Alpha-1-antitrypsin reduces inflammation and exerts chondroprotection in arthritis.

While new treatments have been developed to control joint disease in rheumatoid arthritis, they are partially effective and do not promote structural repair of cartilage. Following an initial identification of α-1-Antitrypsin (AAT) during the resolution phase of acute inflammation, we report here the properties of this protein in the context of cartilage protection, joint inflammation, and associated pain behavior. Intra-articular and systemic administration of AAT reversed joint inflammation, nociception, and cartilage degradation in the KBxN serum and neutrophil elastase models of arthritis. Ex vivo analyses of arthritic joints revealed that AAT promoted transcription of col2a1, acan, and sox9 and downregulated mmp13 and adamts5 gene expression. In vitro studies using human chondrocytes revealed that SERPINA1 transfection and rAAT protein promoted chondrogenic differentiation through activation of PKA-dependent CREB signaling and inhibition of Wnt/ß-catenin pathways. Thus, AAT is endowed with anti-inflammatory, analgesic, and chondroprotective properties that are partially inter-related. We propose that AAT could be developed for new therapeutic strategies to reduce arthritic pain and repair damaged cartilage.

Early detection of hearing loss for infants in Western Australia: Comparison to international benchmarks.

AIM: To assess the degree to which timely audiological assessment of congenital hearing loss is achieved at our institution - Perth Children's Hospital, Western Australia, and to review cases which breached this timeframe in order to address barriers to timely assessment. The benchmark used to determine timely assessment is that set out by The Joint Committee on Infant Hearing (JCIH) in which diagnostic audiological testing occurs by three months of age for those who do not pass newborn hearing screening. METHODS: A retrospective chart review of infants who underwent diagnostic auditory assessment at Perth Children's Hospital between 2016-2019. A total of 151 children were identified as meeting the inclusion criteria and their medical files were reviewed. Time to first dABR was the time point for whether testing was achieved within the 3 month timeframe. RESULTS: Of the 151 children who underwent dABR assessments, 1 was identified as having breached the 90 day time limit (tested on day 91) for which no valid reason for delay could be identified. The timely delivery of dABR assessments in 99.3% of cases within this cohort compares favourably with the literature. CONCLUSIONS: Conclusion Timely diagnostic audiological assessment is achievable for children with congenital hearing loss. The reasons for patients breaching this timeframe are explored in the paper along with factors which may help avoid delays.

The reliability of video otoscopy recordings and still images in the asynchronous diagnosis of middle-ear disease.

OBJECTIVE: To compare the asynchronous assessment of video otoscopic still images to recordings by an audiologist and ear, nose and throat surgeon (ENT) for diagnostic reliability and agreement in identifying middle-ear disease. DESIGN: A prospective cross-sectional study, asynchronously assessing video otoscopy, tympanometry and case history (Dx1). A subset was re-diagnosed (Dx2). STUDY SAMPLE: Video otoscopy and data from 146 children recruited at two public community events; a sub-set of 47 were re-assessed. RESULTS: The intra-rater diagnostic agreement between Dx1 and Dx2 was moderate (k = 0.445-0.552) for the ENT surgeon, and almost-perfect (k = 0.928) for the audiologist, in both procedures. The agreement between the two procedures was substantial (k = 0.624) and moderate (k = 0.416) for the ENT surgeon in Dx1 and Dx2 respectively, and almost-perfect for the audiologist (k = 0.854-0.978) in both rounds. In Dx1, the inter-rater agreement between the clinicians was substantial using still images (k = 0.672) and moderate using recordings (k = 0.593); in Dx2 it was moderate using both procedures (k = 0.477-0.488). CONCLUSION: Both video otoscopic procedures, in addition to tympanometry and case history information, can be reliably used for asynchronous diagnosis of childhood middle-ear disease. An audiologist has a potential role in triaging children with middle-ear abnormalities and, therefore, improving access to ear-health services.

Parent Risk Perceptions, Physical Literacy, and Fundamental Movement Skills in Children With Juvenile Idiopathic Arthritis.

PURPOSE: This pilot study sought to examine the fundamental movement skills (FMS) and physical literacy (PL) of children with juvenile idiopathic arthritis (JIA) and to explore their relationship with physical activity (PA) and parent perceptions of PA-related risks. METHODS: Twenty-five children with JIA and their parents completed questionnaires. Fundamental movement skills were assessed in the laboratory and PA through accelerometry data. RESULTS: Children spent a median of 39.4%, 40.9%, and 18.2% of their day sedentary, in light, and in moderate to vigorous PA, respectively. Fundamental movement skills and PL scores were within the average range, although were related to which joints (upper/lower body) were affected by JIA. Parents who viewed activities such as biking and climbing as risky tended to have children with weaker locomotor skills and lower PL. CONCLUSION: Children with JIA had age-appropriate PA, FMS, and PL; however, parent perceptions of PA-related risks are related to their child's FMS and PL.

Intracellular versus extracellular inhibition of calpain I causes differential effects on pain in a rat model of joint inflammation.

Calpain I is a calcium-dependent cysteine protease which has dual effects on tissue inflammation depending on its cellular location. Intracellularly, calpain I has pro-inflammatory properties but becomes anti-inflammatory when exteriorised into the extracellular space. In this study, the effect of calpain I on joint pain was investigated using the kaolin/carrageenan model of acute synovitis. Evoked pain behaviour was determined by von Frey hair algesiometry and non-evoked pain was measured using dynamic hindlimb weight bearing. Local administration of calpain I reduced secondary allodynia in the acute inflammation model and this effect was blocked by the cell impermeable calpain inhibitor E-64c. Calpain I also blocked the algesic effect of the protease activated receptor-2 (PAR-2) cleaving enzyme mast cell tryptase. The cell permeable calpain blocker E-64d also produced analgesia in arthritic joints. These data suggest that calpain I produces disparate effects on joint pain viz. analgesia when present extracellularly by disarming PAR-2, and pro-algesic when the enzyme is inside the cell.

The Human Medial Temporal Lobe Is Necessary for Remembering Durations within a Sequence of Events but Not Durations of Individual Events.

Recent interest in the role of the hippocampus in temporal aspects of cognition has been fueled, in part, by the observation of "time" cells in the rodent hippocampus-that is, cells that have differential firing patterns depending on how long ago an event occurred. Such cells are thought to provide an internal representation of elapsed time. Yet, the hippocampus is not needed for processing temporal duration information per se, at least on the order of seconds, as evidenced by intact duration judgments in rodents and humans with hippocampal damage. Rather, it has been proposed that the hippocampus may be essential for coding higher order aspects of temporal mnemonic processing, such as those needed to temporally organize a sequence of events that form an episode. To examine whether (1) the hippocampus uses duration information in the service of establishing temporal relations among events and (2) its role in memory for duration is unique to sequences, we tested amnesic patients with medial-temporal lobe damage (including the hippocampus). We hypothesized that medial-temporal lobe damage should impair the ability to remember sequential duration information but leave intact judgments about duration devoid of a sequential demand. We found that amnesics were impaired in making judgments about durations within a sequence but not in judging single durations. This impairment was not due to higher cognitive load associated with duration judgments about sequences. In convergence with rodent and human fMRI work, these findings shed light on how time coding in the hippocampus may contribute to temporal cognition.

The hippocampus is necessary for the consolidation of a task that does not require the hippocampus for initial learning.

During sleep, the hippocampus plays an active role in consolidating memories that depend on it for initial encoding. There are hints in the literature that the hippocampus may have a broader influence, contributing to the consolidation of memories that may not initially require the area. We tested this possibility by evaluating learning and consolidation of the motor sequence task (MST) in hippocampal amnesics and demographically matched control participants. While the groups showed similar initial learning, only controls exhibited evidence of overnight consolidation. These results demonstrate that the hippocampus can be required for normal consolidation of a task without being required for its acquisition, suggesting that the area plays a broader role in coordinating memory consolidation than has previously been assumed.

Hippocampal contributions to value-based learning: Converging evidence from fMRI and amnesia.

Recent evidence suggests that the human hippocampus-known primarily for its involvement in episodic memory-plays a role in a host of motivationally relevant behaviors, including some forms of value-based decision-making. However, less is known about the role of the hippocampus in value-based learning. Such learning is typically associated with a striatal system, yet a small number of studies, both in human and nonhuman species, suggest hippocampal engagement. It is not clear, however, whether this engagement is necessary for such learning. In the present study, we used both functional MRI (fMRI) and lesion-based neuropsychological methods to clarify hippocampal contributions to value-based learning. In Experiment 1, healthy participants were scanned while learning value-based contingencies (whether players in a "game" win money) in the context of a probabilistic learning task. Here, we observed recruitment of the hippocampus, in addition to the expected ventral striatal (nucleus accumbens) activation that typically accompanies such learning. In Experiment 2, we administered this task to amnesic patients with medial temporal lobe damage and to healthy controls. Amnesic patients, including those with damage circumscribed to the hippocampus, failed to acquire value-based contingencies, thus confirming that hippocampal engagement is necessary for task performance. Control experiments established that this impairment was not due to perceptual demands or memory load. Future research is needed to clarify the mechanisms by which the hippocampus contributes to value-based learning, but these findings point to a broader role for the hippocampus in goal-directed behaviors than previously appreciated.

Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice.

BACKGROUND: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. METHODS: MIA (0.3 mg/10 µl) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 µg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 µg i.p. days 0 to 1) and PAR2 knockout animals. RESULTS: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). CONCLUSIONS: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.

Clinician-rated quality of video otoscopy recordings and still images for the asynchronous assessment of middle-ear disease.

INTRODUCTION: Video otoscopy plays an important role in improving access to ear health services. This study investigated the clinician-rated quality of video otoscopy recordings and still images, and compared their suitability for asynchronous diagnosis of middle-ear disease. METHODS: Two hundred and eighty video otoscopy image-recording pairs were collected from 150 children (aged six months to 15 years) by an ear, nose, and throat (ENT) specialist, audiologists, and trained research assistants, and independently rated by an audiologist and ENT surgeon. On a five-point scale, clinicians rated the cerumen amount, field of view, quality, focus, light, and gave an overall rating, and asked whether they could make an accurate diagnosis for both still images and recordings. RESULTS: More video otoscopy recordings were rated as 'good' or 'excellent' compared to still images across all domains. The mean difference between the two otoscopic procedures ratings was significant across almost all domains (p < 0.05), except 'cerumen amount'. The suitability to make a diagnosis significantly improved when using recordings (p<0.05). Younger participant age was found to have a significant, negative impact on the ratings across all domains (p < 0.03). The role of the tester conducting video otoscopy did not have a significant impact on the ratings. DISCUSSION: Video otoscopy recordings were found to provide clearer views of the tympanic membrane and increase the ability to make diagnoses, compared to still images, for both audiologists and ENT surgeons. Research assistants with limited practice were able to obtain video otoscopy images and recordings that were comparable to the ones obtained by clinicians.

Joint Damage and Neuropathic Pain in Rats Treated With Lysophosphatidic Acid.

Joint pain is a complex phenomenon that involves multiple endogenous mediators and pathophysiological events. In addition to nociceptive and inflammatory pain, some patients report neuropathic-like pain symptoms. Examination of arthritic joints from humans and preclinical animal models have revealed axonal damage which is likely the source of the neuropathic pain. The mediators responsible for joint peripheral neuropathy are obscure, but lysophosphatidic acid (LPA) has emerged as a leading candidate target. In the present study, male and female Wistar rats received an intra-articular injection of LPA into the right knee and allowed to recover for 28 days. Joint pain was measured by von Frey hair algesiometry, while joint pathology was determined by scoring of histological sections. Both male and female rats showed comparable degenerative changes to the LPA-treated knee including chondrocyte death, focal bone erosion, and synovitis. Mechanical withdrawal thresholds decreased by 20-30% indicative of secondary allodynia in the affected limb; however, there was no significant difference in pain sensitivity between the sexes. Treatment of LPA animals with the neuropathic pain drug amitriptyline reduced joint pain for over 2 hours with no sex differences being observed. In summary, intra-articular injection of LPA causes joint degeneration and neuropathic pain thereby mimicking some of the characteristics of neuropathic osteoarthritis.

Long-Term Blockade of Nociceptive Nav1.7 Channels Is Analgesic in Rat Models of Knee Arthritis.

The voltage gated sodium channels (Nav) 1.7, 1.8, and 1.9 are primarily located on nociceptors where they are involved in signalling neuropathic pain. This study examined the effect of Nav1.7 blockade on joint pain using either the small molecule inhibitor PF05089771 or an antibody directed towards the intracellular domain of the ion channel. Male Wistar rats were assigned to one of three experimental groups consisting of either intra-articular injection of 3 mg sodium monoiodoacetate (MIA-joint degeneration group), intra-articular injection of 100 µg lysophosphatidic acid (LPA-joint neuropathy group), or transection of the medial meniscus (MMT-posttraumatic osteoarthritis group). G-ratio calculations were performed to determine potential demyelination and immunohistochemistry was used to measure Nav1.7 expression on joint afferent cell bodies. Pain behaviour was evaluated over 3 h by von Frey hair algesiometry and hindlimb weight bearing before and after local administration of PF05089771 (0.1 mg/50 µL). Chronic pain behaviour was assessed over 28 days following peripheral treatment with a Nav1.7 antibody (Ab) in conjunction with the transmembrane carrier peptide Pep1. Demyelination and increased Nav1.7 channel expression were observed in MIA and LPA rats, but not with MMT. Acute secondary allodynia was diminished by PF05089771 while a single injection of Nav1.7 Ab-Pep1 reduced pain up to 28 days. This analgesia only occurred in MIA and LPA animals. Hindlimb incapacitance was not affected by any treatment. These data indicate that joint pain associated with neural demyelination can be alleviated somewhat by Nav1.7 channel blockade. Biologics that inactivate Nav1.7 channels have the potential to reduce arthritis pain over a protracted period of time.

"If I knew then what I know now": parents' reflections on raising a child with cerebral palsy.

In this study we investigated experiences of parents of children with cerebral palsy (CP) to identify areas in which health care providers and educators could improve practice. A second objective was to create educational material for parents of young children newly diagnosed with CP. A purposive sample of nine parents, who previously participated in the Adolescent Study of Quality of Life, Mobility, and Exercise, was recruited through phone. During an interview, parents reflected on the experience of raising a child with CP from birth to young adulthood. These interviews were audiotaped, transcribed, and coded using the International Classification of Functioning, Disability and Health-informed model and analyzed to identify major themes. Parents elaborated upon what was helpful and what could be changed to improve their children's and families' experiences through supports, advocacy, and education at different levels. The results informed the development of tips for parents and children with CP to enhance their families' experiences and interactions with health care providers, educators, and others.

Evaluating the success of a newly introduced Feed and Wrap protocol in magnetic resonance imaging scanning of the temporal bone for the evaluation of congenital sensorineural hearing loss.

OBJECTIVES: Magnetic resonance imaging (MRI) of the temporal bones, specifically of the cochlea and retro-cochlear pathway, is an important investigation in the diagnostic workup and management of congenital hearing loss. However, obtaining a diagnostic quality MRI scan depends upon the need for the infant to remain still for the duration of the scan. The Feed and Wrap (F + W) technique is a method that has been used successfully in infants for scans of other parts of the body, but has not been properly studied in MRI scans performed for hearing loss. The primary aim was to evaluate the diagnostic success rate of a newly introduced Feed and Wrap MRI scanning protocol used for assessment of sensorineural hearing loss in infants at Western Australia's Tertiary Paediatric hospital over the last three years. The secondary aims were to discuss the advantages and disadvantages of this technique and to review the available published literature on this technique and compare it to our case series. METHODS: All F + W MRI scans performed for the investigation of congenital hearing loss between 2016 and 2019 at the King Edward Memorial Hospital for Women and Perth Children's Hospital were retrospectively reviewed. The primary outcome was the diagnostic utility of the MRI scan with a diagnostic scan defined as the ability to diagnose or exclude radiological causes of sensorineural hearing loss. RESULTS: 53 MRI scans of the temporal bone and brain were identified. 86.8% of scans were diagnostic. The mean age of infants who underwent diagnostic scans was 6.8 weeks old compared to 10.9 weeks (p = 0.01) for those who had non-diagnostic scans. The optimal age cut off for F + W technique was ≤10 weeks. The odds of failure are 16.7 (95%CI 6.5-42.8, p = 0.003) times higher above the cut of age of 10 weeks compared to ≤10 weeks. CONCLUSION: The F + W technique is a viable method for obtaining diagnostic quality MRI scans of the inner ear structures in infants with hearing loss, with a greater likelihood of success when applied in younger infants.

Ten years of paediatric airway foreign bodies in Western Australia.

BACKGROUND: Whenever a paediatric airway foreign body (PAFB) is suspected, decisions may be difficult without a clearly defined or accepted treatment algorithm. History and examination are commonly non-diagnostic and the risks associated with either watchful waiting or proceeding to MLB are significant. This paper reviews a 10 year cohort of suspected PAFBs for the predictive utility of history, examination and investigations and subsequent positive findings at MLB. OBJECTIVES: STUDY DESIGN: The medical records of 127 children who underwent MLB for suspected PAFB between 2007 and 2016 were examined. The data was retrospectively reviewed for epidemiological details, history, examination, radiological findings and MLB outcomes. RESULTS: Sensitivity for PAFB on MLB with all three; history, examination and imaging (x-ray) positive for PAFB was 87.7%. Of the patients who were both symptom and sign positive (n = 96), chest x-ray findings did not significantly alter the chance of finding a PAFB. Chest x-ray had a low specificity (17%) in symptom and sign positive patients. Conversely, sensitivity of chest x-ray was high (88%), for symptom and sign positive patients. CONCLUSIONS: For a child with both signs and symptoms, xray is unlikely to assist in decision making around suspected PAFB. When only sign or symptom is present, positive imaging may significantly increase the chance that PAFB is the cause.For patients with a low suspicion of PAFB, consideration of a CT can be a helpful means of excluding a PAFB and avoiding an unnecessary general anaesthetic in this potentially high-risk group.A greater level of public awareness is needed with regards to appropriate food types for children and the importance of eating seated and supervised in order to reduce the risk of PAFB.

Behavioral phenotypes persist after gonadal steroid manipulation in white-throated sparrows.

White-throated sparrows (Zonotrichia albicollis) exhibit a behavioral polymorphism that segregates with a plumage marker. Individuals with a white stripe (WS) on the crown engage in an aggressive strategy that involves more singing, whereas individuals with a tan stripe (TS) sing less and engage in more parental care. Previous work has shown that plasma levels of gonadal steroids differ between the morphs in both sexes, suggesting a hormonal mechanism for the polymorphic behavior in this species. Here, we eliminated morph differences in plasma levels of testosterone (T) in males and estradiol (E2) in females in order to test whether morph differences in behavior would be similarly eliminated. Males and females in non-breeding condition were treated with T or E2, respectively, so that plasma levels in the treated groups were high and equal between the WS and TS morphs. We found that despite hormone treatment, WS and TS birds differed with respect to singing behavior. WS males sang more in response to song playback than did TS males, and WS females exhibited more spontaneous song than TS females. We also found that WS males gave more chip calls, which are often used in contexts of territorial aggression. Overall, these results suggest that WS birds engage in more territorial vocalization, particularly song, than do TS birds, even when T or E2 levels are experimentally equalized. This behavioral difference may therefore be driven by other factors, such as steroid metabolism, receptor expression or function, or steroid-independent neurotransmitter systems.

Inhalational injury and the larynx: A review.

OBJECTIVE: To review and discuss the existing research on the pathophysiology, impact and management of inhalational injury on the larynx and lower respiratory tract. DATA SOURCES: A literature search was conducted on the PubMed, MedLine, Embase, Web of Science and Google Scholar databases based on the keywords "airway burn", "inhalational injury" and "larynx". REVIEW METHODS: Inclusion criteria included English language studies containing original and review data on airway injury. Data was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. CONCLUSIONS: Abnormal laryngeal and lower airway findings are common in burns patients and the incidence tends to increase with severity of the burns. Most patients with abnormal findings remain dysphonic decades after the initial injury. Larynx, the inlet to the airway, is exposed to the most intense thermal damage and highest concentration of chemical in inhalational injury. Airway injury is common and may result in long term morbidity. Healing of this tissue architecture is prolonged and different from cutaneous burn. Many patients receive prolonged intubation for medical complications that arise due to the burn injury. The degree of subglottic damage, however, is more extensive and occurs sooner compared with those without inhalational injuries. IMPLICATIONS FOR PRACTICE: With advances in acute medical and surgical management of burn and inhalational injury, airway injury is an important secondary outcome with lasting impact. Awareness of these potential complications and early involvement of medical and allied health team are important steps in improving patient care. A multi-disciplinary approach to management will optimise the short and long-term morbidity management and ultimately our patients' quality of life.

Self-related processing and future thinking: Distinct contributions of ventromedial prefrontal cortex and the medial temporal lobes.

Episodic future thinking depends on a core network of regions that involves, in addition to the medial temporal lobes (MTL), the ventromedial prefrontal cortex (vmPFC). Neuroimaging studies suggest that vmPFC is particularly involved when future thinking requires consideration of self-relevant information, but lesion evidence for a special role of vmPFC in constructing self-relevant scenarios is limited. To clarify the involvement of vmPFC in future thinking, eight patients with vmPFC lesions were asked to imagine future events pertaining to the self or to another person, and their performance was contrasted with that of eight patients with MTL lesions. Patients with vmPFC lesions were no more detailed in their description of future events pertaining to the self than of events pertaining to another person. In contrast, like controls, patients with MTL lesions showed a self-benefit, despite impoverished performance overall. These findings accord with evidence from neuroimaging studies and elucidate the distinct contributions of vmPFC and MTL to future thinking.

The hippocampus supports deliberation during value-based decisions.

Choosing between two items involves deliberation and comparison of the features of each item and its value. Such decisions take more time when choosing between options of similar value, possibly because these decisions require more evidence, but the mechanisms involved are not clear. We propose that the hippocampus supports deliberation about value, given its well-known role in prospection and relational cognition. We assessed the role of the hippocampus in deliberation in two experiments. First, using fMRI in healthy participants, we found that BOLD activity in the hippocampus increased as a function of deliberation time. Second, we found that patients with hippocampal damage exhibited more stochastic choices and longer reaction times than controls, possibly due to their failure to construct value-based or internal evidence during deliberation. Both sets of results were stronger in value-based decisions compared to perceptual decisions.