Temperature-Mediated Neural Interventions in Knee Osteoarthritis: a Review of Cryoneurolysis and Cooled Radiofrequency Ablation with Ultrasound Guidance.

PURPOSE OF REVIEW: Knee osteoarthritis is a debilitating chronic disease affecting nearly half of the world's population at some point in their lives. Treatment of pain and loss of function associated with this disease has been limited. In this review, we seek to explore how neural interventions with ultrasound guidance may be an emerging option for non-pharmacologic pain relief in patients with knee osteoarthritis. RECENT FINDINGS: Cryoneurolysis techniques have been demonstrated to provide pain relief out to 150 days post-treatment in knee osteoarthritis in select individuals. There have also been studies of cryoneurolysis pre-operatively to total knee replacement providing reduced pain, reduced opioid use post-operatively, and shorter hospital length of stay. Cooled radiofrequency ablation (CRFA) has been demonstrated to significantly reduce pain, improve functionality, and reduce pharmacologic needs in knee osteoarthritis out to 2 years. Both interventions appear to have increased accuracy with ultrasound, and CRFA appears to be associated with improved patient outcomes. The research demonstrates the efficacy of both cryoneurolysis and cooled radiofrequency ablation in the treatment of knee osteoarthritis. Ultrasound guidance in neurolysis provides an additional tool with real-time, high-accuracy nerve localization. These therapies should be considered for certain patients to assist in pain management in the non-operative and post-operative phase of knee osteoarthritis management. Further research is needed to further define the long-term effects and the long-term utility of the techniques in knee pain.

Ultrasound Doppler and tenosynovial fluid analysis in tenosynovitis.

OBJECTIVE: To assess Doppler ultrasound (US) and tenosynovial fluid (TSF) characteristics in tenosynovitis within common rheumatic conditions, as well as their diagnostic utility. METHODS: Subjects with tenosynovitis underwent Doppler US and US-guided TSF aspiration for white cell count (WCC) and crystal analysis. Tenosynovial Doppler scores (DS) were semiquantitatively graded. TSF WCC and DS were compared using Kruskal-Wallis tests and logistic regression between non-inflammatory conditions (NIC), inflammatory conditions (IC) and crystal-related conditions (CRC). Receiver operating curves, sensitivity and specificity assessed the ability of WCC and DS to discriminate IC from NIC. RESULTS: We analysed 100 subjects from 14 sites. The mean age was 62 years, 65% were female, and the mean TSF volume was 1.2 mL. Doppler signal was present in 93.7% of the IC group and was more frequent in IC than in NIC group (OR 6.82, 95% CI 1.41 to 32.97). The TSF median WCC per 109/L was significantly higher in the IC (2.58, p<0.001) and CRC (1.07, p<0.01) groups versus the NIC group (0.38). A TSF cut-off of ≥0.67 WCC per 109/L optimally discriminated IC versus NIC with a sensitivity and specificity each of 81.3%. In the IC group, 20 of 48 (41.7%) subjects had a TSF WCC <2.00 per 109/L. CONCLUSIONS: A negative DS helps rule out IC in tenosynovitis, but a positive DS is non-specific and merits TSF testing. Unlike synovial fluid, a lower TSF WCC better discriminates IC from NIC. US guidance facilitates aspiration of minute TSF volume, which is critical for diagnosing tenosynovial CRC.

Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage.

Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO(3)). Intravenous (IV) administration of NaIO(3) up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5-20 mg/kg) produced concentration-dependent changes in visual function as measured by full-field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1-P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with ≥10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration-dependent outer retinal damage that correlates with functional changes. We conclude that NaIO(3,) is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration-dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors.

Stimulation via a subretinally placed prosthetic elicits central activity and induces a trophic effect on visual responses.

PURPOSE: Subretinal prosthetics are designed to electrically stimulate second-order cells, replacing dysfunctional photoreceptors in diseases such as retinitis pigmentosa (RP). For functional vision to occur, this signal must also reach central visual structures. In the current study, a subretinally implanted prosthetic was evaluated in the Royal College of Surgeons (RCS) rat model of RP, to determine its capacity to activate the retinotectal pathway. METHODS: Prosthetic implants were placed in RCS and wild-type (WT) rats at 4 weeks of age and evaluated 3 months later. Control rats underwent sham surgery, implantation with inactive prosthetics, or no treatment. Implant- and visible-evoked responses were isolated and evaluated in the superior colliculus (SC). RESULTS: In WT and RCS rats with active prosthetics, implant-driven responses were found in 100% of WT and 64% of RCS rats and were confined to a small SC region that corresponded to the retinal sector containing the implant and differed from visible-evoked responses. In addition, visible-evoked responses were more robust at sites that received implant input compared to sites that did not. These effects were not seen in WT rats or RCS control animals; although a general trophic effect on the number of responsive sites was observed in all RCS rats with surgery compared to untreated RCS rats. CONCLUSIONS: Direct activation of the retina by a subretinal implant induces activity in the SC of RCS rats, suggesting that these implants have some capacity to replace dysfunctional photoreceptors. The data also provide evidence for implant-induced neurotrophic effects as a consequence of both its presence and its activity in the retina.

Progression of Pro23His Retinopathy in a Miniature Swine Model of Retinitis Pigmentosa.

PURPOSE: We characterize the progression of retinopathy in Filial 1 (F1) progeny of a transgenic (Tg) founder miniswine exhibiting severe Pro23His (P23H) retinopathy. METHODS: The F1 TgP23H miniswine progeny were created by crossing TgP23H founder miniswine 53-1 with wild type (WT) inbred miniature swine. Scotopic (rod-driven) and photopic (cone-driven) retinal functions were evaluated in F1 TgP23H and WT littermates using full field electroretinograms (ffERGs) at 1, 2, 3, 6, 9, 12, and 18 months of age, as well as the Tg founder miniswine at 6 years of age. Miniswine were euthanized and their retinas processed for morphologic evaluation at the light and electron microscopic level. Retinal morphology of a 36-month-old Tg miniswine also was examined. RESULTS: Wild type littermates reached mature scotopic and photopic retinal function by 3 months, while TgP23H miniswine showed abnormal scotopic ffERGs at the earliest time point, 1 month, and depressed photopic ffERGs after 2 months. Rod and cone photoreceptors (PR) exhibited morphologic abnormalities and dropout from the outer nuclear layer at 1 month, with only a monolayer of cone PR somata remaining after 2 months. The retinas showed progressive neural remodeling of the outer retina that included dendritic retraction of rod bipolar cells and glial seal formation by Müller cells. The TgP23H founder miniswine showed cone PR with relatively intact morphology exclusive to the area centralis. CONCLUSIONS: The F1 Tg miniswine and the TgP23H founder miniswine exhibit similar retinopathy. TRANSLATIONAL RELEVANCE: TgP23H miniswine are a useful large-eye model to study pathogenesis and preservation cone PRs in humans with retinitis pigmentosa.

Cone photoreceptors develop normally in the absence of functional rod photoreceptors in a transgenic swine model of retinitis pigmentosa.

PURPOSE: Human and swine retinas have morphological and functional similarities. In the absence of primate models, the swine is an attractive model to study retinal function and disease, with its cone-rich visual streak, our ability to manipulate their genome, and the differences in susceptibility of rod and cone photoreceptors to disease. We characterized the normal development of cone function and its subsequent decline in a P23H rhodopsin transgenic (TgP23H) miniswine model of autosomal dominant RP. METHODS: Semen from TgP23H miniswine 53-1 inseminated domestic swine and produced TgP23H and Wt hybrid littermates. Retinal function was evaluated using ERGs between postnatal days (P) 14 and 120. Retinal ganglion cell (RGC) responses were recorded to full-field stimuli at several intensities. Retinal morphology was assessed using light and electron microscopy. RESULTS: Scotopic retinal function matures in Wt pigs up to P60, but never develops in TgP23H pigs. Wt and TgP23H photopic vision matures similarly up to P30 and diverges at P60 where TgP23H cone vision declines. There are fewer TgP23H RGCs with visually evoked responses at all ages and their response to light is compromised. Photoreceptor morphological changes mirror these functional changes. CONCLUSIONS: Lack of early scotopic function in TgP23H swine suggests it as a model of an aggressive form of RP. In this mammalian model of RP, normal cone function develops independent of rod function. Therefore, its retina represents a system in which therapies to rescue cones can be developed to prolong photopic visual function in RP patients.

Musculoskeletal ultrasound objective structured clinical examination: an assessment of the test.

OBJECTIVE: To determine the reliability and validity of an objective structured clinical examination (OSCE) for musculoskeletal ultrasound (MSUS). METHODS: A 9-station OSCE was administered to 35 rheumatology fellows trained in MSUS and to 3 expert faculty (controls). Participants were unaware of joint health (5 diseased/4 healthy). Faculty assessors (n = 9) graded image quality with predefined checklists and a 0-5 global rating, blinded to who performed the study. Interrater reliability, correlation between a written multiple choice question examination (MCQ) and OSCE performance, and comparison of fellow OSCE results with those of the faculty were measured to determine OSCE reliability, concurrent validity, and construct validity. RESULTS: Assessors' interrater reliability was good (intraclass correlation coefficient [ICC] 0.7). Score reliability was good in the normal wrist and ankle stations (ICC 0.7) and moderate in the abnormal wrist and ankle stations (ICC 0.4). MCQ grades significantly correlated with OSCE grades (r = 0.52, P < 0.01). The fellows in the bottom quartile of the MCQ scored 3.07 on the OSCE, significantly worse than the top quartile fellows (3.32) and the faculty (3.29; P < 0.01). Scores also significantly discriminated bottom quartile fellows from faculty in the normal wrist and ankle stations (3.38 versus 3.78; P < 0.01), but not in the abnormal stations (3.37 versus 3.49; P = 0.08). CONCLUSION: MSUS OSCE is a reliable and valid method for evaluation of MSUS skill. Normal joint assessment stations are more reliable than abnormal joint assessment stations and better discriminate poorly performing fellows from faculty. Therefore, MSUS OSCE with normal joints can be used for the assessment of MSUS skill competency.

Generation of an inbred miniature pig model of retinitis pigmentosa.

PURPOSE: The Pro23His (P23H) rhodopsin (RHO) mutation underlies the most common form of human autosomal dominant retinitis pigmentosa (adRP). The objective of this investigation was to establish a transgenic miniature swine model of RP using the human P23H RHO gene. METHODS: Somatic cell nuclear transfer (SCNT) was used to create transgenic miniature pigs that expressed the human P23H RHO mutation. From these experiments, six transgenic founders were identified whose retinal function was studied with full-field electroretinography (ffERG) from 3 months through 2 years. Progeny from one founder were generated and genotyped to determine transgene inheritance pattern. Retinal mRNA was isolated, and the ratio of P23H to wild-type pig RHO was measured. RESULTS: A single transgene integration site was observed for five of the six founders. All founders had abnormal scotopic and photopic ffERGs after 3 months. The severity of the ffERG phenotype was grouped into moderately and severely affected groups. Offspring of one founder inherited the transgene as an autosomal dominant mutation. mRNA analyses demonstrated that approximately 80% of total RHO was mutant P23H. CONCLUSIONS: Expression of the human RHO P23H transgene in the retina creates a miniature swine model with an inheritance pattern and retinal function that mimics adRP. This large-animal model can serve as a novel tool for the study of the pathogenesis and therapeutic intervention in the most common form of adRP.

Selective rod degeneration and partial cone inactivation characterize an iodoacetic acid model of Swine retinal degeneration.

PURPOSE. Transgenic pigs carrying a mutant human rhodopsin transgene have been developed as a large animal model of retinitis pigmentosa (RP). This model displays some key features of human RP, but the time course of disease progression makes this model costly, time consuming, and difficult to study because of the size of the animals at end-stage disease. Here, the authors evaluate an iodoacetic acid (IAA) model of photoreceptor degeneration in the pig as an alternative model that shares features of the transgenic pig and human RP. METHODS. IAA blocks glycolysis, thereby inhibiting photoreceptor function. The effect of the intravenous injection of IAA on swine rod and cone photoreceptor viability and morphology was followed by histologic evaluation of different regions of the retina using hematoxylin and eosin and immunostaining. Rod and cone function was analyzed by full-field electroretinography and multifocal electroretinography. RESULTS. IAA led to specific loss of rods in a central-to-peripheral retinal gradient. Although cones were resistant, they showed shortened outer segments, loss of bipolar cell synaptic connections, and a diminished flicker ERG, hallmarks of transition to cone dysfunction in RP patients. CONCLUSIONS. IAA provides an alternative rod-dominant model of retinal damage that shares a surprising number of features with the pig transgenic model of RP and with human RP. This IAA model is cost-effective and rapid, ensuring that the size of the animals does not become prohibitive for end-stage evaluation or therapeutic intervention.

Gout in the axial skeleton.

OBJECTIVE: Gout typically affects the peripheral joints of the appendicular skeleton and rarely involves the axial joints. The literature on axial gout is limited to case reports and case series. This preliminary study was conducted to identify the frequency and characteristics of axial gout. METHODS: Six hundred thirty medical records with ICD codes 274.0, 274.82, and 274.9 for peripheral gout were reviewed. Ninety-two patients had clinical or crystal-proven gout, of which 64 had prior computed tomography (CT) images of the spine performed for various medical reasons. These CT images were reviewed for features of axial gout, which include vertebral erosions mainly at the discovertebral junction and the facet joints, deposits of tophi, and erosions in the vertebral body, epidural space, ligamentum flavum and pars interarticularis. RESULTS: Nine of the 64 patients had radiographic changes suggestive of axial gout. Lumbar vertebrae were most commonly involved, with facet joint erosions being the most common finding. Isolated involvement of the sacroiliac joints was seen in 2 patients. Axial gout had been diagnosed clinically in only one patient. CONCLUSION: Radiologic changes of axial gout were more common than recognized clinically, with a frequency of 14%. Since not all patients had CT images, it is possible that the frequency of axial involvement was even greater. A prospective study is needed to further define this process.

An adaptive ERG technique to measure normal and altered dark adaptation in the mouse.

The time-course of dark adaptation provides valuable insights into the function and interactions between the rod and cone pathways in the retina. Here we describe a technique that uses the flash electroretinogram (ERG) response to probe the functional integrity of the cone and rod pathways during the dynamic process of dark adaptation in the mouse. Retinal sensitivity was estimated from the stimulus intensity required to maintain a 30 microV criterion b-wave response during a 40 min period of dark adaptation. When tracked in this manner, dark adaptation functions in WT mice depended upon the bleaching effects of initial background adaptation conditions. Altered dark adaptation functions, commensurate with the functional deficit were recorded in pigmented mice that lacked cone function (Gnat2 ( cplf3 )) and in WT mice injected with a toxin, sodium iodate (NaIO(3)), which targets the retinal pigment epithelium and also has downstream effects on photoreceptors. These data demonstrate that this adaptive tracking procedure measures retinal sensitivity and the contributions of the rod and/or cone pathways during dark adaptation in both WT control and mutant mice.

Adaptation of spatiotemporal mechanisms by increment and decrement stimuli.

Sawtooth modulation has been used in the past to examine visual sensitivity to luminance increments and decrements. The threshold elevation caused by adaptation depends on the spatial profile of the stimulus field and the polarities of the adaptation and test stimuli. We hypothesized that the adaptation effects reflect a change in the sensitivity of the spatiotemporal channels that detect the stimuli. We used a 2-deg disk centered in a larger surround field. Five levels of contrast between the test field and surround were investigated: equiluminant, three intermediate levels, and dark. At each contrast, observers adapted for 5 s to 2-Hz sawtooth modulation (rapid-on or rapid-off). Immediately after adaptation, thresholds were measured for detection of a single cycle of either a rapid-on or a rapid-off waveform. Varying the contrast of the surround affected observers' sensitivity to the polarity of the sawtooth stimulus to the extent that the pattern of sensitivity with the equiluminant surround was the opposite of that with the dark surround. To examine temporal factors, we measured thresholds for slow (500-ms ramps) and fast (8.3-ms pulses) test stimuli. The adaptation effect was preserved with the ramp stimuli but not with the pulse stimuli. Blurring the edge between the test and surround fields in the equiluminant surround condition raised thresholds for all sawtooth test stimuli, suggesting that spatiotemporal channels sensitive to high spatial frequencies and low temporal frequencies facilitate detection in that condition. These findings suggest that adaptation to sawtooth modulation can differentially effect the sensitivity of ON and OFF pathways, but the relative desensitization of each pathway depends on an interaction with the adaptation state of spatiotemporal channels that are involved in detection.

Time course of adaptation to stimuli presented along cardinal lines in color space.

Visual sensitivity is a process that allows the visual system to maintain optimal response over a wide range of ambient light levels and chromaticities. Several studies have used variants of the probe-flash paradigm to show that the time course of adaptation to abrupt changes in ambient luminance depends on both receptoral and postreceptoral mechanisms. Though a few studies have explored how these processes govern adaptation to color changes, most of this effort has targeted the L-M-cone pathway. The purpose of our work was to use the probe-flash paradigm to more fully explore light adaptation in both the L-M- and the S-cone pathways. We measured sensitivity to chromatic probes presented after the onset of a 2-s chromatic flash. Test and flash stimuli were spatially coextensive 2 degrees fields presented in Maxwellian view. Flash stimuli were presented as excursions from white and could extended in one of two directions along an equiluminant L-M-cone or S-cone line. Probes were presented as excursions from the adapting flash chromaticity and could extend either toward the spectrum locus or toward white. For both color lines, the data show a fast and slow adaptation component, although this was less evident in the S-cone data. The fast and slow components were modeled as first- and second-site adaptive processes, respectively. We find that the time course of adaptation is different for the two cardinal pathways. In addition, the time course for S-cone stimulation is polarity dependent. Our results characterize the rapid time course of adaptation in the chromatic pathways and reveal that the mechanics of adaptation within the S-cone pathway are distinct from those in the L-M-cone pathways.

Improved contact lens electrode for corneal ERG recordings in mice.

The electroretinogram (ERG) is routinely used to study retinal physiology in the clinic and in research. Due to their outstanding properties, contact lens electrodes (CLEs) are widely used for ERG recordings. Though the procedures for ERG recordings in mice are similar to those used in humans and larger vertebrates, use of CLEs in the mouse has been limited because of difficulties involved with the manufacturing of small contact lenses. We describe a simple instrument and method for manufacturing contact lenses and CLEs for stable ERG recordings in mice. The instrument operates like a hole-punch and is based on slip joint pliers incorporating a ball bearing on one jaw and forming plate on the other. These CLEs are simple to manufacture, inexpensive and provide stable, long-term recordings of corneal ERGs in mice. With minor modifications, these CLEs could be made for other small animals such as rats or fish.

Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.

OBJECTIVE: The reported frequency of scleroderma M01-R renal crisis (SRC) in diffuse systemic sclerosis (SSc; scleroderma) is 15-20%. Early use of angiotensin-converting enzyme (ACE) inhibitors has markedly improved outcome. The present analysis reexamines the prognostic factors for and outcome of SRC in a prospective cohort of patients with early diffuse SSc. METHODS: We retrospectively evaluated the cohort of SSc patients who participated in the High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse SSc trial. Patients with diffuse cutaneous scleroderma were enrolled if their disease duration was <18 months. Because the trial failed to show a difference between treatment groups, the data were pooled. RESULTS: One hundred thirty-four SSc patients entered the observation period a mean +/- SD of 0.8 +/- 0.3 years after onset of SSc. SRC occurred in 18 patients a mean +/- SD of 0.9 +/- 1.1 years after entry. During a mean +/- SD 4.0 +/- 1.1 years of followup after entry, 9 of the 18 patients died (mean +/- SD 0.6 +/- 0.9 years after SRC onset). Baseline characteristics that predicted SRC included a modified Rodnan skin thickness score of >or=20 (P < 0.01), enlarged cardiac silhouette on radiograph (P = 0.04), large joint contractures (wrist, elbow, knee) (P = 0.008), and prednisone use at entry (P = 0.01). Baseline characteristics that did not predict SRC included age, sex, race, Health Assessment Questionnaire score, fist closure, handspread, lung involvement, muscle weakness, erythrocyte sedimentation rate, and platelet count. In 5 of 10 subjects for whom at least 2 sequential skin scores were available, skin scores increased significantly (P = 0.012) in the 6 months before onset of SRC. CONCLUSION: SRC occurred in 13% of patients soon (mean 11 months) after entry into the cohort. Predictors of SRC identified in this study included higher than average skin score, prednisone use at study entry, large joint contractures, and heart enlargement. Our data suggest, however, that low-dose prednisone alone was not associated with the onset of SRC, except in the appropriate clinical setting. Although ACE inhibitors and dialysis are now readily available, SRC continues to be associated with poor survival (in this study, 50% of patients with SRC died).