Clinical evaluation of post-surgical scar hyperaesthesia: a longitudinal observational pilot study.

Introduction: The mechanisms underlying persistent scar pain are not fully elucidated and evidence for the clinical evaluation of scar pain is limited. This pilot observational study investigated participation data and sought to identify objective clinical scar evaluation measures for future trials. Methods: With ethical approval and consent, adults undergoing planned hand surgery were enrolled from one NHS hospital. At 1- and 4-months post-surgery scar thermal and mechanical pain thresholds were evaluated with quantitative sensory testing; peri-scar inflammation with infrared thermometry and pliability with durometry. Participation data were analysed with descriptive statistics; the association of clinical measures with patient reported scar pain was analysed. Results: Twenty-one participants (22% eligible patients) enrolled before study closure due to the COVID-19 pandemic; 13 completed follow up. No adverse events or dropouts resulted from clinical scar evaluation. Seventy percent of participants reported undertaking topical, nonprescription scar treatment independently. Neuropathic Pain Symptom Inventory (NPSI) scores were dispersed across the score range, capturing variability in participant-reported scar symptoms. Scar morphology, pliability and inflammation were not associated with scar pain. Differences between scar and contralateral skin in thermal and mechanical pain sensitivity were identified. Conclusion: People with acute hand scars participate in clinical research and independently initiate scar treatment. Clinical testing of acute post-surgical hand scars is well tolerated. The NPSI demonstrates utility for exploring scar pain symptoms and may support the elucidation of mechanisms of persistent scar pain. Clinical tests of thermal and mechanical and sensitivity are promising candidate clinical measures of scar pain for future trials. Lay Summary: Background: it is unknown why some scars remain painful long-term. We do not know if scar flexibility, inflammation or sensitivity to temperature or pressure relate to scar pain. We investigated if patients would enrol in scar research, if scar testing was tolerated and if clinical tests are useful for future scar studies. Study conduct: with ethical approval and consent, adult hand surgery patients were enrolled from one NHS hospital. Scar pain, inflammation and response to thermal, sharp and pressure tests were assessed at 1- and 4-months after surgery. Statistically, we analysed study participation, tolerance for clinical scar tests and if the scar tests related to scar pain. Findings: 21 participants (22% eligible patients) enrolled before study closure due to the COVID-19 pandemic; 13 completed follow up. No participants were injured due to scar testing. 70% of participants reported treating their scar independently. Neuropathic Pain Symptom Inventory (NPSI) allows participants to give a broad range of answers about their scar symptoms. Scores for clinical tests of scar flexibility and inflammation did not relate to participant-reported scar pain. Scars were more sensitive to tests of pin prick and cold than unaffected skin. What we learned: people with new hand scars participate in research and independently initiate scar treatment. Clinical testing of post-surgical hand scars is well tolerated. The NPSI is useful for exploring scar pain symptoms and may help us to learn about persistent scar pain. Pinprick and cold clinical tests may be useful objective pain tests for future scar research.

Could sex-specific subtypes of hand osteoarthritis exist? A retrospective study in women presenting to secondary care.

Introduction: Hand osteoarthritis is more common in women, and its risk increases around the time of the menopause. We set out to describe the timing between menopause and the onset of symptomatic hand osteoarthritis (OA), and associations with the use of hormone replacement therapy (HRT) or its discontinuation, describing any identifiable subgroups of women. Methods: Retrospective healthcare-records study of sequential women referred to a specialist hand OA clinic, 2007-2015. Confirmation of hand OA diagnosis was by clinican, by accepted criteria. Demographics and clinical variables were from healthcare-records, recorded by standardised proforma. Outcomes of interest were reported age of onset of hand symptoms, reported age at final menstrual period (FMP), time from FMP to reported onset of hand symptoms and time from cessation of HRT to reported onset of hand symptoms. Exposure categories for systemic HRT use were never users, current users, previous users. Analysis of Variance compared groups; linear regression analysed associations of exposure with outcome. Results: 82/92(89%) of eligible women were post-menopausal, mean age at FMP 49.9 years (SD5.4). In these post-menopausal women, median time from FMP to hand symptom onset was 3 years. 48/82 (59%) developed hand symptoms within the defined peri-menopausal period (FMP ± 4 years), whilst some women developed their symptoms before or after (range -25, 30 years). In women who discontinued HRT prior to symptom onset, the median time from HRT cessation to onset of hand symptoms was 6 months. Past HRT users were older at hand symptom onset than women who had not taken HRT [coeff.4.7 years (0.92, 8.39); P = 0.015]. Conclusions: This study adds to evidence associating the menopause/sex hormone deficiency with hand OA symptom onset in a sizeable subgroup of women (but not all). HRT use/cessation appears to influence the timing of onset of hand OA symptoms. It is not possible to interpret from this type of study whether sex hormone deficiency is causative of disease or modulates its symptoms. It is also not possible to judge whether painful hand osteoarthritis in post-menopausal women is a subtype of disease. Further investigation is indicated of sex-specific subtypes and potential for personalised medicine for post-menopausal women with hand osteoarthritis, as a clearly definable high-risk subgroup.

Reporting of scar outcomes in the hand and wrist; a state-of-the-art literature review.

OBJECTIVES: The aim of this literature review was to synthesise and report current practice in evaluation and reporting of scar outcomes in hand and wrist clinical research. METHODS: A systematic search from inception to 2022 was conducted using three electronic databases. English language randomized controlled trials and observational cohort studies reporting standardised scar outcome measures and/or scar symptoms, appearance, impairment, function, or mental health outcomes in patients with hand and wrist scars were included. Two independent reviewers determined study eligibility and performed data extraction of a priori identified scar outcome domains. Data analysis included descriptive statistics and identification of discordance in taxonomy. RESULTS: Fifty-nine studies were included. Elective surgery cohorts were the most frequently included clinical population (n = 28; 47%) followed by burns (n = 16; 27%). Six different standardised scar outcome measures were reported by 25% of studies however only 7% of studies utilised a patient-reported measure. Scar symptoms were the most frequently reported outcome domain (81%); but taxonomy was incongruous, constructs lacked working definitions required for generalisability and outcome measurement was variable and unreported. Nineteen different measures of scar appearance and structure were reported by 30 (51%) of studies however only nine (23%) were patient-reported. Seven different hand function PROMs were reported by 25 (43%) studies. Person-centred domains including scar acceptability (12%), mental health impact (5%), and social participation (4%) were rarely reported. CONCLUSIONS: This review highlights that evaluation and reporting of hand and wrist scar outcomes is not standardised, assessment methods and measures are under-reported and there is discordance in taxonomy. Evaluation is not person-centred, rather it is dependent on clinician assessment. Domains including scar acceptability, mental health, and social participation are rarely addressed. A stakeholder consensus derived hand and wrist scar core outcome measurement set will promote standardisation and underpin improvements in clinical research quality, transparency, and rigour.

Creating good veterinary workplaces: how mentoring can offer a helping hand.

Regular mentoring should be part of the core values of a good veterinary workplace, but what benefits can it bring to individuals and practices as a whole? These benefits, and more, will be explored by Donna Kennedy, who will be one of two speakers in a careers session at BVA Live.

Chronic pain and cognitive impairment: a cross-sectional study in people living with HIV.

Cognitive impairment and chronic pain are amongst the most prevalent neurological sequelae of HIV infection, yet little is understood about the potential bidirectional relationship between the two conditions. Cognitive dysfunction can occur in chronic pain populations whilst those with cognitive impairment can display modified responses to experimentally induced painful stimuli. To date, this has not been explored in HIV cohorts.This study aimed to identify any contribution of chronic pain to cognitive impairment in HIV and to determine differences in pain characteristics between those with and without cognitive dysfunction.This was an observational cohort study involving people living with HIV (n = 148) in the United Kingdom. Participants underwent validated questionnaire-based measurement of pain severity, interference and symptom quality as well as conditioned pain modulation and quantitative sensory testing. All participants completed a computer-based cognitive function assessment.Fifty-seven participants met the criteria for cognitive impairment and 73 for chronic pain. The cognitive impairment group had a higher prevalence of chronic pain (p = 0.004) and reported more neuropathic symptoms (p = 0.001). Those with chronic pain performed less well in emotional recognition and verbal learning domains. The interaction identified between chronic pain and cognitive dysfunction warrants further exploration to identify causal links or shared pathology.

VEGF-A and FGF4 Engineered C2C12 Myoblasts and Angiogenesis in the Chick Chorioallantoic Membrane.

Angiogenesis is the formation of new blood vessels from pre-existing vessels. Adequate oxygen transport and waste removal are necessary for tissue homeostasis. Restrictions in blood supply can lead to ischaemia which can contribute to disease pathology. Vascular endothelial growth factor (VEGF) is essential in angiogenesis and myogenesis, making it an ideal candidate for angiogenic and myogenic stimulation in muscle. We established C2C12 mouse myoblast cell lines which stably express elevated levels of (i) human VEGF-A and (ii) dual human FGF4-VEGF-A. Both stably transfected cells secreted increased amounts of human VEGF-A compared to non-transfected cells, with the latter greater than the former. In vitro, conditioned media from engineered cells resulted in a significant increase in endothelial cell proliferation, migration, and tube formation. In vivo, this conditioned media produced a 1.5-fold increase in angiogenesis in the chick chorioallantoic membrane (CAM) assay. Delivery of the engineered myoblasts on Matrigel demonstrated continued biological activity by eliciting an almost 2-fold increase in angiogenic response when applied directly to the CAM assay. These studies qualify the use of genetically modified myoblasts in therapeutic angiogenesis for the treatment of muscle diseases associated with vascular defects.

The association of sensory phenotype and concomitant mood, sleep and functional impairment with the outcome of carpal tunnel surgery.

BACKGROUND: Up to 25% of people who have had carpal tunnel release surgery (CTR) fail to report improvement; however, evidence for prognostic indicators in this surgical cohort is limited. To identify candidate prognostic factors, this study investigated the association of quantitative sensory testing (QST) derived sensory phenotype and attendant impairment with patient-reported surgical outcome. METHODS: With ethical approval and informed consent, this prospective observational longitudinal study recruited patients from two London hospitals. Multimodal phenotyping measures including quantitative sensory testing (QST), pain parameters, insomnia, pain-related worry, mood and function, were evaluated prior to; and at 3- and 6-months post-surgery. Pain in median nerve distribution with electrophysiologically confirmed conduction delay and DN4 score ≥ 4 was defined as neuropathic. Primary outcome was patient-rated change at 6 months, dichotomised as poor outcome; "worse" or "no change" and good outcome; "slightly better", "much better" or "completely cured". RESULTS: Seventy-six patients participated. Prior to surgery, substantial heterogeneity in established categories of somatosensory function was observed with 21% of participants categorised as having a healthy sensory phenotype; 29% with thermal hyperalgesia; 32% mechanical hyperalgesia and 18% sensory loss. Seventy six percent of participants were classified as having neuropathic pain, 33% with high levels of pain related worry and 64% with clinical insomnia. Observed differences in pain, sleep impairment, psychological factors and function, between sensory phenotypic groups, was not significant. At 3- and 6-months post-surgery there was significant improvement in all phenotyping measures with a moderate to large effect size. Thermal and mechanical measures of somatosensation improved (p < 0.001), as did functional ability (p < 0.001). Symptom severity diminished (p < 0.001), as did pain-related worry (p < 0.001), anxiety (p = 0.02) and insomnia (p < 0.001). Patient-rated surgical outcome was good in 92% of the cohort, poor in 8%. Baseline sensory phenotype category was not associated with surgical outcome however pain-related worry, anxiety and functional interference were significantly associated with outcome (p ≤ 0.05). CONCLUSION: In patients undergoing carpal tunnel surgery, pain-related worry, anxiety and pain functional interference are candidate prognostic outcome factors and require further elucidation.

Responsiveness of quantitative sensory testing-derived sensory phenotype to disease-modifying intervention in patients with entrapment neuropathy: a longitudinal study.

ABSTRACT: The German Research Network on Neuropathic Pain (DFNS) quantitative sensory testing (QST) method for sensory phenotyping is used to stratify patients by mechanism-associated sensory phenotype, theorised to be predictive of intervention efficacy. We hypothesised that change in pain and sensory dysfunction would relate to change in sensory phenotype. We investigated the responsiveness of sensory phenotype to surgery in patients with an entrapment neuropathy. With ethical approval and consent, this observational study recruited patients with neurophysiologically confirmed carpal tunnel syndrome. Symptom and pain severity parameters and DFNS QST were evaluated before and after carpal tunnel surgery. Surgical outcome was evaluated by patient-rated change. Symptom severity score of the Boston Carpal Tunnel Questionnaire and associated pain and paraesthesia subgroups were comparators for clinically relevant change. Quantitative sensory testing results (n = 76) were compared with healthy controls (n = 54). At 6 months postsurgery, 92% participants reported a good surgical outcome and large decrease in pain and symptom severity (P < 0.001). Change in QST parameters occurred for thermal detection, thermal pain, and mechanical detection thresholds with a moderate to large effect size. Change in mechanical pain measures was not statistically significant. Change occurred in sensory phenotype postsurgery (P < 0.001); sensory phenotype was associated with symptom subgroup (P = 0.03) and patient-rated surgical outcome (P = 0.02). Quantitative sensory testing-derived sensory phenotype is sensitive to clinically important change. In an entrapment neuropathy model, sensory phenotype was associated with patient-reported symptoms and demonstrated statistically significant, clinically relevant change after disease-modifying intervention. Sensory phenotype was independent of disease severity and may reflect underlying neuropathophysiology.

Common hand and wrist conditions: creation of UK research priorities defined by a James Lind Alliance Priority Setting Partnership.

OBJECTIVE: Prioritisation of important treatment uncertainties for 'Common Conditions Affecting the Hand and Wrist' via a UK-based James Lind Alliance Priority Setting Partnership. SETTING: This process was funded by a national charitable organisation and based in the UK. PARTICIPANTS: Anyone with experience of common conditions affecting the adult hand and wrist, including patients, carers and healthcare professionals. All treatment modalities delivered by a hand specialist, including therapists, surgeons or other allied professionals, were considered. INTERVENTIONS: Established James Lind Alliance Priority Setting Partnership methods were employed.Electronic and paper questionnaires identified potential uncertainties. These were subsequently confirmed using relevant, up-to-date systematic reviews. A final list of top 10 research uncertainties was developed via a face-to-face workshop with representation from patients and clinicians. Impact of research was sought by surveying hand clinicians electronically. OUTCOME MEASURES: The survey responses and prioritisation-both survey and workshop based. RESULTS: There were 889 individually submitted questions from the initial survey, refined to 59 uncertainties across 32 themes. Eight additional uncertainties were added from published literature before prioritisation by 261 participants and the workshop allowed the final top 10 list to be finalised. The top 10 has so far contributed to the award of over £3.8 million of competitively awarded funding. CONCLUSIONS: The Common Conditions in the Hand and Wrist Priority Setting Partnership identified important research questions and has allowed research funders to identify grant applications which are important to both patients and clinicians.

Microvascular Experimentation in the Chick Chorioallantoic Membrane as a Model for Screening Angiogenic Agents including from Gene-Modified Cells.

The chick chorioallantoic membrane (CAM) assay model of angiogenesis has been highlighted as a relatively quick, low cost and effective model for the study of pro-angiogenic and anti-angiogenic factors. The chick CAM is a highly vascularised extraembryonic membrane which functions for gas exchange, nutrient exchange and waste removal for the growing chick embryo. It is beneficial as it can function as a treatment screening tool, which bridges the gap between cell based in vitro studies and in vivo animal experimentation. In this review, we explore the benefits and drawbacks of the CAM assay to study microcirculation, by the investigation of each distinct stage of the CAM assay procedure, including cultivation techniques, treatment applications and methods of determining an angiogenic response using this assay. We detail the angiogenic effect of treatments, including drugs, metabolites, genes and cells used in conjunction with the CAM assay, while also highlighting the testing of genetically modified cells. We also present a detailed exploration of the advantages and limitations of different CAM analysis techniques, including visual assessment, histological and molecular analysis along with vascular casting methods and live blood flow observations.

Pain thresholds and intensities of CRPS type I and neuropathic pain in respect to sex.

BACKGROUND AND AIMS: Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers. METHODS: QST data of 1,252 patients (669 female, 583 male) with PNI (n = 342), PNP (n = 571) or CRPS (n = 339), and average pain intensity reports from previously published studies were included. Absolute and z-values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects. RESULTS: Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p < .05). However, after z-transformation these differences disappeared except for PPT in CRPS (p = .001). DISCUSSION: Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes. SIGNIFICANCE: Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance.

Determining Real Change in Conditioned Pain Modulation: A Repeated Measures Study in Healthy Volunteers.

Conditioned pain modulation (CPM) is a potentially useful biomarker in pain populations; however, a statistically robust interpretation of change scores is required. Currently, reporting of CPM does not consider measurement error. Hence, the magnitude of change representing a "true" CPM effect is unknown. This study determined the standard error of measurement (SEM) and proportion of healthy participants showing a "true" CPM effect with a standard CPM paradigm. Fifty healthy volunteers participated in an intersession reliability study using pressure pain threshold (PPT) test stimulus and contact heat, cold water, and sham conditioning stimuli. Baseline PPTs were used to calculate SEM and >±2 × SEM to determine CPM effect. SEM for PPT was .21 kg/cm2. An inhibitory CPM effect (>+2 SEM) was elicited in 59% of subjects in response to cold stimulus; in 44% to heat. Intrasession and intersession reliability of within-subject CPM response was poor (kappa coefficient <.36). Measurement error is important in determining CPM effect and change over time. Even when using reliable test stimuli, and incorporating measures to limit bias and error, CPM intersession reliability was fair and demonstrated a large degree of within-subject variation. Determining "true" change in CPM will underpin future interrogations of intraindividual differences in CPM. PERSPECTIVE: This study used a distribution-based statistical approach to identify real change in CPM, based on the SEM for the test stimulus. Healthy volunteers demonstrate substantial within-subject variation; CPM effect was paradigm dependent at intrasession testing and unstable to the same paradigm at intersession testing.

The panniculus carnosus muscle: A novel model of striated muscle regeneration that exhibits sex differences in the mdx mouse.

The dermal striated muscle panniculus carnosus (PC), prevalent in lower mammals with remnants in humans, is highly regenerative, and whose function is purported to be linked to defence and shivering thermogenesis. Given the heterogeneity of responses of different muscles to disease, we set out to characterize the PC in wild-type and muscular dystrophic mdx mice. The mouse PC contained mainly fast-twitch type IIB myofibers showing body wide distribution. The PC exemplified heterogeneity in myofiber sizes and a prevalence of central nucleated fibres (CNFs), hallmarks of regeneration, in wild-type and mdx muscles, which increased with age. PC myofibers were hypertrophic in mdx compared to wild-type mice. Sexual dimorphism was apparent with a two-fold increase in CNFs in PC from male versus female mdx mice. To evaluate myogenic potential, PC muscle progenitors were isolated from 8-week old wild-type and mdx mice, grown and differentiated for 7-days. Myogenic profiling of PC-derived myocytes suggested that male mdx satellite cells (SCs) were more myogenic than female counterparts, independent of SC density in PC muscles. Muscle regenerative differences in the PC were associated with alterations in expression of calcium handling regulatory proteins. These studies highlight unique aspects of the PC muscle and its potential as a model to study mechanisms of striated muscle regeneration in health and disease.

HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis.

BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration. Here we show that cells overexpressing CMT-related HSPB1 mutants exhibited increased susceptibility to ER stress-induced cell death and high levels of BIM. These findings identify a novel function for HSPB1 as a negative regulator of BIM protein stability leading to protection against ER stress-induced apoptosis, a function that is absent in CMT-associated HSPB1 mutants.

Reliability of conditioned pain modulation: a systematic review.

A systematic literature review was undertaken to determine if conditioned pain modulation (CPM) is reliable. Longitudinal, English language observational studies of the repeatability of a CPM test paradigm in adult humans were included. Two independent reviewers assessed the risk of bias in 6 domains; study participation; study attrition; prognostic factor measurement; outcome measurement; confounding and analysis using the Quality in Prognosis Studies (QUIPS) critical assessment tool. Intraclass correlation coefficients (ICCs) less than 0.4 were considered to be poor; 0.4 and 0.59 to be fair; 0.6 and 0.75 good and greater than 0.75 excellent. Ten studies were included in the final review. Meta-analysis was not appropriate because of differences between studies. The intersession reliability of the CPM effect was investigated in 8 studies and reported as good (ICC = 0.6-0.75) in 3 studies and excellent (ICC > 0.75) in subgroups in 2 of those 3. The assessment of risk of bias demonstrated that reporting is not comprehensive for the description of sample demographics, recruitment strategy, and study attrition. The absence of blinding, a lack of control for confounding factors, and lack of standardisation in statistical analysis are common. Conditioned pain modulation is a reliable measure; however, the degree of reliability is heavily dependent on stimulation parameters and study methodology and this warrants consideration for investigators. The validation of CPM as a robust prognostic factor in experimental and clinical pain studies may be facilitated by improvements in the reporting of CPM reliability studies.

Methods for studying ER stress and UPR markers in human cells.

Many experimentally induced or disease-related cellular dysfunctions stress the endoplasmic reticulum, commonly resulting in an accumulation of unfolded proteins in the ER lumen which is sensed by three ER-resident transmembrane proteins, PERK, ATF6, and IRE1. Their activation by such ER stress affects the unfolded protein response, which consists of a shutoff of protein translation and at the same time the switching-on of specific transcription factors that control genes which function to reduce the burden of unfolded proteins to the ER. Here, we describe two sets of methods for monitoring the occurrence of ER stress and UPR signaling in human cells by analyzing markers of activation of all three ER stress sensor proteins. The first set of methods is based on the qualitative and quantitative analysis of UPR-induced transcripts by qPCR. The second set of methods consists of Western blot-based analysis of UPR-induced proteins or protein modifications. Their combined analysis allows assessment of activation of all three ER stress-activated signaling pathways that in combination are characteristic for the UPR.

Heat shock preconditioning protects against ER stress-induced apoptosis through the regulation of the BH3-only protein BIM.

A mild heat shock (HS) preconditioning and acquisition of thermotolerance protects cells against a variety of cytotoxic agents that otherwise induce apoptosis. Here we tested whether there is a molecular link between HS preconditioning and endoplasmic reticulum (ER) stress-induced apoptosis. ER stress results from a loss of ER lumen homeostasis, culminating in an accumulation of unfolded/misfolded proteins in the ER and activation of unfolded protein response (UPR). Unresolved, ER stress leads to activation of BH3-only proteins, mitochondrial membrane permeabilization, caspase activation and apoptotic cell death. HS preconditioning (1 h at 42 °C) induced a rapid increase in HSPA1 (HSP70) levels which remained elevated for at least 48 h post-HS. HS preconditioning significantly reduced BAX, caspase activation and apoptosis in cell cultures treated with the ER stress-inducing agents thapsigargin (TG) and tunicamycin (TM). HS-mediated protection was found to be due to regulation of the BH3-only protein BIM. Further, overexpression of HSPA1 could not mimic the effect of HS on BIM expression, suggesting that other HS factors may play a role in inhibiting ER stress-induced apoptosis by regulating BIM.

Regulation of apoptosis by heat shock proteins.

Thermotolerance, the acquired resistance of cells to stress, is a well-established phenomenon. Studies of the key mediators of this response, the heat shock proteins (HSPs), have led to the discovery of the important roles played by these proteins in the regulation of apoptotic cell death. Apoptosis is critical for normal tissue homeostasis and is involved in diverse processes including development and immune clearance. Apoptosis is tightly regulated by both proapoptotic and antiapoptotic factors, and dysregulation of apoptosis plays a significant role in the pathophysiology of many diseases. In the recent years, HSPs have been identified as key determinants of cell survival, which can modulate apoptosis by directly interacting with components of the apoptotic machinery. Therefore, manipulation of the HSPs could represent a viable strategy for the treatment of diseases. Here, we review the current knowledge with regard to the mechanisms of HSP-mediated regulation of apoptosis.

Night-time immobilization of the distal interphalangeal joint reduces pain and extension deformity in hand osteoarthritis.

OBJECTIVE: DIP joint OA is common but has few cost-effective, evidence-based interventions. Pain and deformity [radial or ulnar deviation of the joint or loss of full extension (extension lag)] frequently lead to functional and cosmetic issues. We investigated whether splinting the DIP joint would improve pain, function and deformity. METHODS: A prospective, radiologist-blinded, non-randomized, internally controlled trial of custom splinting of the DIP joint was carried out. Twenty-six subjects with painful, deforming DIP joint hand OA gave written, informed consent. One intervention joint and one control joint were nominated. A custom gutter splint was worn nightly for 3 months on the intervention joint, with clinical and radiological assessment at baseline, 3 and 6 months. Differences in the change were compared by the Wilcoxon signed rank test. RESULTS: The median average pain at baseline was similar in the intervention (6/10) and control joints (5/10). Average pain (primary outcome measure) and worst pain in the intervention joint were significantly lower at 3 months compared with baseline (P = 0.002, P = 0.02). Differences between intervention and control joint average pain reached significance at 6 months (P = 0.049). Extension lag deformity was significantly improved in intervention joints at 3 months and in splinted joints compared with matched contralateral joints (P = 0.016). CONCLUSION: Short-term night-time DIP joint splinting is a safe, simple treatment modality that reduces DIP joint pain and improves extension of the digit, and does not appear to give rise to non-compliance, increased stiffness or joint restriction. TRIAL REGISTRATION: clinical trials.gov, http://clinicaltrials.gov, NCT01249391.

Patients' expectations, experiences and the determinants of satisfaction related to metacarpophalangeal arthroplasty.

PURPOSE: Most previous research has used quantitative patient-rated outcome measures to identify patients' perceptions related to metacarpophalangeal (MCP) arthroplasty. However, little is known about the lived experience of this procedure. The present study aimed to gain an in-depth understanding of patients' expectations and experiences, and the determinants of satisfaction related to MCP arthroplasty and postoperative rehabilitation. METHODS: Semi-structured interviews were conducted with six participants from two London hospitals at four months to three years post-surgery. Interviews were transcribed verbatim and analysed using descriptive phenomenological analysis. RESULTS: Participants' reasons for surgery varied considerably and their expectations were informed by previous surgical experience and information from healthcare professionals. Diverse, and occasionally ambivalent, perceptions of various aspects of postoperative treatment were expressed and all participants emphasized the importance of reassurance and understanding by the healthcare team. When describing the effect of surgery on their lives, all experienced a period of 'frustrating dependence' and adopted a variety of psychological and practical coping mechanisms. Experience of recovery and long-term outcome was influenced by factors extraneous to MCP arthroplasty, including medical condition and disease at adjacent joints. Factors influencing satisfaction included participants' evaluation of the extent to which goals and preoperative expectations had been met and the impact of surgery on their lives. CONCLUSIONS: Joint goal-setting is essential for understanding patients' unique reasons for undergoing MCP arthroplasty and facilitating realistic expectations. Education on all aspects of postoperative care is vital. Patients should be made aware of variability in outcome and the potential for deterioration due to the chronic nature of rheumatoid arthritis.