Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain.

OBJECTIVES: Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia. METHODS: The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12-hydroxy-eicosatetraenoic acid (12-HETE), were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied. RESULTS: We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical stimulation of the knee. Local administration of JNJ-17203212 reversed this sensitisation of joint afferents and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ-17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for increased TRPV1 function in the spinal cord in this model of OA pain. CONCLUSIONS: Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain.

Distinct subdivisions of the cingulum bundle revealed by diffusion MRI fibre tracking: implications for neuropsychological investigations.

The cingulum is a prominent white matter tract that supports prefrontal, parietal, and temporal lobe interactions. Despite being composed of both short and long association fibres, many MRI-based reconstructions (tractography) of the cingulum depict an essentially uniform tract that almost encircles the corpus callosum. The present study tested the validity of dividing this tract into subdivisions corresponding to the 'parahippocampal', 'retrosplenial', and 'subgenual' portions of the cingulum. These three cingulum subdivisions occupied different medial-lateral locations, producing a topographic arrangement of cingulum fibres. Other comparisons based on these different reconstructions indicate that only a small proportion of the total white matter in the cingulum traverses the length of the tract. In addition, both the radial diffusivity and fractional anisotropy of the subgenual subdivision differed from that of the retrosplenial subdivision which, in turn, differed from that of the parahippocampal subdivision. The extent to which the radial diffusivity scores and the fractional anisotropy scores correlated between the various cingulum subdivisions proved variable, illustrating how one subdivision may not act as a proxy for other cingulum subdivisions. Attempts to relate the status of the cingulum, as measured by MRI-based fibre tracking, with cognitive or affective measures will, therefore, depend greatly on how and where the cingulum is reconstructed. The present study provides a new framework for subdividing the cingulum, based both on its known connectivity and MRI-based properties.

Localization of neurones expressing the gap junction protein Connexin45 within the adult spinal dorsal horn: a study using Cx45-eGFP reporter mice.

Connexin (Cx) proteins localized to neuronal and glial syncytia provide the ultrastructural components for intercellular communication via gap junctions. In this study, a Cx45 reporter mouse model in which the Cx45 coding sequence is substituted for enhanced green fluorescent protein (eGFP) was used to characterize Cx45 expressing neurones within adult mouse spinal cord. eGFP-immunoreactive (eGFP-IR) cells were localized at all rostro-caudal levels to laminae I-III of the dorsal horn (DH), areas associated with nociception. The neuronal rather than glial phenotype of these cells in DH was confirmed by co-localisation of eGFP-IR with the neuronal marker NeuN. Further immunohistochemical studies revealed that eGFP-IR interneurones co-express the calcium-binding protein calbindin, and to a lesser extent calretinin. In contrast, eGFP-IR profiles did not co-localize with either parvalbumin or GAD-67, both of which are linked to inhibitory interneurones. Staining with the primary afferent markers isolectin-B4 (IB4) and calcitonin gene-related peptide revealed that eGFP-IR somata within laminae I-III receive close appositions from the former, presumed non-peptidergic nociceptive afferents of peripheral origin. The presence of 5-HT terminals in close apposition to eGFP-IR interneuronal somata suggests modulation via descending pathways. These data demonstrate a highly localized expression of Cx45 in a population of interneurones within the mouse superficial dorsal horn. The implications of these data in the context of the putative role of Cx45 and gap junctions in spinal somatosensory processing and pain are discussed.

Kv3.1b and Kv3.3 channel subunit expression in murine spinal dorsal horn GABAergic interneurones.

GABAergic interneurones, including those within spinal dorsal horn, contain one of the two isoforms of the synthesizing enzyme glutamate decarboxylase (GAD), either GAD65 or GAD67. The physiological significance of these two GABAergic phenotypes is unknown but a more detailed anatomical and functional characterization may help resolve this issue. In this study, two transgenic Green Fluorescent Protein (GFP) knock-in murine lines, namely GAD65-GFP and GAD67-GFP (Δneo) mice, were used to profile expression of Shaw-related Kv3.1b and Kv3.3 K(+)-channel subunits in dorsal horn interneurones. Neuronal expression of these subunits confers specific biophysical characteristic referred to as 'fast-spiking'. Immuno-labelling for Kv3.1b or Kv3.3 revealed the presence of both of these subunits across the dorsal horn, most abundantly in laminae I-III. Co-localization studies in transgenic mice indicated that Kv3.1b but not Kv3.3 was associated with GAD65-GFP and GAD67-GFP immunopositive neurones. For comparison the distributions of Kv4.2 and Kv4.3 K(+)-channel subunits which are linked to an excitatory neuronal phenotype were characterized. No co-localization was found between GAD-GFP +ve neurones and Kv4.2 or Kv4.3. In functional studies to evaluate whether either GABAergic population is activated by noxious stimulation, hindpaw intradermal injection of capsaicin followed by c-fos quantification in dorsal horn revealed co-expression c-fos and GAD65-GFP (quantified as 20-30% of GFP +ve population). Co-expression was also detected for GAD67-GFP +ve neurones and capsaicin-induced c-fos but at a much reduced level of 4-5%. These data suggest that whilst both GAD65-GFP and GAD67-GFP +ve neurones express Kv3.1b and therefore may share certain biophysical traits, their responses to peripheral noxious stimulation are distinct.

Cognitive dysfunction in intensive care survivors.

Cognitive dysfunction is increasingly recognized as a common, often prolonged and potentially disabling complication of critical illness. While demonstrable in patients who have survived a variety of both medical and surgical conditions, its causes remain unclear. Screening of patients in intensive care units and at follow up may help identify those who could benefit from cognitive rehabilitation.

Retrospective analysis of an implant system.

The reliability of dental implants results from a combination of design, placement, and reconstructive techniques. Retrospective analysis is one vehicle for evaluating implant success. This article presents the reliability of these techniques in Bicon dental implants. The survivability of this implant was evaluated retrospectively using life table survival analysis over a 10-year period in 13 practices. The parameters used for success included no implant loss, no mobility, no continuing bone loss that did not stabilize after 1 year, no discomfort, and no purulence.

Replacing posterior teeth with freestanding implants: four-year prosthodontic results of a prospective study.

This article presents prospective four-year prosthetic results of the placement of 432 posterior freestanding, conventionally cemented prosthetic tooth implants in posterior edentulous spaces using the Bicon Dental Implants system (Bicon Dental Implants). Over four years, 0.74 percent of the abutments loosened, 0.5 percent of the abutments fractured, and 2.47 percent of the crowns experienced porcelain fracture, (all porcelain fractures occurred at time of placement). This low rate of problems appears to make free-standing single-tooth implant restorations a reliable solution to treating posterior edentulism.

The locking taper attachment for implant abutments: use and reliability.

The locking taper abutment attachment for implants is a one and one-half-degree tapered post that relies on friction rather than a screw for retention of the abutment to the implant. A retrospective analysis of 1,757 consecutively loaded implants was made to determine the reliability of the locking taper abutment. Five hundred and four implants restored over a 7-year period from one practice and a total of 1,253 implants restored over 4 years from 2 practices were reviewed. Nine abutment posts fractured for a failure rate of 0.05 percent. Thirty one (1.7 percent) of the abutments loosened but were reinserted without further problems. The technique for use of the locking taper implant abutment attachment is described.

Angulation assessment of anterior single tooth root form implants: technical note.

A technique is presented to evaluate the angulation and position of an anterior single tooth root form implant by means of a surgical template, a pilot osteotomy, and an abutment guide. The space available for the restorative materials can be assessed and the angulation modified, if necessary, to improve the esthetic potential. If the angulation is satisfactory and sufficient room is available for the prosthesis, the surgeon can continue with implant placement at the initial site.

Relative production of IL-1 beta and TNF alpha by mononuclear cells after exposure to dental implants.

Interleukin-1 (also known as osteoclast activating factor, OAF) is a cytokine produced primarily by monocytes and macrophages and is thought to mediate many of the immunologic, metabolic, and endocrine alterations seen with microbial infection, tissue injury, inflammatory disease, and bone loss. Stimuli for IL-1 production include microorganisms, endotoxins (LPS), antigen-antibody complexes, clotting components, and other cytokines. The purpose of this study was to determine whether dental implants stimulated peripheral blood mononuclear cells (PBMCs) to produce IL-1 beta (OAF) as well as tumor necrosis factor (TNF alpha). This production may lead to bone loss or failure of an implant. Three duplicates of five different implants were incubated with 2 x 10(6) PBMCs/ml in 20% autologous serum; the esterase positive PBMCs amounted to 14.5%. Measured by radioimmunoassay techniques and compared to controls, all of the implants except one caused significant in vitro generation of IL-1 beta and TNF alpha. The stimulation of IL-1 beta/TNF alpha production by these materials suggests that they are not physiologically inert and that the IL-1 beta (OAF) production may contribute to a less favorable osseoadaptation. OAF has a physiologic (homeostatic) role in maintenance and alteration of osseous structures, but the level at which physiologic becomes pathologic is unknown. Although there were statistical differences between the cellular response to these implants, the clinical significance of the differences remains to be determined.

Occlusal contact variation with changes in head position.

Ten healthy young adults were examined for changes in occlusal contacts related to three head positions: supine, sitting, and head forward. The contacts were analyzed using T-Scan special research software, which measured the time moments of the first five occlusal contacts. Time moment is a descriptive term calculated from a formula that considers both spatial (where contacts are) and temporal (when contact occurs) aspects of tooth contact and provides a quantitative basis for comparing the dynamics of tooth contact. Paired head positions were analyzed for differences using Student's t test, and it appears that in healthy young adults, initial tooth contacts are substantially influenced by posture.

A comparison of mandibular denture base extension in conventional and implant-retained dentures.

A border outline for mandibular implant-retained dentures is described. The lingual extension of the impression is greatly reduced compared with a conventional mandibular denture. Because of the implant attachment, the shortened border is more comfortable and does not compromise denture retention. Improper implant position is also discussed with respect to denture extension.

Variations in occlusal forces with a resilient internal implant shock absorber.

The importance of an internal shock absorber for implant prostheses has concerned many, primarily because the efficacy of a shock absorber to reduce stress has not been demonstrated in vivo. This study examined 15 subjects with unilateral distal extension single implant abutments attached to a single natural tooth abutment to assess the effect of a shock-absorbing element within the implant on occlusal force levels. Occlusal forces and bilateral occlusal similarity were examined using specially adapted research software for the T-Scan occlusal analysis system. The results indicate that there is a significant difference (P less than 0.011) between occlusal forces using an internal shock absorber (18 N) and a titanium internal element (30 N).

Non-surgical embryo transfer and live birth in a llama.

The uteri of two donor female llamas were flushed non-surgically and one viable 7-day-old embryo was recovered. The embryo was transferred non-surgically within four hours into a recipient female llama whose estrous cycle was synchronized with the donor by injection of gonadotropin releasing hormone (GnRH). Pregnancy was confirmed 20 days after transfer, at which time the level of serum progesterone was determined and found to be consistent with that of gestation (>/=100 ng/100 ml). A normal and healthy male weighing 33 1bs was born on October 8, 1984, 326 days following transfer of the embryo to the recipient.

Excessive wear of natural tooth structure by opposing composite restorations.

Extreme care must be taken to evaluate the probable effect of using certain restorative materials to oppose existing tooth structure, particularly when dentin is exposed. In addition, frequent recall examination, every one or two months, is necessary to catch any problems in their beginning stages and to solve them before greater damage can be caused. It is also suggested that evaluation of any occlusal habits be made before deciding on a plan to alter vertical dimension and to carefully consider the effects of the materials used in a restoration on the opposing arch.

The cooperative information project: Part 2: some initial clinical, quality assurance, and practice management studies.

Many of the obstacles inherent in the conduct of primary care research have been overcome by an experimental program in northern New England, the Primary Care Cooperative Information Project. This project uses a medical information network in 44 rural medical practices to carry out both clinical and management research. This paper describes the developmental problems encountered and the results of some initial clinical, quality assurance, and practice management studies conducted by the network and presents observations on its future research directions.