Attenuated psychosis symptoms are related to working alliance between therapist and service user.

AIM: Many trials have demonstrated the efficacy of specific therapy modalities for individuals with attenuated psychosis symptoms (APS). Less is known regarding mechanisms behind positive outcomes, including the role of nonspecific therapeutic factors. This study explored working alliance (WA) in a clinic serving individuals with APS to see how WA changed across the course of treatment and its relation to APS. METHODS: Session level APS and WA data was available for 12 individuals of diverse racial and gender identity, (M = 48 sessions each). Multilevel models with random intercepts tested change in WA and APS over time, and cross-sectional and prospective relations. RESULTS: WA increased and APS decreased over time. Cross sectionally, WA and APS were inversely related. Prospective relations were non-significant. CONCLUSION: When symptoms increase, therapists for individuals with APS should be attentive to potential disruptions in WA, though strong WA may be a cross-sectional protective factor.

Fluorine-18 labelled prostate-specific membrane antigen (PSMA)-1007 positron-emission tomography-computed tomography: normal patterns, pearls, and pitfalls.

Prostate-specific membrane antigen (PSMA)-based positron-emission tomography (PET)-computed tomography (CT) has shown great promise in prostate cancer imaging. This technique has demonstrated particular utility in the staging of high-risk primary cancer and in the localisation of recurrent disease. The use of fluorine-18 PSMA-1007 is advantageous, as it is excreted via the hepatobiliary system rather than urinary and the longer half-life of fluorine-18 compared to gallium tracers, allows for PSMA imaging in centres without a gallium generator. However, imaging with this tracer is not without flaws and areas of ambiguity remain. In this article, the biodistribution, clinical indications, and pearls of 18F-PSMA-1007 PET-CT in patients with prostate cancer will be discussed, as well as the potential pitfalls in the reporting of these studies.

Deconstructing knowledge brokering for commissioned rapid reviews: an observational study.

BACKGROUND: Knowledge brokers are increasingly used by policy agencies, yet little is known about how they engage with policy-makers and facilitate discussions with them about their research needs. This study examines knowledge brokers' behaviour in one-off interactions with policy-makers commissioning rapid reviews. It describes how knowledge brokers engage with policy-makers, build trust and gain agreement about the review's parameters. METHODS: We observed and transcribed 15 structured knowledge brokering sessions and used line-by-line analysis to derive, test and refine a coding schedule. The final coding schedule was applied to all transcripts. We assigned 35 codes to three tasks identified in the data, namely eliciting information, exploring the policy context and negotiating the content of reviews. RESULTS: The knowledge brokers we observed were skilled facilitators who built trust by their open stance, neutrality, and knowledge of research and policy contexts. Trust engendered an interplay of expertise in which review questions and scope were clarified and contextual factors evaluated. Negotiation about the content of the review focused on understanding how it would contribute to the policy process, comparing options and assessing feasibility. Key functions of knowledge brokers included eliciting and clarifying information, linking the review questions to the context and purpose, moving fluidly between policy and research perspectives, and weighing up review options against policy objectives. Four knowledge brokering roles were identified, namely diagnostic, facilitative, deliberative and interpretative. CONCLUSIONS: This study identified ways in which knowledge brokers established rapport with policy-makers who commissioned reviews, enabled disclosure of essential information and explored contextual factors that affected the review's purpose and intended use. Knowledge brokers were competent in the discourse and conventions of both policy and research and were skilled in negotiating complex policy and political environments, assisting policy-makers to evaluate options and craft a review proposal that was targeted, responsive and feasible. Mutuality, respect and an interplay of expertise were integral to the knowledge brokering process. Future research might usefully examine whether other rapid review programmes using knowledge brokers have similar results as well as the transferability of the four knowledge brokering roles to other contexts and settings.

V/Q SPECT imaging of acute pulmonary embolus - a practical perspective.

The following article is intended to illustrate the place of scintigraphy and computed tomography pulmonary angiography (CTPA) in the investigation of acute PE in current practice, and to guide non-radionuclide radiologists and other medical professionals to the best test for patients. We share our early experiences with ventilation-perfusion (V/Q) single-photon-emission computed tomography (SPECT) including image acquisition and interpretation. A comparison of the two techniques is given, along with practical considerations in a variety of clinical scenarios.

Ultrasound findings of masses of the paratesticular space.

Ultrasound is a routine investigation for the assessment of scrotal masses. Many of the detected lesions involve the paratesticular structures. The most common paratesticular masses in clinical practice are epididymal cysts and spermatoceles, but there are a large number of other pathologies that can be encountered and may result in diagnostic uncertainty. This review covers a wide range of the common and the rare, but important, causes of paratesticular masses. The ultrasound findings (both typical and atypical) of these lesions are clarified, and emphasis is given to the features that help to differentiate between them.

The development of synovial joints.

During vertebrate evolution, successful adaptation of animal limbs to a variety of ecological niches depended largely on the formation and positioning of synovial joints. The function of a joint is to allow smooth articulation between opposing skeletal elements and to transmit biomechanical loads through the structure, and this is achieved through covering the ends of bones with articular cartilage, lubricating the joint with synovial fluid, using ligaments to bind the skeletal elements together, and encapsulating the joint in a protective fibrous layer of tissue. The diversity of limb generation has been proposed to occur through sequential branching and segmentation of precartilaginous skeletal elements along the proximodistal axis of the limb. The position of future joints is first delimited by areas of higher cell density called interzones initially through an as yet unidentified inductive signal, subsequently specification of these regions is controlled hierarchically by wnt14 and gdf5, respectively. Joint-forming cell fate although specified is not fixed, and joints will fuse if growth factor signaling is perturbed. Cavitation, the separation of the two opposing skeletal elements, and joint morphogenesis, the process whereby the joint cells organize and mature to establish a functional interlocking and reciprocally shaped joint, are slowly being unraveled through studying the plethora of molecules that make up the unique extracellular matrix of the forming structure. The joint lining tissue, articular cartilage, is avascular, and this limits its reparative capacity such that arthritis and associated joint pathologies are the single largest cause of disability in the adult population. Recent discoveries of adult stem cells and more specifically the isolation of chondroprogenitor cells from articular cartilage are extending available therapeutic options, though only with a more complete understanding of synovial joint development can such options have greater chances of success.

Microdamage and altered vascularity at the enthesis-bone interface provides an anatomic explanation for bone involvement in the HLA-B27-associated spondylarthritides and allied disorders.

OBJECTIVE: To describe the basis for entheseal-associated bone disease in the spondylarthritides, by analyzing microanatomic and histopathologic relationships between soft tissue, bone cortex, and adjacent trabeculae. METHODS: Serial sections from 52 entheses were examined; these entheses encompassed small and large insertions in the upper limb (n = 21), lower limb (n = 27), and spine (n = 4) from 60 cadavers. Enthesis microdamage (fissuring) as well as vascular and reparative changes were evaluated. Contact radiographs were used to ascertain the relationship between entheses and the trabecular network. RESULTS: At virtually all fibrocartilaginous entheses, the deep cortical boundary was extremely thin (typically 50-600 microm) or indistinguishable, and 96% of entheses had small holes in the cortical shell (typically 100-400 microm wide). Such regions were frequent sites of bone formation and renewal (96%) and microdamage (31%); these changes were more common in the lower limb. The presence of blood vessels near holes in the cortical shell was common; in 85% of attachments, blood vessels were present on the soft tissue side of the enthesis. Highly orientated trabeculae were more obvious in the lower limb than the upper limb (59% versus 29%). CONCLUSION: The trabecular network supporting the cortical shell is an integral part of the enthesis, transferring load to an extensive skeletal region. In many cases, tendons/ligaments are anchored directly to such networks. This functional integration is associated with microdamage and repair at the hard tissue-soft tissue interface. These findings have implications for understanding bone involvement in SpA and for the SpA concept in general, especially the hypothesis that enthesis-bone architecture may be important in disease initiation.

Developmental changes in the expression of calbindin and potassium-channel subunits Kv3.1b and Kv3.2 in mouse Renshaw cells.

One class of spinal interneurons, the Renshaw cells, is able to discharge at very high frequencies in adult mammals. Neuronal firing at such high frequencies requires voltage-gated potassium channels to rapidly repolarize the membrane potential after each action potential. We sought to establish the pattern of expression of calbindin and potassium channels with Kv3.1b and Kv3.2 subunits in Renshaw cells at different developmental stages of postnatal mice. The pattern of expression of calbindin changed dramatically during early postnatal development. An adult pattern of calbindin reactive neurons started to emerge from postnatal day 10 to postnatal day 14, with cells in laminae I and II of superficial dorsal horn and the ventral lamina VII. Renshaw cells were identified immunohistochemically by their expression of calbindin and their location in the ventral horn of the spinal cord. Western blot results of the lumbar spinal cord showed that Kv3.1b expression became faintly evident from postnatal day 10, reached a maximum at postnatal day 21 and was maintained through postnatal day 49. Double labeling results showed that all Renshaw cells expressed Kv3.1b weakly from postnatal day 14, and strongly at postnatal day 21. Western blot results showed that Kv3.2 expression became detectable in the lumbar cord from postnatal day 12, and increased steadily until reaching an adult level at postnatal day 28. In contrast to the Kv3.1b results, Kv3.2 was not expressed in Renshaw cells, although some neurons located at laminae VIII and VI expressed Kv3.2. We conclude that Renshaw cells express Kv3.1b but not Kv3.2 from postnatal day 14.

Current strategies for articular cartilage repair.

Defects of articular cartilage that do not penetrate to the subchondral bone fail to heal spontaneously. Defects that penetrate to the subchondral bone elicit an intrinsic repair response that yields a fibrocartilaginous repair tissue which is a poor substitute for hyaline articular cartilage. Many arthroscopic repair strategies employed utilise this intrinsic repair response to induce the formation of a repair tissue within the defect. The goal, however, is to produce a repair tissue that has the same functional and mechanical properties of hyaline articular cartilage. To this end, autologous osteochondral transfer can provide symptomatic relief. This technique involves the excision of healthy cartilage plugs from 'non-load bearing' regions of the joint for implantation into the defect. Cell based transplantation methods currently involve the transplantation of expanded autologous chondrocytes to the defects to form a repair tissue. This technique again involves the excision of healthy cartilage from the joint for expansion. Current research is exploring the potential use of mesenchymal stem cells as a source for tissue engineering, as well as the combination of cells with biodegradable scaffolds. Although current repair strategies improve joint function, further research is required to prevent future degeneration of repair tissue.

Adipose tissue at entheses: the rheumatological implications of its distribution. A potential site of pain and stress dissipation?

OBJECTIVES: To describe the distribution of adipose tissue within and adjacent to entheses in order to assess its functional significance at attachment sites. METHODS: Entheses were removed from 29 different sites in the limbs of formalin fixed, elderly, dissecting room cadavers and the samples prepared for paraffin and/or methylmethacrylate histology. Entheses from four young volunteers with no history of significant musculoskeletal injury were examined by magnetic resonance imaging using T(1) weighted sequences. RESULTS: Adipose tissue was present at several different sites at numerous entheses. Many tendons/ligaments lay on a bed of well vascularised, highly innervated, "insertional angle fat". Endotenon fat was striking between fascicles, where entheses flared out at their attachments. It was also characteristic of the epitenon, where it occurred in conjunction with lamellated and Pacinian corpuscles. Fat filled, meniscoid folds often protruded into joint cavities, immediately adjacent to attachment sites. CONCLUSION: Adipose tissue is a common feature of normal entheses and should not be regarded as a sign of degeneration. It contributes to the increase in surface area of attachment sites, promotes movement between tendon/ligament and bone, and forms part of an enthesis organ that dissipates stress. The presence of numerous nerve endings in fat at attachment sites suggests that it has a mechanosensory role and this could account for the rich innervation of many entheses. Because damage to fat is known to lead to considerable joint pain, our findings may be important for understanding the site of pain in enthesopathies.

The "enthesis organ" concept: why enthesopathies may not present as focal insertional disorders.

OBJECTIVE: The Achilles tendon insertion is associated with a complex of adjacent fibrocartilages, a bursa, and a fat-pad, and is functionally much more than a focal insertion. This has important implications for a better understanding of the spondylarthropathies (SpA). However, the degree to which other insertions form comparable "enthesis organs" has not been established. The aim of this study was to demonstrate the applicability of the enthesis organ concept to other insertion sites. METHODS: Both joint-related (articular) and extraarticular entheses were removed from 28 sites in the limbs of formalin-fixed cadavers (age at death 70-101 years) that had been donated for anatomic study. The samples were prepared for paraffin histologic analysis and sectioned longitudinally. The presence and extent of enthesis organs was evaluated at each site in serial sections stained with Masson's trichrome and toluidine blue. RESULTS: Articular enthesis organs were found at 14 entheses, including the attachments of the digital extensor tendons and collateral ligaments, the cruciate ligaments, tibialis anterior, the lateral collateral ligament of the knee, and the popliteal tendon. Extraarticular enthesis organs were seen at 2 sites, the biceps brachii and patellar tendon insertions. In all enthesis organs, sesamoid and/or periosteal fibrocartilage was present in close association with synovium. CONCLUSION: The concept of an enthesis organ is of general significance in understanding attachment sites and may explain the diverse pathologic changes, including synovitis, bursitis, and extracapsular changes, seen adjacent to tendon/ligament entheses in SpA. These findings may provide insight into the reason the target tissues in SpA are apparently so diverse.

Molecular composition and pathology of entheses on the medial and lateral epicondyles of the humerus: a structural basis for epicondylitis.

OBJECTIVES: To improve the understanding of epicondylitis by describing the normal structure and composition of the entheses associated with the medial and lateral epicondyles and their histopathology in elderly cadavers. METHODS: Medial and lateral epicondyles were obtained from 12 cadavers. Six middle aged cadavers (mean 47 years) were used to assess the molecular composition of "normal" entheses from people within an age range vulnerable to epicondylitis. Cryosections of epicondylar entheses were immunolabelled with monoclonal antibodies against molecules associated with fibrocartilage and related tissues. A further six elderly cadavers (mean 84 years) were used for histology to assess features of entheses related to increasing age. RESULTS: Tendon entheses on both epicondyles fused with those of the collateral ligaments and formed a more extensive structure than hitherto appreciated. Fibrocartilage (which labelled for type II collagen and aggrecan) was a constant feature of all entheses. Entheses from elderly subjects showed extensive microscopic damage, hitherto regarded as a hallmark of epicondylitis. CONCLUSIONS: Fibrocartilage is a normal feature and not always a sign of enthesopathy. Furthermore, pathological changes documented in patients with epicondylitis may also be seen in elderly people. The fusion of the common extensor and flexor tendon entheses with those of the collateral ligaments suggests that the latter may be implicated as well. This may explain why pain and tenderness in epicondylitis may extend locally beyond the tendon enthesis and why some patients are refractory to local treatments.

A cost-effective approach to the development of printed materials: a randomized controlled trial of three strategies.

Printed materials have been a primary mode of communication in public health education. Three major approaches to the development of these materials--the application of characteristics identified in the literature, behavioral strategies and marketing strategies--have major implications for both the effectiveness and cost of materials. However, little attention has been directed towards the cost-effectiveness of such approaches. In the present study, three pamphlets were developed using successive addition of each approach: first literature characteristics only ('C' pamphlet), then behavioral strategies ('C + B' pamphlet) and then marketing strategies ('C + B + M' pamphlet). Each pamphlet encouraged women to join a Pap Test Reminder Service (PTRS). Each pamphlet was mailed to a randomly selected sample of 2700 women aged 50-69 years. Registrations with the PTRS were monitored and 420 women in each pamphlet group were surveyed by telephone. It was reported that the 'C + B' and 'C + B + M' pamphlets were significantly more effective than the 'C' pamphlet. The 'C + B' pamphlet was the most cost-effective of the three pamphlets. There were no significant differences between any of the pamphlet groups on acceptability, knowledge or attitudes. It was suggested that the inclusion of behavioral strategies is likely to be a cost-effective approach to the development of printed health education materials.

The cellular responses of articular cartilage to sharp and blunt trauma.

OBJECTIVE: To determine the response of immature articular cartilage to both sharp and blunt trauma in terms of cell death, cell proliferation and matrix synthesis. DESIGN: Blunt wounds were made with a trephine in full depth immature bovine articular cartilage explants which were cut in half through the center of the trephine wound with a sharp scalpel to produce blunt and sharp trauma on the same explant. Explants were maintained in culture for up to 10 days. Prior to fixation at days 2, 5 and 10, medium was supplemented with 10 microCi ml-1 35S-sulphate, [3H]-proline or [3H]-thymidine for 24h to assess matrix synthesis and cell proliferation. Cell death was assessed using a Live/Dead label. RESULTS: In the case of blunt wounds, a band of cell death was observed adjacent to the lesion edge. Microautoradiography demonstrated little radiolabel incorporation and, therefore, no new matrix synthesis or cell proliferation within this region. In contrast, wounds made with a sharp scalpel showed restricted cell death, with radiolabel incorporation adjacent to the lesion edge at all time points. This demonstrated not only chondrocyte proliferation and new matrix synthesis at the wound margin, but also an up-regulation of matrix synthesis adjacent to the lesion edge. CONCLUSIONS: In terms of clinical relevance, the use of sharp precise instruments during the surgical management of cartilage defects may be necessary to reduce cell death and promote matrix elaboration at the lesion edge in order to facilitate successful integration.

Print material content and design: is it relevant to effectiveness?

Printed materials are widely used in cancer education. There are a considerable number of guidelines in the literature on the content and design characteristics of print materials. However, there is little outcome-based evidence about whether materials containing these characteristics are more effective under real-world conditions. Six pamphlets were designed such that two had most of these characteristics, one had content characteristics only, one had design characteristics only and two had few of the characteristics. The pamphlets encouraged women aged 50-69 years to join a Pap Test Reminder Service (PTRS). The pamphlets were mailed to a randomly selected sample of 7668 women. Registrations with the PTRS were monitored. Receipt, readership, acceptability, knowledge and attitudes were assessed by telephone interview. There were no significant differences between the pamphlet groups in registrations with the PTRS, receipt, readership, acceptability, knowledge or attitudes. It was concluded that the inclusion of content and design characteristics does not result in more effective print materials.

The phosphoinositide 3-kinase and p70 S6 kinase regulate long-term potentiation in hippocampal neurons.

The mechanisms by which long-term changes in synaptic efficacy (e.g., long-term potentiation) are maintained are not well understood. There is evidence that reorganization of the neuronal actin cytoskeleton is important for consolidation of long-term potentiation. In non-neuronal cells, phosphoinositide 3-kinase and p70 S6 kinase have been shown to regulate actin polymerization. We have investigated the subcellular localization of these enzymes in cultured hippocampal pyramidal neurons and their possible role in hippocampal long-term potentiation. Immunohistochemical analysis revealed enrichment of both enzymes in the growth cones and filopodia of extending neurites, whereas p70 S6 kinase was also present at the soma. Antibodies to the phosphorylated form of p70 S6 kinase confirmed its activity in these locations. Interestingly, both enzymes displayed strong colocalization with F-actin in discrete regions of developing neurites. In hippocampal slices, the maintenance of long-term potentiation was attenuated by either rapamycin or 2-(4-morpholinyl)-8-phenyl-1(4H)-1-benzopyran-4-one, inhibitors of p70 S6 kinase and phosphoinositide 3-kinase, respectively. Our findings provide evidence for a novel biochemical pathway involving phosphoinositide 3-kinase and p70 S6 kinase that is important for the maintenance of hippocampal long-term potentiation, possibly via regulation of actin dynamics.

Investigating breast symptoms in primary care: enhancing concordance with current best advice.

The purpose of this study was to determine whether a targeted intervention could improve primary care practitioners' concordance with guidelines regarding management of women with breast symptoms. One hundred and twelve practitioners from randomly selected areas around Australia prospectively audited their investigations for each woman with a new breast symptom over two 12-week periods, before and five months after the release of national guidelines. Between the two audits, doctors received feedback on practice in relation to peers and attended one seminar in their local areas led by specialists from the Royal Australasian College of Physicians and the Royal Australasian College of Surgeons. For five recommendations, there were statistically significant improvements at the second audit in line with standard Investigation of a New Breast Symptom (INBS) guidelines. All these were for investigations of breast lumps. At first audit, there were seven recommendations where practitioners were already managing more than 80% of women in accordance with the INBS, and where there were no statistically significant increases in concordance at second audit. Another six recommendations had lower concordance with the recommendations prior to the release of the guidelines and did not significantly improve at second audit. These tended to be for less-common presentations and where clinical findings were not consistent with other test results. We concluded that a targeted intervention improved physician concordance with current best advice for investigating women who present with new breast symptoms in a primary care setting. Further educational programs are needed to improve investigations for rarer symptoms, and to enhance physicians' confidence in the results of their clinical examinations.

Differences in repair responses between immature and mature cartilage.

Cartilage has a poor reparative capacity although it is unclear as to what extent this may be dependent on age or maturation. In the current study, the cellular responses of chondrocytes to experimental wounding in vitro using embryonic, immature, and mature cartilage have been compared. In all cases, the response was consistent (a combination of cell death that included apoptosis and proliferation). The speed of response varied in terms of cell death with embryonic cartilage showing the most rapid response and mature cartilage showing the slowest response. Intrinsic repair as assessed by the ability to heal the lesion was not detected in any of the culture systems used. It was concluded that the poor repair potential of cartilage is not maturation dependent in the systems studied.