Pharmacokinetics and preliminary safety evaluation of azithromycin in adult horses.

Azithromycin is widely used in foals but has not been studied in adult horses. The goals of this study were to determine the pharmacokinetic profile and to make a preliminary assessment of the safety of azithromycin in adult horses. Azithromycin was administered intravenously (5 mg/kg) and intragastrically (10 mg/kg) to six healthy mares in a crossover design. Serial plasma samples, blood neutrophils, and pulmonary macrophages were collected for the measurement of azithromycin concentrations. Azithromycin was also administered orally (10 mg/kg) once a day for 5 days to five healthy mares for preliminary evaluation of safety in adult horses. The bioavailability of azithromycin following intragastric administration was 45 ± 12%. Concentrations within peripheral neutrophils and bronchoalveolar macrophages were several fold higher than that of plasma. Mild decreases in appetite (n = 3) and alterations in fecal consistency (n = 3) were noted following repeated oral administration. The pharmacokinetic profiles of azithromycin in adult horses, especially the slow elimination rate and intraneutrophil and intrapulmonary macrophage accumulation, demonstrate that it is conducive to use in this age group. Because of the gastrointestinal alterations noted, further studies are warranted before azithromycin can be recommended for use in adult horses.

Poor decision making among older adults is related to elevated levels of neuroticism.

BACKGROUND: A well-studied index of reasoning and decision making is the Iowa Gambling Task (IGT). The IGT possesses many features important to medical decision making, such as weighing risks and benefits, dealing with unknown outcomes, and making decisions under uncertainty. PURPOSE: There exists a great deal of individual variability on the IGT, particularly among older adults, and the present study examines the role of personality in IGT performance. We explored which of the five-factor model of personality traits were predictive of decision-making performance, after controlling for relevant demographic variables. METHODS: One hundred and fifty-two healthy cognitively intact adults (aged 26-85) were individually administered the IGT and the NEO Five-Factory Inventory. RESULTS: In the older adults, but not the younger, higher NEO neuroticism was associated with poorer IGT performance. CONCLUSIONS: Our findings are discussed in the context of how stress may impact cognitive performance and cause dysfunction of neural systems in the brain important for decision making.

Length of incubation and hatchling body weight in quail selected for reduced or exaggerated adrenocortical responsiveness to brief restraint.

1. While changes in corticosterone (B) during late embryogenesis are thought to play a role in the hatching process, only a scant and controversial literature exists concerning the effects of in ovo B on the length of incubation and chick body weight at hatching. Because female Japanese quail selected for exaggerated (high stress, HS) rather than reduced (low stress, LS) plasma B response to brief mechanical restraint deposit more B into their eggs, these stress lines provide an excellent model to study the relationship between embryonic B and incubation length and hatchling body weight. 2. Differences in the duration of incubation and chick body weight at emergence were assessed using eggs laid by LS and HS quail. 3. On average, eggs from HS hens hatched 3.7 h sooner than did eggs from LS hens while mean body weight at emergence was similar in hatchlings of both lines. Thus, selection for exaggerated adrenocortical responsiveness is associated with a reduction in the length of egg incubation without altering hatchling body weight. 4. This finding is important to the poultry industry because it warns layer, breeder farm and hatchery managers that unless stress in hens during egg formation is avoided, an abbreviated incubation period may result.

Comparison of function of created wetlands of two age classes in central Pennsylvania.

Hydrogeomorphic (HGM) functional assessment models were used to assess whether function in created wetlands of two ages (1 year old and >12 years old) was equivalent to that of natural (reference) mainstem floodplain wetlands. Reference wetlands scored higher than both created age classes for providing energy dissipation and short-term surface water storage. Reference wetlands scored higher in maintaining native plant community and structure than 1-year-old sites, and 12-year-old wetlands scored higher than reference sites for providing vertebrate habitat structure. Analysis of individual model variables showed that reference wetlands had greater vegetative biomass and higher soil organic matter content than both created wetland age classes. Created wetlands were farther from natural wetlands and had smaller mean forest patch sizes within a 1-km-radius circle around the site than did the reference sites, indicating less hydrologic connectivity. Created wetlands also had less microtopographic variation than reference wetlands. The 1-year-old created sites were placed in landscape settings with greater land use diversity and road density than reference sites. The 12-year-old sites had a higher gradient and a higher percentage of their surrounding area in urban land use. These results show that the created wetlands were significantly structurally different (if not functionally so) from reference wetlands even after 12 years. The most profound differences were in hydrology and the characteristics of the surrounding landscape. More attention needs to be focused on placing created wetlands in appropriate settings to encourage proper hydrodynamics, eliminate habitat fragmentation, and minimize the effects of stressors to the site.

Losing function through wetland mitigation in central Pennsylvania, USA.

In the United States, the Clean Water Act requires mitigation for wetlands that are negatively impacted by dredging and filling activities. During the mitigation process, there generally is little effort to assess function for mitigation sites and function is usually inferred based on vegetative cover and acreage. In our study, hydrogeomorphic (HGM) functional assessment models were used to compare predicted and potential levels of functional capacity in created and natural reference wetlands. HGM models assess potential function by measurement of a suite of structural variables and these modeled functions can then be compared to those in natural, reference wetlands. The created wetlands were built in a floodplain setting of a valley in central Pennsylvania to replace natural ridge-side slope wetlands. Functional assessment models indicated that the created sites differed significantly from natural wetlands that represented the impacted sites for seven of the ten functions assessed. This was expected because the created wetlands were located in a different geomorphic setting than the impacted sites, which would affect the type and degree of functions that occur. However, functional differences were still observed when the created sites were compared with a second set of reference wetlands that were located in a similar geomorphic setting (floodplain). Most of the differences observed in both comparisons were related to unnatural hydrologic regimes and to the characteristics of the surrounding landscape. As a result, the created wetlands are not fulfilling the criteria for successful wetland mitigation.

Maternal corticosterone further reduces the reproductive function of male offspring hatched from eggs laid by quail hens selected for exaggerated adrenocortical stress responsiveness.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis can depress the hypothalamic-pituitary-testicular axis. Male quail cloacal gland (CG) size and foam production shows androgen dependency, and males selected for exaggerated [high stress (HS)] rather than reduced [low stress (LS)] plasma corticosterone (B) stress response exhibit reduced CG and testes development. High stress hens also deposit more B into egg yolks than LS ones, and quail hens given B produce chicks that have a reduced growth rate and adults with heightened HPA responsiveness. Herein, we gave LS and HS hens no B [empty implants, control (CON)] or B-filled implants and assessed the reproductive performances of these hens and their male offspring. Mortality was similarly elevated in LS and HS B-treated hens, but only HS B-implanted hens showed reduced egg production. In male offspring, CG volume (CVOL), intensity of CG foam production (CFP), and the proportion of individuals that produced CG foam were measured from 4 to 11 wk of age. At 6 wk, BW, and at 15 wk, BW, testes weight (TWT), and TWT relative to BW were also determined. Hen treatments did not affect male chick CVOL at 4 wk, but CVOL differed thereafter as follows: LS CON > LS B = HS CON = HS B at 5 and 6 wk and LS CON > LS B > HS CON = HS B from 7 to 11 wk. By 8 wk, and thereafter, CFP differed as follows: LS CON > LS B > HS CON > HS B. Group differences in the proportion of individuals that produced CG foam generally supported CFP findings from 4 to 8 wk of age. Body weight did not differ by treatment at 6 wk of age. By 15 wk, TWT were similarly depressed in both HS groups. However, similarly higher 15-wk BW in the LS-CON and HS-B groups contributed to TWT relative to BW differences as follows: LS-B > LS-CON > HS-B; LS-CON = HS-CON; LS-B > HS-CON; and, HS-CON = HS-B. Both selection for exaggerated HPA responsiveness and maternal B treatment negatively affected the reproductive function of HS male offspring.

Cloacal gland and gonadal photoresponsiveness in male Japanese quail selected for divergent plasma corticosterone response to brief restraint.

Corticosterone is linked to testicular depression, and in Coturnix, a relatively photorefractory species, day length and androgen dependency in cloacal gland development and foam production are evident. Furthermore, male quail selected for reduced (low stress, LS) rather than exaggerated (high stress, HS) plasma corticosterone stress response show more photo-induced reproductive development, greater resistance to reproductive declines induced by exposure to very short days, and a quicker recovery to a higher reproductive level upon return to long days. To determine whether a milder reduction in day length would also influence stress line reproductive photoresponsiveness, and perhaps photorefractoriness, males grown on 16 h of light were given 13 h of light for 4 wk followed by a return to long days for 12 wk. Cloacal gland measurements were made following the initial stimulatory photoperiod and weekly thereafter during the 2 light treatments. Plasma testosterone was determined initially, after 4 wk of light reduction, and at the end of the study, along with BW, testes weight (TWT), and TWT relative to BW. Cloacal gland volume (CVOL) was greater in LS than HS males grown on long days. Whereas exposure to 13 h of light reduced CVOL in both lines, line differences (LS > HS) persisted during the first 3 wk of light reduction. Moreover, by 2 wk of rephotostimulation, and weekly thereafter, line differences (LS > HS) in CVOL reemerged. Cloacal gland foam production and the proportion of individuals that produced cloacal gland foam responses reflected changes in CVOL. The BW did not differ by line, yet LS males had a higher TWT and TWT relative to BW than HS ones. All individuals, however, exhibited relative photorefractory responses. Whereas none of the LS males completely resisted reproductive regression induced by a 3 h light reduction, LS males showed other reproductive benefits upon mild photocastration and subsequent rephotostimulation (e.g., greater resistance to CVOL and cloacal gland foam production losses during a mild light crash and quicker restoration to full reproductive potential upon relighting).

Founder's Award, Society for Biomaterials. Sixth World Biomaterials Congress 2000, Kamuela, HI,May 15-20, 2000. Really smart bioconjugates of smart polymers and receptor proteins.

Over the past 18 years we have been deeply involved with the synthesis and applications of stimuli-responsive polymer systems, especially polymer-biomolecule conjugates. This article summarizes our work with one of these conjugate systems, specifically polymer-protein conjugates. We include conjugates prepared by random polymer conjugation to lysine amino groups, and also those prepared by site-specific conjugation of the polymer to specific amino acid sites that are genetically engineered into the known amino acid sequence of the protein. We describe the preparation and properties of thermally sensitive random conjugates to enzymes and several affinity recognition proteins. We have also prepared site-specific conjugates to streptavidin with temperature-sensitive polymers, pH-sensitive polymers, and light-sensitive polymers. The preparation of these conjugates and their many fascinating applications are reviewed in this article.

Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma.

Metabolism of the antidepressant drug nefazodone was studied in humans after single and multiple 50 and 200 mg oral doses of [14C] nefazodone as part of a single and multiple dose balance study. Deuterium was included in the molecule to facilitate structural characterization of the metabolites by mass spectrometry. Metabolites were isolated from a 0-24 hr pooled urine from three subjects and purified to homogeneity by HPLC. Chemical structures of the metabolites were proposed based on collisionally induced dissociation (CID) and electron impact ionization MS. The profile of radioactivity showed three main urinary metabolites, one of which was a conjugate, and several minor metabolites. The three major metabolites were identified as the phenoxyethyl triazolone propionic acid resulting from N-dealkylation of both nefazodone and hydroxynefazodone (OH-Nef), as well as a corresponding phenoxyethyl triazolone propanol metabolite of N-dealkylated nefazodone, present exclusively as a conjugate. The more polar minor components were not identified. The excretion of total radioactivity in the 24-hr sample was 49% of the dose, of which the identified metabolites comprised 38% of the dose. There was no difference in the qualitative or quantitative urinary profile of the metabolites at 50 or 200 mg dose levels after single or multiple oral dosing. These N-dealkylated metabolites were also present in pooled human plasma samples along with nefazodone, OH-Nef, and an unknown metabolite that was present in plasma in large amounts relative to nefazodone and OH-Nef. This metabolite was isolated from plasma and from a human liver S9 incubation and identified by CID tandem MS and NMR as the triazoledione of nefazodone.(ABSTRACT TRUNCATED AT 250 WORDS)

Activated, N-substituted acrylamide polymers for antibody coupling: application to a novel membrane-based immunoassay.

A room-temperature-precipitable, activated terpolymer consisting of N-isopropylacrylamide (NIPAAm)/N-n-butylacrylamide(nBAAm)/N-acryloxysuccinimide (NASI) (LCST = 7-13 degrees C) at a monomer feed ratio of 60:40:2.5, respectively, was prepared and conjugated to an antibody. The conjugate was evaluated in a novel cellulose acetate (CA) membrane-based immunoassay which utilizes the especially strong physical attachment of the polymer to CA to bind and concentrate the polymer attached protein onto the membrane. When compared in the CA membrane immunoassay to the antibody-poly(NIPAAm) conjugate prepared via anhydrous copolymerization of NIPAAm and NASI at the monomer feed ratio of 40:1, respectively, the performance of the NIPAAm/nBAAm/NASI terpolymer was superior to that of the NIPAAm/NASI copolymer (LCST = 32 degrees C) when the studies were carried out at room temperature. However, the terpolymer and copolymer gave equivalent performance when the assay mixture was heated to 45 degrees C. These results indicate the importance of the LCST of the polymer component of the Ab-polymer conjugate to its adsorption and binding on the CA membrane.

Temperature-dependent absorption/desorption behavior of lower critical solution temperature (LCST) polymers on various substrates.

We have been studying adsorption and retention (resistance to desorption) behavior of temperature sensitive LCST polymers on different substrates as a function of temperature. According to our studies with Poly 64 (a copolymer of 60% (mol) NIPAAm and 40% (mol) NnBAAm, LCST = 8.5 degrees C in water), the copolymer retention depends on the rinse temperature. When the rinse temperature is above the LCST, the polymer adheres well to most surfaces. On the contrary, at rinse temperatures below the LCST, most of the adsorbed polymer is easily rinsed off. These studies are relevant to our work on the thermally reversible adsorption of LCST polymers conjugated to peptides and proteins, such as affinity ligands, for uses in immunoassays and affinity separations. The interaction between the LCST polymer and most hydrophobic polymer surfaces is mainly due to hydrophobic interactions, and the critical surface tension (gamma c) and the solubility parameter (delta) of the solid polymer substrate are the most important factors which influence the LCST polymer adsorption and retention. The critical surface tension appears to correlate best with the LCST polymer adsorption levels on different substrates, while the solubility parameter correlates best with the retention of the adsorbed polymer. According to our preliminary study, n-butyl groups probably interact more strongly with the substrates than isopropyl groups because of the greater hydrophobic surface area of the former groups.

Effect of sodium salicylate, aspirin, and ibuprofen on enzymes required by the chondrocyte for synthesis of chondroitin sulfate.

OBJECTIVE: To examine the effects of sodium salicylate (Sal), aspirin [acetylsalicylic acid (ASA)] and ibuprofen (Ibu) (as the racemic mixture and the R- and S-enantiomers) on the activities of 2 enzymes involved in the biosynthesis of the hexose components of chondroitin sulfate (CS), i.e., UDP-glucose dehydrogenase (UDP-GD) and glutamine-fructose-6-phosphate-aminotransferase (GFAT), and of glucuronosyltransferase (GT), an enzyme involved in elongation of the nascent CS chain. METHODS: UDP-GD and GT were obtained commercially. A homogenate of bovine articular cartilage chondrocytes was employed as a source of GFAT. In each case, enzymatic activity was measured spectrophotometrically. RESULTS: Neither UDP-GD nor GFAT was inhibited by concentrations of Sal, ASA or Ibu that were achieved clinically in joint tissues (e.g., 1.0 mM Sal and ASA, 170 microM Ibu). In contrast, GT activity was inhibited by Sal and ASA in a concentration dependent fashion; at 1.0 mM, a concentration commonly reached in synovial fluid of patients treated with an antiinflammatory dose of the drug, GT activity in the presence of Sal and ASA was 54% (p = 0.001) and 75% (p = 0.05), respectively, of the control value. In contrast, a clinically relevant concentration of Ibu had no effect on GT activity. CONCLUSION: Salicylates may suppress cartilage proteoglycan synthesis by inhibiting GT.

Distinguishing negligence from intentional tort when a health care provider deviates from a patient's consent.

A number of California appellate courts have held that a health care provider's unintentional deviation from a patient's consent will support a cause of action for "technical battery"--an intentional tort. This policy has allowed plaintiffs to circumvent California's statutory malpractice damage limits and seek punitive damages, thus posing a significant threat to the foundation of California medical malpractice tort law reform. The California Supreme Court recently acknowledged the problem and appears to be taking steps toward a solution.

Health care litigation: a common theory of noneconomic damages compensation.

In this article and the preceding article, the sixth and seventh in a series on health care litigation, the topic of noneconomic damages in medical malpractice cases is discussed. The preceding article addressed the law regarding noneconomic damages for emotional distress to third parties. This article describes a number of recent attempts to expand other categories of noneconomic damages, shows how this expansion can result in tort law problems, and suggests a possible solution.

Health care litigation: achieving fairness and reasonableness in punitive damages awards.

This article, the eighth in a series on health care litigation, discusses whether due process considerations require that the common-law procedures for awarding punitive damages be modified and whether juries have undue discretion in awarding punitive damages. The authors analyze an important recent United States Supreme Court punitive damages case and examine the changes states may need to make in their punitive damages assessment procedures to conform with the Supreme Court's holding.

Health care litigation: assuring consistency and proportionality in punitive damages awards.

This article, the ninth in a series on health care litigation, explains possible reforms that could be implemented to prevent juries from awarding unreasonable and unfair amounts of punitive damages. One way to minimize this problem would be to establish a system that promotes consistency in punitive damages awards. Another reform would involve instituting mechanisms to ensure proportionality in punitive damages awards. This article explores the steps involved in establishing a new system, and the benefit to defendants if the punitive damages system is reformed.

Application of a thermally-reversible polymer-antibody conjugate in a novel membrane-based immunoassay.

We have developed a novel method to immobilize antibodies onto a cellulose acetate membrane using a conjugate of an N-isopropylacrylamide polymer covalently bound to the antibody. When compared with the unconjugated antibody, over 30-fold increase in retention of the antibody on the membrane was observed when it was conjugated to poly (N-isopropylacrylamide). Studies of the polymer-membrane interaction suggest a combination of hydrophobic and ionic forces, especially the former, is responsible for the high retention. We applied this novel immobilization technology in the development of a membrane-based immunoassay.

Health care litigation: recent trends in the law of noneconomic damages--emotional distress.

This article and an article to follow, the sixth and seventh in a series, will address the topic of noneconomic damages in medical malpractice cases. Pain and suffering, emotional distress, loss of consortium, loss of a chance, hedonic damages, and other forms of nonpecuniary damages have played a major role in the increased recovery of compensatory damages from health care providers. This article will provide an overview of the subject of noneconomic damages and an in-depth discussion of the law regarding damages for emotional distress to third parties as it has evolved in the State of California.

Health care litigation: the arbitration alternative for dispute resolution.

This is the second in a series of articles on health care litigation. This article focuses on the benefits of arbitration as an alternative dispute mechanism for health care providers. The use of arbitration offers speed and economy to the parties. For the health care provider, arbitration can reduce litigation expense and the likelihood of "runaway" jury verdicts.