Determining predictive metabolomic biomarkers of meniscal injury in dogs with cranial cruciate ligament rupture.

OBJECTIVES: This study used hydrogen nuclear magnetic resonance spectroscopy for the first time to examine differences in the metabolomic profile of stifle joint synovial fluid from dogs with cranial cruciate ligament rupture with and without meniscal injuries, in order to identify biomarkers of meniscal injury. Identifying a biomarker of meniscal injury could then ultimately be used to design a minimally invasive diagnostic test for meniscal injuries in dogs. MATERIALS AND METHODS: Stifle joint synovial fluid was collected from dogs undergoing stifle joint surgery or arthrocentesis for lameness investigations. We used multi-variate statistical analysis using principal component analysis and univariate statistical analysis using one-way analysis of variance and analysis of co-variance to identify differences in the metabolomic profile between dogs with cranial cruciate ligament rupture and meniscal injury, cranial cruciate ligament rupture without meniscal injury, and neither cranial cruciate ligament rupture nor meniscal injury, taking into consideration clinical variables. RESULTS: A total of 154 samples of canine synovial fluid were included in the study. Sixty-four metabolites were annotated to the hydrogen nuclear magnetic resonance spectroscopy spectra. Six spectral regions were found to be significantly altered (false discovery rate adjusted P-value <0.05) between groups with cranial cruciate ligament rupture with and without meniscal injury, including three attributed to nuclear magnetic resonance mobile lipids [mobile lipid -CH3 (P=0.016), mobile lipid -n(CH3 )3 (P=0.017), mobile unsaturated lipid (P=0.031)]. CLINICAL SIGNIFICANCE: We identified an increase in nuclear magnetic resonance mobile lipids in the synovial fluid of dogs with meniscal injury which are of interest as potential biomarkers of meniscal injury.

Sex-based differences in timely emergency department evaluations for patients with drug poisoning.

OBJECTIVES: Unintentional poisoning was the leading cause of injury-related death in the United States in 2017. Prescribed and illicit drugs are the most common cause of poisoning, and timely management in the emergency department (ED) is important. Our aim was to identify any disparities in wait times associated with sex for drug poisoning-related ED visits. STUDY DESIGN: We examined ED visits using data from the 2009-2017 National Hospital Ambulatory Medical Care Survey (NHAMCS). METHODS: Drug poisoning-related visits were identified using the International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification codes. Delayed assessment was defined as wait times exceeding the recommended triage time. Weighted logistic regression was used. RESULTS: The average age was 36 years (standard error = 1.1), 54% female, 87% White and 29% had delayed assessment. Most common drugs were psychotropics (45%) and opioids (32%). Adjusting for race, payment source, urgency, multiple drug types and NSAIDs, females who had poisoning by substances other than opioids had 2.1 times higher likelihood of having a delayed assessment compared with males (odds ratio [95% confidence interval]: 2.1 [1.03-4.2]), although there was no difference between sexes among visits with opioid poisoning (P = 0.27). Neither race (P = 0.23) nor payment source (P = 0.22) were associated with delayed assessment, and the sex association was consistent across these groups. CONCLUSIONS: Females with non-opioid drug poisoning were more likely to have delayed assessment than men. None of the other demographic factors demonstrated a correlation. Identifying more populations vulnerable to delays in the ED can help guide the development of interventions and policies to expedite care and attenuate existing disparities.

Symptomatology and Serum Nuclear Magnetic Resonance Metabolomics; Do They Predict Endometriosis in Fertile Women Undergoing Laparoscopic Sterilisation? A Prospective Cross-sectional Study.

Endometriosis is a common, chronic inflammatory condition, thought to have a higher incidence in symptomatic women, yet, commonly associated symptoms do not always correlate with the presence or severity of disease and diagnosis requires surgery. We prospectively collected data and assessed symptomology and NMR spectroscopy-based metabolomics of 102 women undergoing laparoscopic sterilisation at a tertiary referral centre in a cross-sectional study. Twelve women were incidentally diagnosed with endometriosis (11.7%). According to the pre-operative questionnaire, presence and absence of many symptoms usually attributed to endometriosis were declared at similar frequencies in women with or without endometriosis. Women with endometriosis reported apparently more persistent heavy periods (50% vs 18.9%), prolonged periods (25% versus 7.8%) and problems conceiving (27.3% versus 9%) than those without endometriosis. NMR could not discern any distinguishable differences in the serum metabolome between those with and without endometriosis. Our paper highlights the complex symptomology experienced by women, regardless of a surgical diagnosis of endometriosis. Previous literature and the current study failed to identify clear, distinguishable symptoms or biomarkers pertinent to surgically confirmed endometriosis in the general population. Therefore, development of effective, non-invasive tests for identifying this heterogenous benign condition, endometriosis, is likely to be challenging.

Metabolomic analysis of synovial fluid from Thoroughbred racehorses diagnosed with palmar osteochondral disease using magnetic resonance imaging.

BACKGROUND: Palmar osteochondral disease (POD) is a common cause of lameness in competition horses. Magnetic resonance imaging (MRI) is the most sensitive diagnostic modality currently available, however it may not be financially or logistically practical for routine screening of POD. There is increasing interest in the use of metabolomics for diagnosis prior to progression to irreversible damage. OBJECTIVES: To determine metabolite levels in synovial fluid (SF) of horses with a clinical diagnosis of POD based on diagnostic analgesia and MRI, with the hypothesis that metabolomic profiles differ between diseased and healthy joints. STUDY DESIGN: Prospective clinical study. METHODS: Synovial fluid was collected from metacarpo/tarsophalangeal joints (MC/TPJ) of 29 horses (n = 51 joints), including 14 controls (n = 26) and 15 cases (n = 25), the latter with lameness localised to the MC/TPJ and MR changes consistent with POD (n = 23). Spectra were produced using 1 H-nuclear magnetic resonance (NMR) spectroscopy and analysed. RESULTS: Twenty-five metabolites were recognised associated with various biosynthetic and degradation pathways. The metabolite abundances within the controls demonstrated increased variability compared with the clinical group. The low level of variance between the spectra of the two groups was explained by five principal components. Cross-validation of the cohort demonstrated modest separation of predictive power (R2  = 0.67; Q2  = 0.34). Although statistical significance was not achieved, the most influential metabolites were glucose and lactate. MAIN LIMITATIONS: The modest sample size and variation in signalment, background and presenting condition of the controls may have impacted the discriminative power of the constructed models. The lack of matched controls, differences in time of fluid collection and freezing times may have also reduced accuracy when representing metabolite profiles. CONCLUSIONS: This study identified and quantified metabolites present in MC/TPJ SF of clinical cases with POD.

Giant Cell Arteritis Presenting as an Ischaemic Upper Limb

Aim To present an interesting case of giant cell arteritis presenting as ischaemic upper limb. Methods Data was collected from the patient's chart and from radiology and laboratory systems in our institution. Results The patient had a temporal artery biopsy confirming the diagnosis of temporal arteritis. This was successfully treated with high dose steroids leading to resolution of symptoms in the arm. Conclusion Arteritis is an important consideration to consider in patients who present with limb ischaemia as it is a reversible cause which can be treated effectively.

Using an NMR metabolomics approach to investigate the pathogenicity of amyloid-beta and alpha-synuclein.

INTRODUCTION: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention. OBJECTIVES: To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states. METHOD: Neuroblastoma SH-SY5Y cells were employed to design a robust routine system to perform a statistically rigorous NMR metabolomics study into cellular effects of sub-toxic levels of alpha-synuclein, amyloid-beta 40 and amyloid-beta 42 in monomeric, oligomeric and fibrillar conformations. RESULTS: This investigation developed a rigorous model to monitor intracellular metabolic profiles of neuronal cells through combination of existing methods. This model revealed eight key metabolites that are altered when neuroblastoma cells are challenged with proteins in different aggregation states. Metabolic pathways associated with lipid metabolism, neurotransmission and adaptation to oxidative stress and inflammation are the predominant contributors to the cellular variance and intracellular metabolite levels. The observed metabolite changes for monomer and oligomer challenge may represent cellular effort to counteract the pathogenicity of the challenge, whereas fibrillar challenge is indicative of system shutdown. This implies that although markers of stress are more prevalent under oligomeric challenge the fibrillar response suggests a more toxic environment. CONCLUSION: This approach is applicable to any cell type that can be cultured in a laboratory (primary or cell line) as a method of investigating how protein challenge affects signalling pathways, providing additional understanding as to the role of protein aggregation in neurodegenerative disease initiation and progression.

Utility of Ecological Risk Factors for Evaluation of Transplant Center Performance.

There is substantial evidence across different healthcare contexts that social determinants of health are strongly associated with morbidity and mortality in the United States. These factors, including socioeconomic status, behavior and environmental risks, education, social support, healthy food, and access to healthcare also vary widely by region and individual communities. One of the implications of heterogeneity in these risks is the potential impact on measured quality of healthcare providers. In particular, there is concern that providers treating disproportionally vulnerable communities may be disadvantaged by lack of risk adjustment for these factors that affect health but not indicators of quality of care. Recently, the National Quality Forum has endorsed risk adjustment for sociodemographic characteristics based on these concerns. These issues are salient to transplant programs since social determinants of health impact transplant patient outcomes and vary by region. In this viewpoint, we argue that integration of ecological (area-level) factors in risk adjustment models used to assess transplant center quality should be strongly considered. We believe this reform could be accomplished rapidly, would attenuate disparities in access to care by reducing disincentives to treat patients from vulnerable communities, and improve risk adjustment and calibration of models used for center evaluations.

1H, 15N and 13C assignment of the amyloidogenic protein medin using fast-pulsing NMR techniques.

Thirty-one proteins are known to form extracellular fibrillar amyloid in humans. Molecular information about many of these proteins in their monomeric, intermediate or fibrillar form and how they aggregate and interact to form the insoluble fibrils is sparse. This is because amyloid proteins are notoriously difficult to study in their soluble forms, due to their inherent propensity to aggregate. Using recent developments in fast NMR techniques, band-selective excitation short transient and band-selective optimized flip-angle short-transient heteronuclear multiple quantum coherence we have been able to assign a 5 kDa full-length amyloidogenic protein called medin. Medin is the key protein component of the most common form of localised amyloid with a proposed role in aortic aneurysm and dissection. This assignment will now enable the study of the early interactions that could influence initiation and progression of medin aggregation. The chemical shifts have been deposited in the BioMagRes-Bank accession Nos. 25399 and 26576.

Diagnosis and treatment of sleep related breathing disorders in children: 2007 to 2011.

Sleep related breathing disorders (SRBD) have historically been under-recognised and under-treated. Obstructive sleep apnoea (OSA) affects approximately 3% of children. In line with the increased recognition of SRBD there has been an increase in demand for diagnostic services. We determined the awareness of SRBD amongst Irish paediatricians, examined the provision of sleep services to children throughout the country between 2007 and 2011 and audited diagnostic sleep services in a tertiary centre in 2011. Amongst respondents there was an awareness of SRBD but a poor understanding of diagnostic evaluation with 31/46 (67) referring to inappropriate services. There has been a sharp increase in both diagnostic sleep tests (433-1793 [414]) and in the use of non-invasive ventilation (NIV) (31-186 [627]) for treatment of SRBD between 2007 and 2011. Paediatric sleep services are organized in an ad-hoc manner nationally with significant service variation. The use of domiciliary overnight oximetry reduced the requirement for more formal polysomnography by 70%.

Second toe swelling: Nora's lesion or glomus tumour, case report and literature review.

INTRODUCTION: We report a rare case of bizarre parosteal osteochondromatous proliferation (BPOP, Nora's lesion) of the right second toe in a 60-year-old man who presented with painful, bluish and bulbous swelling of the right second toe without any break in the skin. INVESTIGATIONS: Physical examination, plain radiography and magnetic resonance imaging (MRI) scan of the foot, histology of the excised tissue. DIAGNOSIS: Bizarre parosteal osteochondromatous proliferation. MANAGEMENT: Radiographs showed a calcified/ossified lesion adjacent to the tuft of the terminal phalanx of the second toe. MRI showed a small low signal nodule on T1- and T2-weighted images in a subungual position adjacent to the terminal phalanx with sclerosis. The second toe was excised and the histology from excised tissue was consistent with "bizarre parosteal osteochondromatous proliferation". There was no malignant change on histology. Local excision of the entire lesion was done and there has been no recurrence to date. CONCLUSION: BPOP, although a benign lesion, behaves aggressively with rapid growth and has a high risk of local recurrence after local resection (Nora et al. in Am J Surg Pathol 7(3):245-250, 1983; Meneses et al. in Am J Surg Pathol 17(7):691-697, 1993). Its clinical presentation can be confused with glomus tumour, subungual exostosis and enchondroma. The distinguishing features of BPOP and several relevant different differential diagnoses are discussed in this case report.