Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients.

OBJECTIVE: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. METHODS: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. RESULTS: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. CONCLUSION: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs.

Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model.

Low back pain, related to degeneration of the intervertebral disc (IVD), affects millions of people worldwide. Clinical studies using oral cyclooxygenase-2 (COX-2) inhibitors have shown beneficial effects, although side-effects were reported. Therefore, intradiscal delivery of nonsteroidal anti-inflammatory drugs can be an alternative treatment strategy to halt degeneration and address IVD-related pain. In the present study, the controlled release and biologic potency of celecoxib, a selective COX-2 inhibitor, from polyesteramide microspheres was investigated in vitro. In addition, safety and efficacy of injection of celecoxib-loaded microspheres were evaluated in vivo in a canine IVD degeneration model. In vitro, a sustained release of celecoxib was noted for over 28 days resulting in sustained inhibition of inflammation, as indicated by decreased prostaglandin E2 (PGE2) production, and anti-catabolic effects in nucleus pulposus (NP) cells from degenerated IVDs on qPCR. In vivo, there was no evidence of adverse effects on computed tomography and magnetic resonance imaging or macroscopic evaluation of IVDs. Local and sustained delivery of celecoxib prevented progression of IVD degeneration corroborated by MRI, histology, and measurement of NP proteoglycan content. Furthermore, it seemed to harness inflammation as indicated by decreased PGE2 tissue levels and decreased neuronal growth factor immunopositivity, providing indirect evidence that local delivery of a COX-2 inhibitor could also address pain related to IVD degeneration. In conclusion, intradiscal controlled release of celecoxib from polyesteramide microspheres prevented progression of IVD degeneration both in vitro and in vivo. Follow-up studies are warranted to determine the clinical efficacy of celecoxib-loaded PEAMs in chronic back pain.

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis.

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

The vestibular nuclei and vestibuloreticular connections in the mallard (Anas platyrhynchos L.). An anterograde and retrograde tracing study.

The vestibular apparatus provides information about the position and movements of the head. Craniocervical muscles position the head with respect to the upper part of the neck. Motoneurons innervating these muscles are located in the supraspinal nucleus and ventral horn of the rostral cervical cord. Premotor neurons of craniocervical muscles have been found in the medial two-thirds of the medullary reticular formation: the ventromedial part of the parvocellular reticular formation and the gigantocellular reticular formation. In the present study, projections from vestibular nuclei upon craniocervical premotor neurons were investigated using anterograde and retrograde tracers. Vestibulospinal fibers run bilaterally in the medial vestibulospinal tract and ipsilaterally in the lateral vestibulospinal tract. Vestibuloreticular projections are mainly ipsilateral, and originate from the n. vestibularis lateralis pars ventralis and pars dorsalis, and from the n. vestibularis descendens. Terminal labeling is found in the border zone between the parvocellular and gigantocellular reticular formation. These projections show that in addition to direct bilateral vestibulo-craniocervical projections an indirect vestibular pathway to craniocervical motor nuclei exists. The direct pathway probably is the neural substrate for the vestibulocollic reflex, whereas the vestibular projection upon the reticular formation might influence head orientation during various kinds of activities, such as pecking, preening and so on.

Intrinsic and extrinsic religiousness: genetic and environmental influences and personality correlates.

This report presents findings for the Intrinsic (IR) and Extrinsic (ER) religiousness scales from the Minnesota Study of Twins Reared Apart. The scales were shown to be internally consistent, sufficiently distinct from the scales of the California Psychological Inventory and the Multidimensional Personality Questionnaire and unrelated to a number of measures of response style to justify treating them as distinct traits. The I scales also showed considerable evidence of construct validity in its correlations with religious fundamentalism and authoritarianism as assessed by the MMPI and Altemeyer's Right-Wing Authoritarianism scale. Data on IR and ER from 35 pairs of monozygotic twins reared apart (MZA) and 37 pairs of dizygotic twins reared apart (DZA) were fitted to a biometric model and demonstrated significant heritability (0.43 and 0.39), with a model containing genetic plus environmental factors fitting significantly better than a model containing only an environmental component. Twin similarity could not be explained by placement on a self-reported measure of family Moral Religious Emphasis as measured by the Family Environment Scale.

Competence in the context of adversity: pathways to resilience and maladaptation from childhood to late adolescence.

Competent outcomes in late adolescence were examined in relation to adversity over time, antecedent competence and psychosocial resources, in order to investigate the phenomenon of resilience. An urban community sample of 205 (114 females, 90 males; 27% minority) children were recruited in elementary school and followed over 10 years. Multiple methods and informants were utilized to assess three major domains of competence from childhood through adolescence (academic achievement, conduct, and peer social competence), multiple aspects of adversity, and major psychosocial resources. Both variable-centered and person-centered analyses were conducted to test the hypothesized significance of resources for resilience. Better intellectual functioning and parenting resources were associated with good outcomes across competence domains, even in the context of severe, chronic adversity. IQ and parenting appeared to have a specific protective role with respect to antisocial behavior. Resilient adolescents (high adversity, adequate competence across three domains) had much in common with their low-adversity competent peers, including average or better IQ, parenting, and psychological well-being. Resilient individuals differed markedly from their high adversity, maladaptive peers who had few resources and high negative emotionality. Results suggest that IQ and parenting scores are markers of fundamental adaptational systems that protect child development in the context of severe adversity.

Location of reticular premotor areas of a motor center innervating craniocervical muscles in the mallard (Anas platyrhynchos L.).

The supraspinal nucleus (SSp) in the mallard, which lies in the rostral spinal cord and caudal brainstem, is a motor nucleus that forms the rostral continuation of the ventral horn. It contains part of the motoneurons innervating the craniocervical muscles. Injections with horseradish peroxidase (HRP) and wheat germ agglutinin conjugated to HRP (WGA) in the SSp were used to localize the craniocervical premotor neurons in the medullary reticular formation. A mixture of WGA and HRP (WGA/HRP) or biotinylated dextran amine (BDA) were injected in the different reticular areas to test the results. Small numbers of craniocervical premotor neurons were found bilaterally in the ventromedial part of the parvocellular reticular formation (RPcvm) and in the caudal extension of RPcvm, the nucleus centralis dorsalis of the medulla oblongata, and the gigantocellular reticular formation (RGc). In a second series of experiments, WGA/HRP and BDA injections in these reticular areas were used to visualize afferent fibers and terminals in the SSp. The combination of the two types of experiments shows that RPcvm and RGc contain modest numbers of craniocervical premotor neurons. Because the reticular formation also contains jaw and tongue premotor neurons and receives a variety of sensory projections, the present results suggest that the medullary reticular formation plays a role in the coordination of complex movements (e.g., feeding). The pattern of afferent and efferent connections of the reticular formation is used to redefine its subdivisions in the myelencephalon of the mallard.

Individual differences in adult ego development: sources of influence in twins reared apart.

A behavior genetic analysis of the personality dimension of ego development, as assessed by the Washington University Sentence Completion Test, was carried out on a sample of 45 pairs of monozygotic twins and 28 pairs of same-sex dizygotic twins. The twins ranged in age from 16 to 70 years at the time of assessment, had been separated during infancy, and had been raised apart in adoptive homes before being reunited in adulthood. Analyses indicated that reared-apart twins were similar in trait levels of ego development and that such similarity could not solely be attributed to measured similarity in cognitive ability, including verbal reasoning. Estimates of broad similarity for ego development (46%) were comparable to values reported for other major personality dimensions. Phenotypic variance in adult levels of ego development appears to have substantial genetic and environmental sources.

A crossed projection from the optic tectum to craniocervical premotor areas in the brainstem reticular formation. An anterograde and retrograde tracing study in the mallard (Anas platyrhynchos L.).

The optic tectum in birds receives visual information from the contralateral retina. This information is passed through to other brain areas via the deep layers of the optic tectum. In the present study the crossed tectobulbar pathway is described in detail. This pathway forms the connection between the optic tectum and the premotor area of craniocervical muscles in the contralateral paramedian reticular formation. It originates predominantly from neurons in the ventromedial part of stratum griseum centrale and to a lesser extent from stratum album centrale. The fibers leave the tectum as a horizontal fiber bundle, and cross the midline through the caudal radix oculomotorius and rostral nucleus oculomotorius. On the contralateral side fibers turn to ventral and descend caudally in the contralateral paramedian reticular formation to the level of the obex. Labeled terminals are found in the ipsilateral medial mesencephalic reticular formation lateral to the radix and motor nucleus of the oculomotor nerve, and in the contralateral paramedian reticular formation, along the descending tract. Neurons in the medial mesencephalic reticular formation in turn project to the paramedian reticular formation. Through the crossed tectobulbar pathway visual information can influence the activity of craniocervical muscles via reticular premotor neurons.

Central connections of the nucleus mesencephalicus nervi trigemini in the mallard (Anas platyrhynchos L.).

BACKGROUND: In the mallard duck, functionally distinct groups of jaw muscles are each innervated by a different subnucleus of the main trigeminal (mV) or facial (mVII) motor nucleus. The other subnuclei of mV and mVII innervate several head muscles, including lingual muscles. The reticular premotor cells of the trigeminal and facial jaw motor subnuclei occupy different areas in the parvocellular reticular formation (RPc). The cell bodies of jaw muscle spindle afferents are situated in the mesencephalic nucleus (MesV). In the present study, the central connections of MesV with jaw motor subnuclei and their premotor areas are investigated. METHODS: In a first series of experiments, horseradish peroxidase (HRP) injections were made in electrophysiologically identified trigeminal and facial subnuclei. In a second series of experiments, HRP was delivered iontophoretically at different parts of RPc. Anterograde tracing with tritiated leucine was used to confirm the central connections of MesV. Double labeling with fluorescent tracers was used to investigate whether MesV collaterals reach both the rostral and caudal parts of RPc. RESULTS: MesV projects to only two of the five different subnuclei of the trigeminal motor nucleus. The subnuclei that receive spindle afferents innervate jaw adductor muscles (mV2) or pro- and retractors of the mandible (pterygoid muscles; mV1). The three other subnuclei innervate jaw-opener muscles or other head muscles. MesV fibers also project to the rostral part of the dorsolateral RPc (RPcdl), which serves as a premotor area for the motor subnuclei of adductor and pterygoid muscles. The intermediate part of RPcdl does not contain premotor cells of mV or mVII, and a clear projection of MesV to this area is absent. The caudal part of RPcdl projects to the mV and mVII subnuclei that innervate jaw-opener muscles. This part of RPc receives a projection from the same MesV cells as the rostral RPcdl. The MesV projection to RPc does not include premotor cells of mV and mVII in the ventromedial part of RPc (RPcvm). CONCLUSIONS: Spindle afferents from jaw-closer muscles project only to mV subnuclei innervating jaw-closer muscles (mV1, mV2) and to a population of premotor cells in the rostral RPcdl that innervates these subnuclei. The mixed population of premotor cells in RPcvm, which innervates both jaw-opener and jaw-closer subnuclei, does not receive a MesV projection. However, a premotor area for jaw-opener subnuclei in the caudal part of RPcdl does receive MesV input and may serve as a relay through which proprioceptive information from jaw closer spindles can reach jaw opener muscles.

Evaluating the similarity of MMPI-2 and MMPI profiles: reply to Dahlstrom and Humphrey.

We review issues that have arisen in exchanges with Dahlstrom and Humphrey (Dahlstrom & Humphrey, 1996; Humphrey & Dahlstrom, 1995) about assessing the comparability of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and the MMPI. We point out the limitations of Q correlations (without contending that D(2) is "the only legitimate function of profile comparability," as Dahlstrom and Humphrey, 1996, p. 350, claim we do), and explain why Dahlstrom and Humphrey's (1996) new Q-correlational results, correctly interpreted, are consistent with our own previous observations and conclusions. We stress again the importance of both overall profile elevation and profile "definition" in making code-type assignments. Nonrestrictive code types ignore these profile characteristics, and their use needlessly lowers MMPI-2/MMPI code-type congruences and raises the incidence of profile misinterpretations. Our recommendation of well-defined MMPI-2 code types stands.

Do craniocervical and jaw motor nuclei receive input from the same population of reticular premotor neurons? A double labeling tracing study in the mallard (Anas platyrhynchos).

As part of a study concerning the organization of premotor areas in the medullary reticular formation in birds we used a fluorescent retrograde double labeling technique to localize the premotor neurons of the trigeminal (mV) and supraspinal motor nucleus (SSp). Diamidino Yellow injections in mV and Fast Blue injections in SSp demonstrated that mV and SSp do not share premotor neurons, but the premotor neurons form a mixed population in the ventromedial part of the parvocellular reticular formation.

The structure and coherence of competence from childhood through adolescence.

The structure and coherence of competence from childhood (ages 8-12) to late adolescence (ages 17-23) was examined in a longitudinal study of 191 children. Structural equation modeling was utilized to test a conceptual model and alternative models. Results suggest that competence has at least 3 distinct dimensions in childhood and 5 in adolescence. These dimensions reflect developmental tasks related to academic achievement, social competence, and conduct important at both age levels in U.S. society, and the additional tasks of romantic and job competence in adolescence. As hypothesized, rule-breaking versus rule-abiding conduct showed strong continuity over time, while academic achievement and social competence showed moderate continuity. Results also were consistent with the hypothesis that antisocial behavior undermines academic attainment and job competence.

How (not) to evaluate the comparability of MMPI and MMPI-2 profile configurations: a reply to Humphrey and Dahlstrom.

Humphrey and Dahlstrom (1995) presented a study on the comparability of MMPI/MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) profiles in which they concluded that "the bases for clinical interpretation derived from the MMPI and MMPI-2 profiles were sufficiently at variance to require different conclusions" [sic] (p. 2). In this brief critique, we identify procedural and data-analytical deficiencies that invalidate Humphrey and Dahlstrom's argument. Their blanket recommendation based on this argument, namely, that clinicians routinely plot both MMPI and MMPI-2 profiles, is unwarranted.

Differential convergence of self-report and informant data for multidimensional personality questionnaire traits: implications for the construct of negative emotionality.

Construct validation work on Tellegen's (1982) Multidimensional Personality Questionnaire (MPQ) resulted in further inferences about Negative Emotionality. Two hundred thirty-two students were rated by three knowledgeable informants, yielding a total of 928 participants. The median monotrait correlation of MPQ primary scores with summed observer ratings was .48, and all were significant, p < .01. These data show higher self-report to informant rating convergences in the Positive Emotionality (Extroversion) domain than in the Negative Emotionality (Neuroticism) domain. Furthermore, in the Negative Emotionality domain, peers, mothers, and fathers were not equivalent as classes of raters. Stress Reaction ratings showed uniformly lower levels of convergence with self-report (relative to Positive Emotionality traits) across all rater classes. For Alienation, peer and maternal ratings were comparable, but paternal ratings correlated significantly less with self-report scores than did maternal ratings. And finally, with Aggression, peer ratings correlated significantly higher with self-report than either maternal or paternal ratings. These findings, taken in the context of the literature, have implications for a hierarchical model of Negative Emotionality, support inferences about the display of cues of Negative Emotionality, and offer new cautions for rating-based assessment.

Location of premotor neurons of the motor nuclei innervating craniocervical muscles in the mallard (Anas platyrhynchos L.).

Reticular premotor neurons of craniocervical muscles in the duck were localized with the retrograde tracer HRP and the anterograde tracer WGA-HRP. In the reticular formation neck premotor neurons were found in the gigantocellular reticular nucleus and in the ventromedial part of the parvocellular reticular nucleus rostral to the obex, and caudal to the obex in the nucleus centralis ventralis of the medulla. Results were compared with premotor areas of jaw muscles. The ventromedial part of the parvocellular reticular formation contains neck as well as jaw premotor neurons. This area may serve as the neural substrate for the coordination of neck and jaw movements.

Heritability of interests: a twin study.

The authors administered inventories of vocational and recreational interests and talents to 924 pairs of twins who had been reared together and to 92 pairs separated in infancy and reared apart. Factor analysis of all 291 items yielded 39 identifiable factors and 11 superfactors. The data indicated that about 50% of interests variance (about two thirds of the stable variance) was associated with genetic variation. The authors show that heritability can be conservatively estimated from the within-pair correlations of adult monozygotic twins reared together. Evidence for nonadditive genetic effects on interests may explain why heritability estimates based on family studies are so much lower. The authors propose a model in which precursor traits of aptitude and personality, in part genetically determined, guide the development of interests through the mechanisms of gene-environment correlation and interaction.

Is human mating adventitious or the result of lawful choice? A twin study of mate selection.

Pairs of middle-aged twins and their spouses provided data on 74 mainly psychological variables. Neither spousal similarity nor idiosyncratic criteria could account for specific mate selection in these 738 couples. Of the twins (and their spouses), 547 independently rated their initial attraction to their twin's mate (or to their spouse's twin): Findings suggest that characteristics both of the chooser and the chosen constrain mate selection only weakly. This article proposes that it is romantic infatuation that commonly determines the final choice from a broad field of potential eligibles and that this phenomenon is inherently random, in the same sense as is imprinting in precocial birds.

Code-type comparability of the MMPI and MMPI-2: analysis of recent findings and criticisms.

The introduction of the MMPI-2 has stimulated studies of its comparability with the MMPI. Graham, Timbrook, Ben-Porath, and Butcher (1991) consider the congruence between MMPI-2 and MMPI code types substantial, but Dahlstrom (1992) has questioned their appraisal, criticizing their use of "well-defined" code types. Our own analysis supports Graham and colleagues' (1991) conclusions and provides reasons for favoring narrow code types (such as well- defined code types) over nonrestrictive ones. We also offer a brief historical review of MMPI code typology as background for our recommendation that future MMPI-2 research not be limited to studies of code-type correlates.

Emergenesis. Genetic traits that may not run in families.

Traits that are influenced by a configuration--rather than by a simple sum--of polymorphic genes may not be seen to be genetic unless one studies monozygotic twins (who share all their genes and thus all gene configurations) because such "emergenic" traits will tend not to run in families. Personal idiosyncrasies that have been found to be surprisingly concordant among MZ twins separated in infancy and reared apart may be emergenic traits. More speculatively, important human traits like leadership, genius in its many manifestations, being an effective therapist or parent, as well as certain psychopathological syndromes may also be emergenic. These ideas reemphasize the importance of the role played in human affairs by genetic variation.