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.

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.

Full-field electroretinogram response to increment and decrement stimuli.

PURPOSE: The d-wave is typically elicited after the termination of an increment flash, but a decrement flash provides an alternative, and perhaps more appropriate, stimulus to elicit the d-wave. Here, we investigated the affects of stimulus polarity on the electroretinogram (ERG) response. METHODS: ERG responses elicited to increment and decrement flashes of varying intensity and duration from different background levels were measured from human participants to assess the b-wave and d-wave responses as a function of adaptation level and flash polarity. Response amplitudes were measured using standard metrics for waveform analysis. RESULTS: The amplitude of the b-wave is larger than the d-wave regardless of flash polarity when using different background levels which maximized the dynamic range of the two waveforms. However, when response amplitudes are measured from a common background, the d-wave elicited with decrement flash was larger than the b-wave elicited by an increment flash. This trend was evident across a range of background levels. The b-wave and d-wave become separate entities when flash duration reaches approximately 50 ms. Rapid-on and rapid-off sawtooth stimuli were also tested against increment and decrement step stimuli that were matched in mean luminance. These two stimulus types produced different amplitude b-wave and d-wave responses, suggesting asymmetric effects of the two stimulus types on the retinal response. CONCLUSIONS: We conclude that the response properties of the b-wave and d-wave are influenced by the duration, polarity and waveform of the stimulus, as well as the background from which the stimuli arise.

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.

Teaching medical students ultrasound to measure liver size: comparison with experienced clinicians using physical examination alone.

BACKGROUND: Ultrasound is increasingly recognized as a valuable addition to medical school curriculum. PURPOSE: In this study, we tested the ability of rising second year students to learn and conduct an ultrasound examination of vertical liver span at the point of care. METHODS: Six patients from a GI clinic volunteered to have their liver size measured. Ten students were trained to measure vertical liver span with ultrasound. Four physicians were recruited to measure liver span with standard methods. Student and physician measurements were compared to each other and to a reference ultrasound measurement for accuracy and variability. RESULTS: Compared to the reference, students overestimated liver size an average of 1.5 cm. Physicians underestimated liver size an average of 6.7 cm. Variance in student measurements for each patient was 10% to 17% and among physicians 20% to 50%. CONCLUSION: With limited instruction and clinical experience medical students can obtain liver size measurements with ultrasound that are more accurate and have less variability than those by physicians using physical examination. Given the ease with which students can learn to use ultrasound and the teaching and clinical value of ultrasound, ultrasound should be considered as a standard of medical education in the future.

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.

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.

Autoimmune thyroid disease and chronic urticaria.

We report six cases of autoimmune thyroid disease associated with chronic urticaria and briefly review the literature, including the histopathological nature of such lesions, and their aetiology and pathogenesis. In view of the prevalence of thyroid disease in patients with chronic urticaria, screening measurements of thyrotropin and anti-thyroperoxidase antibodies are recommended, although negative antibodies do not exclude a relationship between urticaria and thyroid autoimmunity. After failure of conventional therapy for urticaria, patients who are apparently clinically euthyroid may be considered for a trial with levothyroxine. Improvement of urticaria was seen with levothyroxine treatment in three of four patients with only marginal abnormalities in thyroid function.

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.

Management of the antiphospholipid syndrome.

Antiphospholipid antibodies are associated with a hypercoagulable state leading to a wide variety of systemic manifestations and obstetric complications. The different pathologic manifestations can be a result of arterial and venous thrombosis, microthrombotic angiopathy, embolization, obstetric disease, and non-thrombotic phenomenon. Presently, the treatment centers on anticoagulation. Two randomized prospective studies in patients with antiphospholipid syndrome with initial thromboembolic event support the target international normalized ratio of 2.0 to 3.0 for the prevention of future thrombotic events. With pregnancy, the combination of aspirin and heparin is still the standard of care. In addition, non-thrombotic features and any associated autoimmune disease may need to be treated. Underlying risk factors precipitating the thromboembolic phenomenon need to be addressed as well.

The transcription factor Nr2e3 functions in retinal progenitors to suppress cone cell generation.

The transcription factor Nr2e3 is an essential component for development and specification of rod and cone photoreceptors; however, the mechanism through which it acts is not well understood. In this study, we use Nr2e3(rd7/rd7) mice that harbor a mutation in Nr2e3, to serve as a model for the human retinal disease Enhanced S Cone Syndrome. Our studies reveal that NR2E3 is expressed in late retinal progenitors and differentiating photoreceptors of the developing retina and localized to the cell bodies of mature rods and cones. In particular, we demonstrate that the abnormal increase in cone photoreceptors observed in Nr2e3(rd7/rd7) mice arise from ectopic mitotic progenitor cells that are present in the outer nuclear layer of the mature Nr2e3(rd7/rd7) retina. A prolonged phase of proliferation is observed followed by abnormal retinal lamination with fragmented and disorganized photoreceptor synapses that result in a progressive loss of rod and cone function. An extended and pronounced wave of apoptosis is also detected at P30 and temporally correlates with the phase of prolonged proliferation. Approximately twice as many apoptotic cells were detected compared to proliferating cells. This wave of apoptosis appears to affect both rod and cone cells and thus may account for the concurrent loss of rod and cone function. We further show that Nr2e3(rd7/rd7) cones do not express rod specific genes and Nr2e3(rd7/rd7) rods do not express cone specific genes. Our studies suggest that, based on its temporal and spatial expression, NR2E3 acts simultaneously in different cell types: in late mitotic progenitors, newly differentiating post mitotic cells, and mature rods and cones. In particular, this study reveals the function of NR2E3 in mitotic progenitors is to repress the cone generation program. NR2E3 is thus one of the few genes known to influence the competency of retinal progenitors while simultaneously directing the rod and cone differentiation.

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.