Exploring the experiences of novice clinical instructors in physical therapy clinical education: a phenomenological study.

OBJECTIVE: To explore the perceptions of novice physical therapy clinical instructors (CIs) about their interactions and teaching behaviours with physical therapy students. DESIGN: A phenomenological approach using semi-structured interviews and a focus group. PARTICIPANTS: Six novice physical therapy CIs (less than two years as a CI and supervised fewer than three students) were recruited purposefully from a large metropolitan area in the USA. All participants were credentialed by the American Physical Therapy Association as CIs. MAIN OUTCOME MEASURES: Transcripts of interview data and focus group data were analysed using interpretative analysis for themes and subthemes. RESULTS: Participants viewed the transition of students from the classroom to the clinic as their primary role, using strategies of 'providing a way in', 'fostering critical thinking', 'finding a balance', 'overcoming barriers' and 'letting go'. CONCLUSION: While novice CIs showed skill in fostering student reflection and providing orientation, they struggled with student autonomy and balancing the competing obligations of patient care and clinical instruction. They expressed issues related to anxiety and lack of confidence. In the future, novice CIs could benefit from training and support in these areas.

Reducing methylmercury accumulation in the food webs of San Francisco Bay and its local watersheds.

San Francisco Bay (California, USA) and its local watersheds present an interesting case study in estuarine mercury (Hg) contamination. This review focuses on the most promising avenues for attempting to reduce methylmercury (MeHg) contamination in Bay Area aquatic food webs and identifying the scientific information that is most urgently needed to support these efforts. Concern for human exposure to MeHg in the region has led to advisories for consumption of sport fish. Striped bass from the Bay have the highest average Hg concentration measured for this species in USA estuaries, and this degree of contamination has been constant for the past 40 years. Similarly, largemouth bass in some Bay Area reservoirs have some of the highest Hg concentrations observed in the entire US. Bay Area wildlife, particularly birds, face potential impacts to reproduction based on Hg concentrations in the tissues of several Bay species. Source control of Hg is one of the primary possible approaches for reducing MeHg accumulation in Bay Area aquatic food webs. Recent findings (particularly Hg isotope measurements) indicate that the decades-long residence time of particle-associated Hg in the Bay is sufficient to allow significant conversion of even the insoluble forms of Hg into MeHg. Past inputs have been thoroughly mixed throughout this shallow and dynamic estuary. The large pool of Hg already present in the ecosystem dominates the fraction converted to MeHg and accumulating in the food web. Consequently, decreasing external Hg inputs can be expected to reduce MeHg in the food web, but it will likely take many decades to centuries before those reductions are achieved. Extensive efforts to reduce loads from the largest Hg mining source (the historic New Almaden mining district) are underway. Hg is spread widely across the urban landscape, but there are a number of key sources, source areas, and pathways that provide opportunities to capture larger quantities of Hg and reduce loads from urban runoff. Atmospheric deposition is a lower priority for source control in the Bay Area due to a combination of a lack of major local sources. Internal net production of MeHg is the dominant source of MeHg that enters the food web. Controlling internal net production is the second primary management approach, and has the potential to reduce food web MeHg in some habitats more effectively and within a much shorter time-frame. Controlling net MeHg production and accumulation in the food web of upstream reservoirs and ponds is very promising due to the many features of these ecosystems that can be manipulated. The most feasible control options in tidal marshes relate to the design of flow patterns and subhabitats in restoration projects. Options for controlling MeHg production in open Bay habitat are limited due primarily to the highly dispersed distribution of Hg throughout the ecosystem. Other changes in these habitats may also have a large influence on food web MeHg, including temperature changes due to global warming, sea level rise, food web alterations due to introduced species and other causes, and changes in sediment supply. Other options for reducing or mitigating exposure and risk include controlling bioaccumulation, cleanup of contaminated sites, and reducing other factors (e.g., habitat availability) that limit at-risk wildlife populations.

Inactivation of the p16 cyclin-dependent kinase inhibitor in high-grade canine non-Hodgkin's T-cell lymphoma.

The significance of p16/Rb tumor suppressor pathway inactivation in T-cell non-Hodgkin's lymphoma (NHL) remains incompletely understood. We used naturally occurring canine NHL to test the hypothesis that p16 inactivation has specific pathologic correlates. Forty-eight samples (22 T-cell NHL and 26 B-cell NHL) were included. As applicable, metaphase- or array-based comparative genomic hybridization, Southern blotting, promoter methylation, and Rb phosphorylation were used to determine the presence, expression, and activity of p16. Fisher's exact test was used to test for significance. Deletion of p16 (or loss of dog chromosome 11) was restricted to high-grade T-cell NHL (lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified). These were characterized by a concomitant increase of tumor cells with Rb phosphorylation at canonical CDK4 sites. Rb phosphorylation also was seen in high-grade B-cell NHL (diffuse large B-cell lymphoma and Burkitt-type lymphoma), but in those cases, it appeared to be associated with c-Myc overexpression. The data show that p16 deletion or inactivation occurs almost exclusively in high-grade T-cell NHL; however, alternative pathways can generate functional phenotypes of Rb deficiency in low-grade T-cell NHL and in high-grade B-cell NHL. Both morphologic classification according to World Health Organization criteria and assessment of Rb phosphorylation are prognostically valuable parameters for canine NHL.

The marital and family functioning of adults with ADHD and their spouses.

Little is known about the family relationships of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Thus, the marital adjustment and family functioning of 33 married adults with ADHD and their spouses was compared to 26 non-ADHD control participants and their spouses. Results revealed that married adults with ADHD reported poorer overall marital adjustment on the Dyadic Adjustment Scale (DAS; Spanier, 1989) and more family dysfunction on the Family Assessment Device (FAD; Eptein, Baldwin, & Bishop, 1983) than control adults. The spouses of adults with ADHD did not differ from control spouses in reports of overall marital adjustment and family dysfunction. A greater proportion of their marital adjustment scores, however, fell within the maladjusted range. The ADHD adults' perceptions of the health of their marriages and families were more negative than their spouses' perceptions. The way in which spouses of ADHD adults compensated for their partners' difficulties were explored through clinical interviews. The findings in this study underscore the need for assessments and treatments to address marital and family functioning of adults with ADHD.

Multiple complex developmental disorder: the "multiple and complex" evolution of the "childhood borderline syndrome" construct.

OBJECTIVES: To provide an overview of the history, evolution, and nosology of the diagnostic constructs for "borderline syndrome of childhood," also known as "multiple complex developmental disorder." METHOD: The authors synthesized information found via electronic searches of databases (MEDLINE, PsycINFO, Current Contents, Humanities Abstracts, and Social Sciences Abstracts) and bibliographic directed searches. RESULTS: Although early publications (prior to 1980) were either highly anecdotal or lacking in scientific rigor, they were nonetheless noted for their historic value and influence on research trends. The recent publications (1990s) were characterized by more rigorous methodology and greater generalizability. Current classifications, proposals for diagnostic criteria, epidemiological data, and nosological suggestions were summarized. CONCLUSION: The literature supports the creation of a new diagnostic label to describe a population of children whose symptoms are currently subsumed under the labels "borderline" or "multiple complex developmental disorder." A full characterization of the syndrome, including its evolution, would require prospective studies and may differ from the known evolution for personality disorders and/or pervasive developmental disorders. The authors propose a process by which a new nomenclature is derived.

Inpatient treatment of severe disruptive behaviour disorders with risperidone and milieu therapy.

OBJECTIVES: To evaluate the therapeutic impact of adding risperidone to milieu therapy of latency-aged inpatients with severe disruptive disorders. METHODS: The charts of 90 latency-aged patients consecutively admitted to a psychiatry ward were reviewed retrospectively. Fifteen of these patients received risperidone treatment, were nonpsychotic, and did not suffer from pervasive developmental disorder (12 male, 3 female; mean age 9.99 years, SD 1.76). Their scores on the Children's Global Assessment Scale (CGAS) were compared at admission, before risperidone treatment, and at discharge. RESULTS: All subjects were diagnosed with a disruptive behavioural disorder. Ten (66.67%) had additional learning difficulties, and 13 (86.7%) had pathological personality traits. The characteristics of the sample suggested borderline pathology or multiple complex developmental disorder. Following a mean of 38 days after admission (SD 22.3), the patients received risperidone for a mean of 46 days (SD 28.2) before being discharged. The mean maintenance dose of risperidone was 1.27 mg daily (SD 0.36). Mean CGAS scores increased from admission (21.9, SD 7.0) to before risperidone treatment (26.8, SD 7.6, P < 0.0001) and to discharge (50.3, SD 5.3, P < 0.0001). Only 2 patients had documented side effects. CONCLUSIONS: Low-dose risperidone used adjunctively to milieu therapy led to statistically and clinically significant additional improvement in the functioning of hospitalized latency-aged children with severe behavioural disorders. Low-dose risperidone is a safe and effective adjunct to milieu therapy for treating this population in inpatient settings. Prospective randomized controlled trials are needed to confirm these findings.

CD44 is not an adhesive receptor for osteopontin.

Osteopontin is a secreted glycoprotein with adhesive and migratory functions. Cellular interactions with osteopontin are mediated through integrin receptors which recognize the RGD domain. Recently, CD44, a non-integrin, multifunctional adhesion molecule was identified as an osteopontin receptor. CD44 is a ubiquitous surface molecule that exists as a number of different isoforms, generated by alternative splicing. To analyze which forms of CD44 mediate binding to osteopontin, we used the standard form of CD44 as CD44-human immunoglobulin fusion proteins and several splice variants in enzyme-linked immunosorbant assays. Multiple preparations of osteopontin were used including native osteopontin derived from smooth muscle cells, human urinary osteopontin, full-length recombinant osteopontin, and two recombinant osteopontin fragments expected to be formed following thrombin cleavage. Our data show that although the CD44-hlg fusion proteins could interact with hyaluronic acid as expected, there was no interaction between CD44H, CD44E, CD44v3,v8-v10, or CD44v3 with osteopontin. These studies suggest that CD44-osteopontin interactions may not be common in vivo and may be limited to a specific CD44 isoform(s), and/or a particular modified form of osteopontin.

Characterization of the heparan sulfate and chondroitin sulfate assembly sites in CD44.

Isoforms of CD44 are differentially modified by the glycosaminoglycans (GAGs) chondroitin sulfate (CS), heparan sulfate (HS), and keratan sulfate. GAG assembly occurs at serines followed by glycines (SG), but not all SG are utilized. Seven SG motifs are distributed in five CD44 exons, and in this paper we identify the HS and CS assembly sites that are utilized in CD44. Not all the CD44 SG sites are modified. The SGSG motif in CD44 exon V3 is the only HS assembly site; this site is also modified with CS. HS and CS attachment at that site was eliminated by mutation of the serines in the V3 motif to alanine (AGAG). Exon E5 is the only other CD44 exon that supports GAG assembly and is modified with CS. Using a number of recombinant CD44 protein fragments we show herein that the eight amino acids located downstream of the SGSG site in V3 are responsible for the specific addition of HS to this site. If the eight amino acids located downstream from the first SG site in CD44 exon E5 are exchanged with those located downstream of the SGSG site in exon V3, the SG site in E5 becomes modified with HS and CS. Likewise if the eight amino acids found downstream from the first SG in E5 are placed downstream from the SGSG in V3, this site is modified with CS but not HS. We also show that these sequences cannot direct the modification of CD44 with HS from a distance. Constructs containing CD44 exon V3 in which the SGSG motif was mutated to AGAG were not modified with HS even though they contained other SG motifs. Thus, a number of sequence and structural requirements that dictate GAG synthesis on CD44 have been identified.

Generation of artificial proteoglycans containing glycosaminoglycan-modified CD44. Demonstration of the interaction between rantes and chondroitin sulfate.

All CD44 isoforms are modified with chondroitin sulfate (CS), while only those containing variably spliced exon V3 are modified with both CS and heparan sulfate (HS). The CS is added to a serine-glycine (SG) site in CD44 exon E5, while HS and CS are added to the SGSG site in exon V3. Site-directed mutagenesis and other molecular biology techniques were used to determine the minimal motifs responsible for the addition of CS and HS to CD44 (see accompanying paper (Greenfield, B., Wang, W.-C., Marquardt, H., Piepkorn, M., Wolff, E. A., Aruffo, A., and Bennett, K. L. (1999) J. Biol. Chem. 274, 2511-2517)). We have used this information to generate artificial proteoglycans containing the extracellular domain of the cell adhesion protein lymphocyte function-associated antigen-3 (LFA-3) (CD58) and CD44 motifs modified with CS or a combination of CS and HS. Analysis of the CD44-modified LFA-3 protein showed that it retains the ability to engage and trigger the function of its natural ligand CD2, resulting in T cell activation. In addition, the glycosaminoglycan-modified artificial proteoglycan is capable of binding the chemokine RANTES (regulated upon activation, normally T cell expressed and secreted) and delivering it to human T cells, resulting in enhanced T cell activation. These data demonstrate that artificial proteoglycans can be engineered with functional domains that have enhanced activity by codelivering glycosaminoglycan-binding molecules. The artificial proteoglycans were also used as a model system to explore the glycosaminoglycan binding properties of basic-fibroblast growth factor and the chemokine RANTES. While basic-fibroblast growth factor was shown to bind HS alone, this model revealed that RANTES binds not only HS, as has been demonstrated in the past, but also CS. Thus, artificial proteoglycans can be used for studying the glycosaminoglycan binding patterns of growth factors and chemokines and provide a means to manipulate the levels, types, and activity of glycosaminoglycan-binding proteins in vitro and in vivo.

Function of the nasal muscles in normal subjects assessed by dynamic MRI and EMG: its relevance to rhinoplasty surgery.

The external nose is generally considered to have a relatively static shape. Movement of the nose and the potential for change of external shape and the internal airway have been assessed by (1) cadaver dissection and (2) dynamic studies during a standardized series of facial expressions in 13 subjects; video recording of the movement of skin markers, electromyography, and moving magnetic resonance images. A standard description of muscle anatomy is presented. The dynamic investigations indicated the following. Video analysis showed the components of muscle action: dilatation, constriction of the nostril, depression of the tip, vertical contraction in the bridge, and elevation of the alar, in different expressions. Electromyography confirmed muscle actions during expression and phonation. Magnetic resonance imaging demonstrated large changes in the external shape of the nose and nasal aperture due to muscle actions. Muscle function should be given greater consideration in aesthetic and cleft rhinoplasty.

Identification of CD44 residues important for hyaluronan binding and delineation of the binding site.

CD44 is a widely distributed cell surface protein that plays a role in cell adhesion and migration. As a proteoglycan, CD44 is also implicated in growth factor and chemokine binding and presentation. The extracellular region of CD44 is variably spliced, giving rise to multiple CD44 isoforms. All isoforms contain an amino-terminal domain, which is homologous to cartilage link proteins. The cartilage link protein-like domain of CD44 is important for hyaluronan binding. The structure of the link protein domain of TSG-6 has been determined by NMR. Based on this structure, a molecular model of the link-homologous region of CD44 was constructed. This model was used to select residues for site-specific mutagenesis in an effort to identify residues important for ligand binding and to outline the hyaluronan binding site. Twenty-four point mutants were generated and characterized, and eight residues were identified as critical for binding or to support the interaction. In the model, these residues form a coherent surface the location of which approximately corresponds to the carbohydrate binding sites in two functionally unrelated calcium-dependent lectins, mannose-binding protein and E-selectin (CD62E).

Deleted in colorectal carcinoma (DCC) binds heparin via its fifth fibronectin type III domain.

DCC (deleted in colorectal carcinoma) is a broadly expressed cell-surface receptor. Netrin-1 was recently identified as a DCC ligand in brain, but the possibility of other DCC ligands was suggested by the finding that an anti-DCC antibody (clone AF5) neutralized netrin-1-dependent commissural axon outgrowth without blocking DCC/netrin-1 interactions. Here we have searched for alternative cell-surface DCC ligands. A DCC-Ig fusion protein bound to neural and epithelial derived cell lines, indicating that these lines express ligand(s) for DCC. The cell-surface binding activity was mediated by the loop between beta-strands F and G of the fifth fibronectin type III repeat FNIII-D5. The loop included the sequence KNRR, which resembles heparin-binding motifs in other proteins. Heparinase and heparitinase treatment of cells reduced binding of DCC-Ig, suggesting that heparan sulfate proteoglycans are cell-surface DCC ligand(s). This was further supported by heparin blocking experiments and by binding of DCC-Ig to immobilized heparan sulfate. The interaction between DCC-Ig and heparan sulfate/heparin, both on the surface of cells and immobilized on plastic, was blocked by the same anti-DCC antibody that blocks netrin-1-dependent commissural axon outgrowth. Taken together, these findings suggest that the DCC-Ig/heparin interaction may contribute to the biological activity of DCC.

Juvenile onset bipolar disorder.

This article reviews juvenile onset bipolar disorder with regard to history, diagnosis, comorbidity, differential diagnosis, prevalence, etiology, treatment, and outcome. Specifically, it deals with past and current diagnostic criteria for juvenile onset bipolar disorder, the controversy around its comorbidity with attention deficit hyperactivity disorder (ADHD), and how to differentiate it from ADHD, conduct disorder, drug and alcohol abuse, and schizophrenia, Genetic and neuroimaging studies investigating the possible etiology of this condition are also described. Treatment, both pharmacological (eg, lithium, neuroleptics, anticonvulsants, benzodiazepines, antidepressants) and psychosocial (eg, psychoeducation of child and family, school intervention, family, group and/or individual therapy) are outlined. Finally, long-term outcome and factors which may influence outcome are addressed.

Patterns of coordinated lower facial muscle function and their importance in facial reanimation.

Coordinated patterns of lower facial muscle activity have been observed using 8-channel electromyography (surface electrodes in a bipolar configuration) on 11 healthy volunteers to provide a picture of the patterns of muscle activity during function. Measurements of integrated electrical activity were made to allow comparison of different muscle groups during active, active-against-resistance, and passive movements. A contraction reflex was assessed by an electromechanical device and noted in 8 of 11 subjects. Lower facial movements were found to involve simultaneous bilateral activity in all the muscle groups tested bilaterally and to require a balance between dilator and constrictor forces. The significance for facial reanimation surgery is that it is desirable to reconstruct balanced constrictor and dilator forces, the latter having vector pulls upwards, downwards and laterally to reconstruct the normal mechanism of lower facial movement.

Activation of human monocytes through CD40 induces matrix metalloproteinases.

The activation of monocytes/macrophages to secrete pro-inflammatory cytokines and matrix metalloproteinases (MMPs) is critically important in the development of chronic inflammatory diseases. However, the consequence of interactions between activated T cells and monocytes in these inflammatory processes is not well understood. In this study we have investigated the induction of MMPs in human monocytes by activated T cells. We show that fixed cells and the cell membranes from a T cell line, BMS-2, that expresses high levels of the CD40 ligand gp39 (also called TRAP, TBAM, or CD40L) stimulate both the expression of mRNA and the production of MMPs by human monocytic cells. Activation of monocytes by the human T cells could be significantly inhibited by a F(ab')2 fragment of a neutralizing Ab specific for human gp39, but not by an Ab that recognizes murine gp39. Furthermore, recombinant soluble gp39 (sgp39) alone induced marked increases in the levels of a 92-kDa metalloproteinase (gelatinase) in both the human monocytic cell line, THP-1, and peripheral human monocytes, and induction was blocked by the anti-human gp39 Ab. Pretreatment with IFN-gamma significantly enhanced gp39 induction of MMPs in THP-1 cells but not in peripheral monocytes. Up-regulation of mRNA for the 92-kDa MMP by gp39 could be detected within 6 h of stimulation and was maximal 24 h after treatment. MMP enzymatic activity was detectable in the culture medium 12 to 18 h following stimulation of the cells and remained high through 48 h. These results suggest the interaction of T cells with monocytes/macrophages via the gp39-CD40 counter receptors may be significant in development or maintenance of chronic inflammatory lesions.

Regulation of CD44 binding to hyaluronan by glycosylation of variably spliced exons.

The hyaluronan (HA)-binding function (lectin function) of the leukocyte homing receptor, CD44, is tightly regulated. Herein we address possible mechanisms that regulate CD44 isoform-specific HA binding. Binding studies with melanoma transfectants expressing CD44H, CD44E, or with soluble immunoglobulin fusions of CD44H and CD44E (CD44H-Rg, CD44E-Rg) showed that although both CD44 isoforms can bind HA, CD44H binds HA more efficiently than CD44E. Using CD44-Rg fusion proteins we show that the variably spliced exons in CD44E, V8-V10, specifically reduce the lectin function of CD44, while replacement of V8-V10 by an ICAM-1 immunoglobulin domain restores binding to a level comparable to that of CD44H. Conversely, CD44 bound HA very weakly when exons V8-V10 were replaced with a CD34 mucin domain, which is heavily modified by O-linked glycans. Production of CD44E-Rg or incubation of CD44E-expressing transfectants in the presence of an O-linked glycosylation inhibitor restored HA binding to CD44H-Rg and to cell surface CD44H levels, respectively. We conclude that differential splicing provides a regulatory mechanism for CD44 lectin function and that this effect is due in part to O-linked carbohydrate moieties which are added to the Ser/Thr rich regions encoded by the variably spliced CD44 exons. Alternative splicing resulting in changes in protein glycosylation provide a novel mechanism for the regulation of lectin activity.

Middle ear effusion--allergy relationships.

Middle ear effusion (MEE), in its various forms, is one of the most common disorders of childhood. There are several possible etiologies, depending on the makeup of the effusion. However, the common factor in many middle ear effusions is eustachian tube dysfunction, and the role of allergy, although only one of many possible causes, is significant. A relatively large number of children with MEE are found to have atopic disorders. Nonetheless, allergy treatment alone must not preclude the use of conventional medical and surgical therapy. Optimal results will be obtained if recurrent or persistent MEE is managed in a coordinated manner by the otologist, pediatrician and allergist.