Longitudinal transcriptomic analysis of mouse sciatic nerve reveals pathways associated with age-related muscle pathology.

BACKGROUND: Sarcopenia, the age-associated decline in skeletal muscle mass and strength, has long been considered a disease of muscle only, but accumulating evidence suggests that sarcopenia could originate from the neural components controlling muscles. To identify early molecular changes in nerves that may drive sarcopenia initiation, we performed a longitudinal transcriptomic analysis of the sciatic nerve, which governs lower limb muscles, in aging mice. METHODS: Sciatic nerve and gastrocnemius muscle were obtained from female C57BL/6JN mice aged 5, 18, 21 and 24 months old (n = 6 per age group). Sciatic nerve RNA was extracted and underwent RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were validated using quantitative reverse transcription PCR (qRT-PCR). Functional enrichment analysis of clusters of genes associated with patterns of gene expression across age groups (adjusted P-value < 0.05, likelihood ratio test [LRT]) was performed. Pathological skeletal muscle aging was confirmed between 21 and 24 months by a combination of molecular and pathological biomarkers. Myofiber denervation was confirmed with qRT-PCR of Chrnd, Chrng, Myog, Runx1 and Gadd45ɑ in gastrocnemius muscle. Changes in muscle mass, cross-sectional myofiber size and percentage of fibres with centralized nuclei were analysed in a separate cohort of mice from the same colony (n = 4-6 per age group). RESULTS: We detected 51 significant DEGs in sciatic nerve of 18-month-old mice compared with 5-month-old mice (absolute value of fold change > 2; false discovery rate [FDR] < 0.05). Up-regulated DEGs included Dbp (log2 fold change [LFC] = 2.63, FDR < 0.001) and Lmod2 (LFC = 7.52, FDR = 0.001). Down-regulated DEGs included Cdh6 (LFC = -21.38, FDR < 0.001) and Gbp1 (LFC = -21.78, FDR < 0.001). We validated RNA-seq findings with qRT-PCR of various up- and down-regulated genes including Dbp and Cdh6. Up-regulated genes (FDR < 0.1) were associated with the AMP-activated protein kinase signalling pathway (FDR = 0.02) and circadian rhythm (FDR = 0.02), whereas down-regulated DEGs were associated with biosynthesis and metabolic pathways (FDR < 0.05). We identified seven significant clusters of genes (FDR < 0.05, LRT) with similar expression patterns across groups. Functional enrichment analysis of these clusters revealed biological processes that may be implicated in age-related changes in skeletal muscles and/or sarcopenia initiation including extracellular matrix organization and an immune response (FDR < 0.05). CONCLUSIONS: Gene expression changes in mouse peripheral nerve were detected prior to disturbances in myofiber innervation and sarcopenia onset. These early molecular changes we report shed a new light on biological processes that may be implicated in sarcopenia initiation and pathogenesis. Future studies are warranted to confirm the disease modifying and/or biomarker potential of the key changes we report here.

[Place of preperitoneal pelvic packing in severe pelvic traumatisms: 20 cases in a French level 1 trauma center]. / Place du packing pré-péritonéal pelvien dans les traumatismes graves du bassin : étude à partir de 20 cas réalisés dans un trauma center de niveau 1 français.

BACKGROUND: The overall mortality of hemodynamically unstable patients with pelvic trauma is high. Their management is controversial concerning places of arterioembolization and pelvic packing associated with pelvic stabilization. The aim of this study was to collect the pre-peritoneal pelvic packing (PPP) performed in our institution over 10years in order to propose a management algorithm. METHOD: From January 2010 to December 2020, all patients with a hemodynamically unstable pelvic fracture who had PPP combined with pelvic stabilization were included. Data were collected prospectively and analyzed retrospectively. The main judgement criteria were early hemorrhage-induced mortality (<24h) and overall mortality (<30d). RESULTS: Twenty patients had PPP out of 287 polytrauma patients with pelvic fracture. The first-line PPP proposed in our algorithm significantly reduced the number of red blood cells (RBCs) (P=0.0231) and improved systolic blood pressure (SBP) (P<0.001) within 24hours of first-line PPP (compared with preoperative). Six patients (30%) were embolized postoperatively for active bleeding not necessarily pelvic. The overall mortality at 30days was 50% (10/20). CONCLUSION: PPP is a fast, easy, effective and safe procedure for venous, bone and sometimes arterial bleeding. PPP is part of damage control surgery and we propose it as a first-line procedure. AE remains complementary in a second step.

Novel outreach settings to enhance sexually transmitted infection/HIV awareness, diagnosis and treatment in hard-to-reach populations.

Despite recent rises in the number of cases of sexually transmitted infections (STIs) such as syphilis and gonorrhoea in England and increasing rates of HIV diagnosis among several men who have sex with men populations, many individuals are still not engaging with sexual health services. The John Hunter Clinic for Sexual Health, Chelsea and Westminster Hospital, London set up outreach clinics at the two world's largest adult lifestyle exhibitions in 2013 and 2015. This was the first time that a sexual health screening and promotion service was available at these large-scale (over 10,000 attendees at each) adult lifestyle events. A total of 381 individuals underwent STI screening across the two events. Nineteen (5.0%) patients were diagnosed with an infection. Twelve (3.1%) patients with Chlamydia trachomatis, three (0.8%) patients with syphilis, one (0.3%) patient with Neisseria gonorrhoeae, one (0.3%) patient with HIV, one (0.3%) patient with hepatitis B and one (0.3%) patient with hepatitis C. All 19 patients were promptly contacted with their results and had arrangements made for treatment or were referred for specialist follow up. Where possible, contact tracing was also performed. Implementing such outreach-based projects is challenged by lack of on-site laboratory support, high staffing demands and potentially high costs. However, we achieved a total HIV screening uptake rate of 94.5% amongst our outreach clinic attendees (versus 67% nationally in conventional sexual health clinic attendees) with an HIV positivity rate of 0.3% (versus 0.2% nationally in high HIV prevalence band populations). Additionally, 30.7% had never been tested for HIV previously (versus 20.7% nationally). Our work demonstrates that these strategies can help to address issues related to lack of STI/HIV screening in hard-to-reach populations and promote risk reduction behaviour.

Neuropathic pain in cancer: systematic review, performance of screening tools and analysis of symptom profiles.

BACKGROUND: The objectives of this study were to evaluate the methodological quality of rigorous neuropathic pain assessment tools in applicable clinical studies, and determine the performance of screening tools for identifying neuropathic pain in patients with cancer. METHODS: Systematic literature search identified studies reporting use of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 (DN4) or painDETECT (PDQ) in cancer patients with a clinical diagnosis of neuropathic or not neuropathic pain. Individual patient data were requested to examine descriptor item profiles. RESULTS: Six studies recruited a total of 2301 cancer patients of which 1564 (68%) reported pain. Overall accuracy of screening tools ranged from 73 to 94%. There was variation in description and rigour of clinical assessment, particularly related to the rigour of clinical judgement of pain as the reference standard. Individual data from 1351 patients showed large variation in the selection of neuropathic pain descriptor items by cancer patients with neuropathic pain. LANSS and DN4 items characterized a significantly different neuropathic pain symptom profile from non-neuropathic pain in both tumour- and treatment-related cancer pain aetiologies. CONCLUSIONS: We identified concordance between the clinician diagnosis and screening tool outcomes for LANSS, DN4 and PDQ in patients with cancer pain. Shortcomings in relation to standardized clinician assessment are likely to account for variation in screening tool sensitivity, which should include the use of the neuropathic pain grading system. Further research is needed to standardize and improve clinical assessment in patients with cancer pain. Until the standardization of clinical diagnosis for neuropathic cancer pain has been validated, screening tools offer a practical approach to identify potential cases of neuropathic cancer pain.

Integration of oncology and palliative care: setting a benchmark.

BACKGROUND: Integration of oncology and palliative care (PC) should be the standard model of care for patients with advanced cancer. An expert panel developed criteria that constitute integration. This study determined whether the PC service within this Health Service, which is considered to be fully "integrated", could be benchmarked against these criteria. METHODS: A survey was undertaken to determine the perceived level of integration of oncology and palliative care by all health care professionals (HCPs) within our cancer centre. An objective determination of integration was obtained from chart reviews of deceased patients. Integration was defined as >70% of all respondents answered "agree" or "strongly agree" to each indicator and >70% of patient charts supported each criteria. RESULTS: Thirty-four HCPs participated in the survey (response rate 69%). Over 90% were aware of the outpatient PC clinic, interdisciplinary and consultation team, PC senior leadership, and the acceptance of concurrent anticancer therapy. None of the other criteria met the 70% agreement mark but many respondents lacked the necessary knowledge to respond. The chart review included 67 patients, 92% of whom were seen by the PC team prior to death. The median time from referral to death was 103 days (range 0-1347). The level of agreement across all criteria was below our predefined definition of integration. CONCLUSION: The integration criteria relating to service delivery are medically focused and do not lend themselves to interdisciplinary review. The objective criteria can be audited and serve both as a benchmark and a basis for improvement activities.

An open-label pilot study of oral vitamin C as an opioid-sparing agent in patients with chronic pain secondary to cancer.

PURPOSE: The purpose of this study is to assess the efficacy of oral Vitamin C as an opioid-sparing agent when used in conjunction with opioids and standard adjuvant therapy in the management of chronic cancer pain. METHODS: An open-label pilot study of patients ≥18 years of age with chronic pain secondary to cancer and/or its treatment and a Brief Pain Inventory average pain score of ≥3/10. In addition to opioid analgesia, patients received 1 g of vitamin C twice daily over 3 days (total daily dose of 2 g). Patients' usual medications, including breakthrough medications, were continued throughout the study period. The primary endpoint was total daily opioid use during vitamin C administration compared with that immediately prior to study. RESULTS: Thirty-four patients were enrolled in the study. Seven failed to complete the trial. Across the 17 evaluable patients, the median daily opioid consumption was 360 mg oral morphine equivalents (OME) on the days prior to vitamin C and 390 mg when administered with vitamin C. CONCLUSION: This study failed to demonstrate any clinically significant benefit from vitamin C in conjunction with opioids in cancer-related pain and does not provide support for embarking on a larger randomised trial to determine efficacy.

An unusual mediastinal mass.

We report a case of a mediastinal mass indenting the left lateral tracheal wall of a 35-year-old male who presented with weight loss, cough and breathlessness. Flow volume loop and thyroid function tests were normal and thyroid peroxidase antibodies were negative. Technetium scintigraphy and positron emission tomography both showed no uptake. Endobronchial ultrasound-guided fine needle aspiration confirmed ectopic mediastinal thyroid tissue. Mediastinal ectopic thyroid tissue is very rare. Most patients are asymptomatic and euthyroid with positive signals on scintigraphy. False negative technetium scintigraphy can occur in areas of necrosis, carcinoma and from substernal tissue. Ectopic thyroid tissue is a rare but important differential diagnosis when investigating mediastinal lesions and should be considered even if scintigraphy is negative in the right clinical context. Endobronchial ultrasound-guided fine needle aspiration can be used when scintigraphy is not diagnostic.

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

[Pansclerotic morphea with a rapidly fatal outcome in an 11-year-old girl]. / Morphée pansclérotique d'évolution rapidement létale chez une jeune fille de 11ans.

BACKGROUND: Pansclerotic morphea is a poorly described but extremely debilitating variant of localized scleroderma. We report a case with a rapidly fatal outcome in an 11-year-old girl. PATIENTS AND METHODS: An 11-year-old girl with a 2-year history of morphea presented at our institution in April 2012. The sclerosis had started on her trunk and progressed rapidly to involve her entire skin. Initial treatment with corticosteroids was ineffective and she presented extremely painful ulcerations of the lower limbs. The outcome was rapidly fatal, in early 2014, due to cachexia and sepsis after two amputations and several failed treatments including methotrexate. DISCUSSION: Pansclerotic morphea is characterized by rapidly progressing sclerosis involving the entire skin, trophic cutaneous ulcers, painful contraction and limited joint mobility. The prognosis is poor since the disease has an incapacitating and potentially fatal outcome. No reliably effective treatment has yet been established. CONCLUSION: Our case highlights the clinical characteristics of this uncommon form of localized scleroderma, the extremely severe prognosis, and the therapeutic challenge involved.

Pre- and postoperative complications of adult forearm fractures treated with plate fixation.

INTRODUCTION: Adult forearm fractures account for 1-2% of all fractures of the limbs. The main objective of this retrospective multicenter study was to evaluate pre- and postoperative complications of forearm fractures. The secondary objective was to evaluate functional and radiological results of plate osteosynthesis for these fractures. MATERIAL AND METHODS: Between January 2008 and March 2014, 131 forearm fractures were reviewed retrospectively. Fractures were classified preoperatively according to the AO classification. Clinical outcomes were classified into four categories according to the Tschnerne and Oestern classification. Pre- and postoperative complications were sought systematically. RESULTS: Before surgery, 12 patients had neurological impairment (9%). At the last follow-up, nine patients had persistent neurological disorders (6.9%). Union of forearm fractures was obtained in 122 patients at 4.6 months on average (±2.6). Nine patients with nonunion were observed (6.9%) and five patients had radioulnar synostosis (3.8%). DISCUSSION: The frequency of neurological complications concomitant to forearm fractures is noteworthy. Similar cases with essentially irritative neurological disease have been reported in the literature, in particular for the ulnar nerve. Fracture nonunion is a relatively common complication: between 2 and 10% of cases depending on the study. LEVEL OF EVIDENCE: IV.

Endoscopic ulnar nerve release at the elbow: Indications and outcomes.

BACKGROUND: Ulnar nerve entrapment at the elbow is the second most common nerve entrapment syndrome at the upper limp, after carpal tunnel syndrome. Many surgeons feel that ulnar nerve instability contra-indicates endoscopic nerve release. Published studies, however, found no evidence that pre-operative or intra-operative ulnar nerve instability adversely affected clinical outcomes. The objective of this prospective study was to define the indications and describe the outcomes of endoscopic ulnar nerve release at the elbow. HYPOTHESIS: Endoscopic ulnar nerve release at the elbow is a valid option even in patients with ulnar nerve instability and regardless of the severity of the compression. MATERIAL AND METHODS: We conducted a prospective single-centre study of patients scheduled for surgery based on clinical and electromyographic manifestations of ulnar nerve entrapment at the elbow. Ulnar nerve instability (incomplete dislocation, i.e., Childress A) before or during surgery was not a contra-indication to the procedure. The patients were re-evaluated 12 months after surgery. RESULTS: Seventeen patients were included in the statistical analysis. The modified Bishop's score indicated excellent or good outcomes in 15 (88%) patients (excellent in 4 and good in 11) and a fair outcome in 2 patients. Functional outcomes were not associated with the presence of ulnar nerve instability before surgery. DISCUSSION: We elected to include patients with Childress A ulnar nerve instability. Clinical outcomes in these patients were similar to those in patients without ulnar nerve instability. LEVEL OF EVIDENCE: IV, open prospective study of treatment outcomes.

Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila.

Caspases are the executioners of apoptosis. Although much is known about their physiological roles and structures, detailed analyses of missense mutations of caspases are lacking. As mutations within caspases are identified in various human diseases, the study of caspase mutants will help to elucidate how caspases interact with other components of the apoptosis pathway and how they may contribute to disease. DrICE is the major effector caspase in Drosophila required for developmental and stress-induced cell death. Here, we report the isolation and characterization of six de novo drICE mutants, all of which carry point mutations affecting amino acids conserved among caspases in various species. These six mutants behave as recessive loss-of-function mutants in a homozygous condition. Surprisingly, however, two of the newly isolated drICE alleles are gain-of-function mutants in a heterozygous condition, although they are loss-of-function mutants homozygously. Interestingly, they only behave as gain-of-function mutants in the presence of an apoptotic signal. These two alleles carry missense mutations affecting conserved amino acids in close proximity to the catalytic cysteine residue. This is the first time that viable gain-of-function alleles of caspases are described in any intact organism and provides a significant exception to the expectation that mutations of conserved amino acids always abolish the pro-apoptotic activity of caspases. We discuss models about how these mutations cause the gain-of-function character of these alleles.

Pharmacological options for the management of refractory cancer pain-what is the evidence?

Refractory cancer pain that does not respond to standard opioid and/or co-analgesic therapy occurs in 10-20 % of patients. Risk factors include young age, neuropathic pain type, incident pain, psychological distress, previous opioid use, high tolerance, a history of addiction and impaired cognition. The management of patients with refractory pain remains a challenge. Treatment options include opioid manipulation (parenteral delivery, rotation, combination, methadone and buprenorphine), non-opioids and co-analgesics (paracetamol, non-steroidal anti-inflammatory agents, antidepressants and anticonvulsants), NMDA receptor antagonists, cannabinoids, lignocaine and corticosteroids. The evidence of benefit for any of these agents is weak, and each additional agent increases the risk of adverse events. Evidence-based guidelines cannot, therefore, be developed at present. New approaches are recommended including targeted opioid therapy, multimodal analgesia, a goal-oriented approach to pain management and increasing use of the multidisciplinary team and support services.

Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps.

Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca(2+) in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca(2+) concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca(2+) concentration.

Implementing practice change in chronic cancer pain management: clinician response to a phase III study of ketamine.

BACKGROUND: An adequately powered, double-blind, multisite, randomised controlled trial has shown no net clinical benefit for subcutaneous ketamine over placebo in the management of cancer pain refractory to combination opioid and co-analgesic therapy. The results of the trial were disseminated widely both nationally and internationally. AIM: To determine whether the trial had impacted on clinical practice in Australasia. METHODS: Members of the Australia and New Zealand Society of Palliative Medicine were sent an online ketamine utilisation survey. RESULTS: A total of 123/392 clinicians responded (31% response rate). The majority of respondents had practised for more than 10 years in a metropolitan hospital setting. Ketamine had been prescribed by 91% of respondents, and 92% were aware of the trial. As a result, 65% of respondents had changed practice (17% no longer prescribed ketamine, 46% used less and 2% more). Thirty-five per cent had not changed practice. Reasons for change included belief in the results of the study, concerns over the toxicity reported or because there were alternatives for pain control. Of those who prescribed less, over 80% were more selective and would now only use the drug in certain clinical situations or pain types, or when all other medications had failed. CONCLUSIONS: Although two-thirds of respondents reported practice change as a result of the randomised controlled trial, a minority remained convinced of the benefit of the drug from their own observations and would require additional evidence.