase from Candida antarctica (Novozym 435) catalyzes the enantioselective acetylation of syn-10 (in 40% conversion and >99% ee), allowing isolation of the key intermediate (R)-14 in enantiomerically pure form following its cleavage from the poly(ethylene) glycol (PEG) scaffold. The PEG matrix is both compatible with the multipolymer enzymatic transformation and allows for rapid purification and facile NMR characterization of all intermediates throughout the synthesis.

Parent-child relationship disorders: what do the Child Vulnerability Scale and the Parent Protection Scale measure?

While scales exist to aid clinicians in the assessment of parent-child relationship disorders, there are minimal data regarding their clinical usefulness. This study examined the ability of parent responses to questions regarding the child's health, behavior, and development to predict total scores on the Child Vulnerability Scale and the Parent Protection Scale. Of 120 potential participants, 103 parents (92% mothers, 69% white, 54% married, 44% lower socioeconomic status) with children aged 2-5 years completed the Child Health and Family Functioning Questionnaire. Logistic regression yielded a correct prediction rate of 77% for perceived child vulnerability and 76% for parental overprotection. Our data provide support for the independence of parental perceptions of increased child vulnerability and parental overprotection as well as for the content validity of the Child Vulnerability Scale and the Parent Protection Scale.

Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones.

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.

A simple method for coupling aldehydes to solid support.

A new method for attaching aldehydes to solid supports has been developed employing a 2,2-bis(hydroxymethyl)propionic acid (DMPA) functionalized resin. High loading levels are obtained for both aryl and alkyl aldehydes protected as their respective acetals. Treatment of the derivatized resin with 95% TFA then cleanly affords the recovered aldehyde in high yield.

Parental overprotection and its relation to perceived child vulnerability.

A study of 280 parents with a child age 5-10 years examined the relation between and correlates of parental overprotection (less education, younger child age, being an only child) and parental perception of increased child vulnerability (history of life-threatening illness, child medical condition, first child). One-third of parents who considered their child vulnerable were also considered overprotective.

The 2-year stability of parental perceptions of child vulnerability and parental overprotection.

Clinicians often identify parent-child relationships that are believed to be problematic for the child's future emotional growth, yet there are minimal outcome data on which to base anticipatory guidance. This 2-year follow-up study examined the stability and child behavioral correlates of parental perceptions of increased child vulnerability and parental overprotection. Of 192 potential participants, 114 parents (93% mothers, 86% white, 75% married, 90% middle-upper socioeconomic status) with children age 4 to 7 years successfully completed the Parent Protection Scale, Child Vulnerability Scale, Child Behavior Checklist 4-18, and the Parental Bonding Instrument. The 2-year stability of high parental overprotection was 37%; for high parental perception of child vulnerability, it was 31%. High perceived vulnerability at enrollment was significantly associated with both internalizing (somatic complaints, anxious/depressed) and externalizing (aggressive) behaviors at follow-up. A history of overprotection in the parent's childhood was not associated with current parental report of overprotective behaviors toward the child.

Differences in health care utilization between parents who perceive their child as vulnerable versus overprotective parents.

While a parental perception of child vulnerability to illness/injury is often used interchangeably with parental overprotection, research suggests that they are independent constructs. We hypothesized more frequent pediatric nonwell-child visits for perceived child vulnerability, but not for parental overprotection. The parents of 300 children, ages 2-5 years, enrolled in a health maintenance organization, were sampled. For children without medical conditions, there were no differences in nonwell-child care visits between the high perceived vulnerability and high parental protection groups (Wilcoxon Rank Sum Test, WRST, P = .31). As expected, high parental protection was not significantly associated with increased nonwell-child care visits compared with the low parental protection group (WRST, P = .14). These findings suggest that markers other than health care utilization are required to identify these forms of parent-child relationship disorders.

Parent-child relationship disorders. Part II. The vulnerable child syndrome and its relation to parental overprotection.

Parents who are excessively concerned about their child's health are often characterized as being overprotective. We hypothesized that parental overprotection is independent of parental perception of child vulnerability to illness or injury despite their presumed interchangeability. A community-based sample of 892 parents (92% white, 84% married, 88% middle-upper socioeconomic status, 90% mothers) completed a three-part protocol (clinical background data, the Child Vulnerability Scale, and the Parent Protection Scale). Correlates of high parental perception of child vulnerability included a medical condition in the child, a history of life-threatening illness or injury, and the child being seen for a sick visit. Correlates of high parental overprotection included younger age of child and parent. Only 20% of those parents who considered their child vulnerable were also considered overprotective.

Parent-child relationship disorders. Part I. Parental overprotection and the development of the Parent Protection Scale.

There is a spectrum of parental protective behaviors promoting child safety and security, ranging from neglect to overprotection. This paper describes the development and psychometric properties of a new measure of parental protective behaviors toward children age 2 to 10 years, the Parent Protection Scale (PPS). Items were selected to represent key dimensions of protective behaviors. Factor analyses suggested four subscales: Supervision, Separation Problems, Dependence, and Control. The PPS has acceptable internal consistency, test-retest reliability, and clinical validity. Norms by child age in the form of cutoff points corresponding to +1 SD were determined. Clinical and research uses for the PPS are noted.

Curved Crystal Transmission Optics for Energy-Dispersive X-ray Absorption Spectroscopy.

The development of a curved crystal monochromator of the Laue type for energy-dispersive X-ray absorption spectroscopy is presented. The quality of the X-ray absorption spectra at high photon energies is compared with spectra measured with silicon crystals in the more frequently used Bragg geometry. In the Bragg case, an asymmetric broadening of the reflectivity profile leads to strong distortions of the near-edge fine structure and to a reduction in spectral resolution. The reflectivity profiles of fiat and curved crystals for Laue and Bragg geometry have been calculated using dynamical theory and are compared with experimental data. The new optics have been used for in situ time-resolved X-ray absorption spectroscopy. An example of the application of the technique for the characterization of a Pd catalyst is given. The X-ray absorption fine structure at the Pd K-edge has been measured during the activation and during the heterogeneous catalytic oxidation of carbon monoxide.

The vulnerable child syndrome revisited.

Dimensions of the vulnerable child syndrome are clarified in a critical review of the research and clinical literature. The central construct of the vulnerable child syndrome, an increased parental perception of child vulnerability to illness or injury, is examined in the context of separation and loss. Measures of perceived child vulnerability are reviewed. A new conceptual model of parental perception of child vulnerability is presented that takes into account child, parent, parent-child, parent-clinician, and family factors. Directions for future research are suggested.

Inhibition of human neutrophil elastase. 3. An orally active enol acetate prodrug.

Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[3,3,4,4,4-penta fluoro-1- (1-methylethyl)-2-oxobutyl]-L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE). Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P1. In vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo. The ED50 value for (E)-N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2- (acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-buteny l]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.

Pediatric resident support group. A 7-year longitudinal experience.

OBJECTIVE: To describe the structure and format of a long-term pediatric resident support group and describe its evolution over time. DESIGN: Survey with a semistructured questionnaire of all available current and past group members (N = 59). SETTING: University-based pediatric residency training program. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: The pediatric resident support group has met weekly and continuously during the past 7 years. Most residents (80%) attend regularly and completed the survey. Based on their responses, the coleaders' clinical experience, and review of the literature, guidelines are proposed for the structure and process of the group, including the group composition, format, and the leaders' role which account for its ongoing success. Specific issues in initiating the group and negotiating the July transition are discussed. CONCLUSIONS: Residents have consistently valued this pediatric resident support group as an integral part of their training program where feelings and information can be shared in a nonjudgemental setting. Optimally, it can involve residents at all levels of training, with leaders defining and maintaining the boundaries and format.

Parental overprotection revisited.

Dimensions of parental overprotection are clarified in a critical review of the research and clinical literature. An indulgent style of parenting is distinguished from an overprotective parent-child relationship. Differential antecedents and outcomes are proposed for each of these forms of parent-child interaction. Measures of protection are reviewed. A new conceptual model of parental overprotection is presented which takes into account child, parent, family, socio-cultural, environmental and resiliency factors. Directions for future research are suggested.