Biochemical Markers Of Disease Research Articles

A268 1 YEAR FOLLOW-UP OF PEDIATRIC ULCERATIVE COLITIS USING INTESTINAL ULTRASOUND

Abstract Background Intestinal ultrasound (IUS) is an emerging tool that offers a non-invasive method for monitoring inflammatory bowel disease in pediatric patients, with increasing popularity worldwide. Assessment of IUS for monitoring pediatric Ulcerative Colitis (UC) has been previously limited to small samples of patients with no long-term follow up. Aims This project aims to utilize intestinal ultrasound assessments obtained at routine time points to determine changes in IUS parameters within 12 months of study enrollment in newly diagnosed children with UC, and their relationship to biochemical markers, clinical assessments, and endoscopic findings. Methods Pediatric patients with suspected ulcerative colitis were prospectively enrolled through the Edmonton Pediatric IBD Clinic. Participants underwent IUS, clinical assessments, bloodwork for biomarkers, and fecal calprotectin (FCP) testing at baseline, 1-, 3-, 6-, and 12-month visits, as well as endoscopy at baseline and 6-12 months. In each IUS assessment, the bowel wall thickness (BWT), presence of hyperemia, abnormal haustrations, and fat wrapping was determined in 4 bowel segments (right, transverse, descending, and sigmoid colon). The Pediatric Ulcerative Colitis Activity Index (PUCAI) scores and Ulcerative Colitis Intestinal Ultrasound Scores (UC-IUS) were calculated at each visit. Results 42 patients (55% male) were included. Median UC-IUS total scores and BWT alone improved in all bowel segments over the study period. For the most affected bowel segment for all patients, median percent reduction of BWT was 39.6%, 34.2%, 33.7%, and 42.5%, at the 1-, 3-, 6-, and 12-month assessment respectively. The biggest decrease in UC-IUS scores and BWT occurred with the initiation of therapy between baseline and 1-month. UC-IUS scores significantly correlated with endoscopy at 12-months, clinical assessments at all time points, and biochemical markers of disease at all time points over the 12-month study period (pampersand:003C0.05). BWT measurement alone also had significant correlation with endoscopy at 12 months; clinical assessment at 1-, 3-, and 6-months; and with biochemical markers at every time point (pampersand:003C0.05). Patients with inflammatory bowel markers (indicated by elevated FCP (ampersand:003E250)) at 12-months were found to have significantly thicker BWT and UC-IUS scores at 3- and 6-months. Conclusions BWT and UC-IUS performed well in pediatric patients with newly-diagnosed UC, with UC-IUS scores and BWT measurements alone correlating significantly with endoscopic, clinical, and biochemical disease activity over the 12-month study period. BWT alone performed similarly to total UC-IUS scores. This data suggests that IUS can offer a non-invasive method to monitor long-term pediatric UC disease severity. Funding Agencies TRIANGLE, WCHRI, Stollery Children's Hospital Foundation.

P417 1 year follow-up of pediatric ulcerative colitis using intestinal ultrasound

Abstract Background Intestinal ultrasound (IUS) is an emerging tool that offers a non-invasive method for monitoring inflammatory bowel disease in pediatric patients, with increasing popularity worldwide. Assessment of IUS for monitoring pediatric Ulcerative Colitis (UC) has been limited to small samples of patients with no long-term follow up. Our aim is to utilize intestinal ultrasound assessments obtained at routine time points to determine changes in IUS parameters within 12 months of study enrollment in newly diagnosed children with UC, and their relationship to biochemical markers, clinical assessments, and endoscopic findings. Methods Pediatric patients with suspected ulcerative colitis were prospectively enrolled through the Edmonton Pediatric IBD Clinic. Participants underwent IUS, clinical assessments, bloodwork for biomarkers, and fecal calprotectin (FCP) testing at baseline, 1-, 3-, 6-, and 12-month visits, as well as endoscopy at baseline and 6-12 months. In each IUS assessment, the bowel wall thickness (BWT), presence of hyperemia, abnormal haustrations, and fat wrapping was determined in 4 bowel segments (right, transverse, descending, and sigmoid colon). The Pediatric Ulcerative Colitis Activity Index (PUCAI) scores and Ulcerative Colitis Intestinal Ultrasound Scores (UC-IUS) were calculated at each visit. Results 42 patients (55% male) were included. Median UC-IUS total scores and BWT alone improved in all bowel segments over the study period. For the most affected bowel segment for all patients, median percent reduction of BWT was 39.6%, 34.2%, 33.7%, and 42.5%, at the 1-, 3-, 6-, and 12-month assessment respectively. The biggest decrease in UC-IUS scores and BWT occurred with the initiation of therapy between baseline and 1-month. UC-IUS scores significantly correlated with endoscopy at 12-months, clinical assessments at all time points, and biochemical markers of disease at all time points over the 12-month study period (p<0.05). BWT measurement alone also had significant correlation with endoscopy at 12 months; clinical assessment at 1-, 3-, and 6-months; and with biochemical markers at every time point (p<0.05). Patients with inflammatory bowel markers (indicated by elevated FCP (>250)) at 12-months were found to have significantly thicker BWT and UC-IUS scores at 3- and 6-months. Conclusion BWT and UC-IUS performed well in pediatric patients with newly-diagnosed UC, with UC-IUS scores and BWT measurements alone correlating significantly with endoscopic, clinical, and biochemical disease activity over the 12-month study period. BWT alone performed similarly to total UC-IUS scores. This data suggests that IUS can offer a non-invasive method to monitor long-term pediatric UC disease severity.

Predictors of Cardiovascular Morbidities in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.

The prevalence of cardiovascular and metabolic complications among adults with 21-hydroxylase deficiency (21OHD) is unknown. We sought to determine the prevalence of cardiovascular and metabolic morbidities among adults with 21OHD and to identify clinical factors and biomarkers associated with cardiovascular outcomes. A 10-year retrospective cross-sectional analysis was conducted on adult patients with confirmed 21OHD, aged 18 to 70 years, who had at least one clinical visit for assessment at the University of Michigan. The presence of cardiovascular diseases (CVDs) and other metabolic comorbidities was extracted from medical records based on International Classification of Diseases (ICD) codes. Medical treatments, glucocorticoid (GC) and mineralocorticoid doses, as well as specific biomarkers of disease control since age 18, were collected for analysis. A total of 254 patients with 21OHD, median age of 35 years (interquartile range, 28.25-46 y), were included in the analysis. The prevalence of CVDs in the entire cohort was 7.5%. An increase in prevalence was seen from early adulthood, reaching 25% in patients older than 60 years. Increasing age (adjusted odds ratio [OR], 1.05; 95% CI, 1.01-1.09), hypertension (OR, 4.27; 95% CI, 1.41-12.92), and higher GC doses (OR, 1.51; 95% CI, 1.11-2.06) were significantly associated with prevalent CVDs. Higher plasma renin activity was significantly associated with CVDs (OR, 1.07; 95% CI, 1.01-1.15) but not other biochemical markers of disease. Cardiometabolic morbidities are prevalent among adults with 21OHD. Hypertension, age, and GC exposure are the main predictive factors of established CVDs in our cohort.

Implementation of a Whole Food Plant Based Diet in a Food as Prevention Program in a Resource Constrained Environment.

The efficacy of a Whole Food Plant-based (WFPB) diet has been shown in randomized controlled trials in diabetes, cardiovascular disease and obesity. However, it's effectiveness in routine clinical settings is less well documented. This study describes the implementation and outcomes of a "Food as Prevention" program run by a single clinician. Participants were referred to a "Food as Prevention" program run by a single gastroenterologist at an academic teaching center. The program included 5 physician-led discussion and small group educational sessions. Data collected included demographics, weight and biochemical measurements before and after completion of the program. Statistical analysis included paired t-test and Pearson correlation coefficients were used to assess differences before and after WFPB implementation. A total of 17 participants (age 59 years; 59% female) with an average weight of 90.0 kg attended a median of 3 group sessions. Majority of patients had hyperlipidemia (71%) followed by hypertension (47%) and coronary artery disease (35%), fatty liver disease (35%) and diabetes mellitus (29%). Adoption of a WFPB diet led to significant decreases in weight (4.3 kg; p < 0.01), total cholesterol (0.72 mmol/L; p = 0.046), and triglycerides (0.53 mmol/L; p = 0.005) with an increase in high-density lipoprotein (HDL) (0.10 mmol/L; p = 0.01).Conclusions Implementation of the WFPB diet in this novel pilot program led to weight loss and improvement in biochemical markers of disease. Future studies are needed to implement this model on a larger scale.

Canakinumab for the treatment of autoinflammatory very early onset- inflammatory bowel disease.

IntroductionTherapeutic options are critically needed for children with refractory very early onset inflammatory bowel disease (VEO-IBD). Our aim was to evaluate clinical response to canakinumab, an anti-IL-1β monoclonal antibody, in patients with VEO-IBD whose phenotype resembles those with monogenic autoinflammatory disease.MethodsThis is a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of identified monogenic disease treated with canakinumab for >6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events.ResultsNineteen patients were included: 47% with infantile onset, 58% classified as IBD-U, and 42% classified as CD. At baseline, 37% were biologic naïve, and canakinumab was used as dual therapy in 74% of patients. Clinical response was achieved in 89% with statistically significant improvement in PCDAI and PUCAI. Clinical remission was achieved in 32% of patients. There was significant improvement in the clinical manifestations of AIP and the biochemical markers of disease. Number of hospitalizations (p<0.01) and length of stay (p<0.05) decreased. Growth improved with median weight-for-length Z-score increasing from -1.01 to 1.1 in children less than 2 years old. There were minimal adverse events identified during the study period.ConclusionCanakinumab may be an effective and safe treatment for a subset of children with VEO-IBD with AIP, as well as older patients with IBD. This study highlights the importance of a precision medicine approach in children with VEO-IBD.

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Comparing Effectiveness of a Generic Oral Nutritional Supplement With Specialized Formula in the Treatment of Active Pediatric Crohn's Disease.

Exclusive enteral nutrition (EEN) is the recommended induction treatment of mild to moderate active pediatric Crohn's disease (CD). This study compared outcomes of 2 proprietary polymeric formulas. Treatment effectiveness was examined along with practical aspects of formula delivery and differences in estimated treatment costs. Data were retrospectively collected from patients with CD who received a generic oral nutritional supplement (Fortisip) across 2 centers (RCH, Melbourne and RHSC, Edinburgh). This was compared with a prospective cohort (RHC, Glasgow) that used a specialized formula (Modulen IBD). The data collected included patient demographics, remission rates, biochemical markers, administration method, and anthropometrics. The estimated treatment cost was performed by comparing price per kcal between each formula. One hundred seventy-one patients were included (106 Fortisip, 65 Modulen IBD, 70 female; median age 13.3 yrs). No difference was demonstrated in remission rate (Fortisip n = 67 of 106 [63%] vs Modulen IBD n = 41 of 64 [64%], P = .89), nonadherence rate (Fortisip n = 7 of 106 [7%] vs Modulen IBD 3 of 64 [5%], P = .57) or method of administration (NGT Fortisip use n = 16 of 106 [12%] vs Modulen IBD 14 of 65 [22%]; P = .31). There was no difference in reduction of biochemical disease markers between the groups (C-reactive protein , P = .13; erythrocyte sedimentation rate, P = .49; fecal calprotectin, P = .94). However, there was a cost-saving of around £500/patient/course if the generic oral nutritional supplement was used. The generic oral nutritional supplement and specialized formulas both had similar clinical effectiveness in induction of remission in pediatric CD. However, there is considerable cost-saving when using a generic oral nutritional supplement.

Effects of chronic dietary nitrate supplementation on longevity, vascular function and cancer incidence in rats

RationaleDietary nitrate and nitrite have a notoriously bad reputation because of their proposed association with disease, in particular cancer. However, more recent lines of research have challenged this dogma suggesting that intake of these anions also possess beneficial effects after in vivo conversion to the vital signaling molecule nitric oxide. Such effects include improvement in cardiovascular, renal and metabolic function, which is partly mediated via reduction of oxidative stress. A recent study even indicates that low dose of dietary nitrite extends life span in fruit flies. MethodsIn this study, 200 middle-aged Wistar rats of both sexes were supplemented with nitrate or placebo in the drinking water throughout their remaining life and we studied longevity, biochemical markers of disease, vascular reactivity along with careful determination of the cause of death. ResultsDietary nitrate did not affect life span or the age-dependent changes in markers of oxidative stress, kidney and liver function, or lipid profile. Ex vivo examination of vascular function, however, showed improvements in endothelial function in rats treated with nitrate. Neoplasms were not more common in the nitrate group. ConclusionWe conclude that chronic treatment with dietary nitrate does not affect life span in rats nor does it increase the incidence of cancer. In contrast, vascular function was improved by nitrate, possibly suggesting an increase in health span.

A183 TELEHEALTH USE IN RURAL SASKATCHEWAN AND INFLAMMATORY BOWEL DISEASE OUTCOMES

BackgroundAppropriate management of inflammatory bowel disease (IBD) often requires multiple specialist appointments per year. Living in rural locations may pose a barrier to regular specialist care. Saskatchewan (SK) has a large rural population. Prior to COVID-19, telehealth (TH) in SK was not routinely used for either patient assessment or follow up. Furthermore, TH was exclusively between hospitals and specific TH sites without direct contact using patient’s personal phones.AimsThe objective of this study was to assess the differences in demographics, disease characteristics, outcomes, and health care utilization between patients from rural SK with IBD who used TH and those who did not.MethodsA retrospective chart review was completed on all rural patients (postal code S0*) with IBD in SK who were followed at the Multidisciplinary IBD Clinic in Saskatoon between January 2018 and February 2020. Patients were classified as using TH if they had ever used it. Information on demographics, disease characteristics, and access to IBD-related health care in the year prior to their last IBD clinic visit or endoscopy was collected. Data was not collected for clinic visits after March 1, 2020 as all outpatient care became remote secondary to the COVID-19 pandemic. Mean, standard deviations, median and interquartile ranges (IQR) were reported. Mann-Witney U and Chi-Square tests were used to determine differences between the groups.ResultsIn total, 288 rural SK IBD patients were included, 30 (10.4%) used TH and 258 (89.6%) did not. Patient demographics were not significantly different between the two groups; although, there was a statistically significant difference in the proportion of ulcerative colitis patients (17% TH vs. 38% non-TH, p=0.02). The percentage of patients with clinical remission was 87% for TH patients and 74% for non-TH patients (p=0.13). There were no significant differences in health care utilization patterns and biochemical markers of disease, including c-reactive protein (CRP) and fecal calprotectin (FCP) (p>0.05).ConclusionsPrior to the pandemic, a small percentage of patients with IBD in rural SK ever used TH. A small proportion of UC patients used TH. No significant differences in disease characteristics, outcomes, or health care utilization were identified. Further study is warranted to identify barriers to use of this technology to tailor care to this patient group and improve access to care, especially now as the COVID-19 pandemic has drastically changed the use of virtual care.Telehealth (n=30)Non-Telehealth (n=258)P-valueHarvey-Bradshaw Index, median (IQR)2(0.25–4)1(0–4.25)0.62Partial Mayo Score, median (IQR)0(0–0.25)0(0–2)0.14CRP<5, n(%)23(79)176(72)0.38FCP<50, n(%)9(47)52(29)0.12Clinical Remission, n(%)26(87)191(74)0.13Clinic visits within the last 12 months, median (IQR)2 (1–2.25)2 (1–3)0.18Funding AgenciesNone

Studying Autism Using Untargeted Metabolomics in Newborn Screening Samples

Main risk factors of autism spectrum disorder (ASD) include both genetic and non-genetic factors, especially prenatal and perinatal events. Newborn screening dried blood spot (DBS) samples have great potential for the study of early biochemical markers of disease. To study DBS strengths and limitations in the context of ASD research, we analyzed the metabolomic profiles of newborns later diagnosed with ASD. We performed LC-MS/MS-based untargeted metabolomics on DBS from 37 case-control pairs randomly selected from the iPSYCH sample. After preprocessing using MZmine 2.41, metabolites were putatively annotated using mzCloud, GNPS feature-based molecular networking, and MolNetEnhancer. A total of 4360 mass spectral features were detected, of which 150 (113 unique) could be putatively annotated at a high confidence level. Chemical structure information at a broad level could be retrieved for 1009 metabolites, covering 31 chemical classes. Although no clear distinction between cases and controls was revealed, our method covered many metabolites previously associated with ASD, suggesting that biochemical markers of ASD are present at birth and may be monitored during newborn screening. Additionally, we observed that gestational age, age at sampling, and month of birth influence the metabolomic profiles of newborn DBS, which informs us on the important confounders to address in future studies.

Characterization of Monophasic Solvent-Based Tissue Extractions for the Detection of Polar Metabolites and Lipids Applying Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry Clinical Metabolic Phenotyping Assays.

Metabolic phenotyping of tissues uses metabolomics and lipidomics to measure the relative polar and nonpolar (lipid) metabolite levels in biological samples. This approach aims to understand disease biochemistry and identify biochemical markers of disease. Sample preparation methods must be reproducible, sensitive (high metabolite and lipid yield), and ideally rapid. We evaluated three biphasic methods for polar and nonpolar compound extraction (chloroform/methanol/water, dichloromethane/methanol/water, and methyl tert-butyl ether [MTBE]/methanol/water), a monophasic method for polar compound extraction (acetonitrile/methanol/water), and a monophasic method for nonpolar compound extraction (isopropanol/water). All methods were applied to mammalian heart, kidney, and liver tissues. Polar extracts were analyzed by hydrophilic interaction chromatography (HILIC) ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS) and nonpolar extracts by C18 reversed-phase UHPLC-MS. Method reproducibility and yield were assessed using multiple annotated endogenous compounds (putatively and MS/MS annotated). Monophasic methods had the highest yield and high reproducibility for both polar (positive ion: median relative standard deviation (RSD) < 18%; negative ion: median RSD < 28%) and nonpolar (positive and negative ion: median RSD < 15%) extractions for heart, kidneys, and liver. The polar monophasic method extracted higher levels of lipid than biphasic polar extractions, and these lipids caused minimal detection suppression for other compounds during HILIC UHPLC-MS. The nonpolar monophasic method had similar or greater detection responses of all detected lipid classes compared to biphasic methods (including increased phosphatidylinositol, phosphatidylserine, and cardiolipin responses). Monophasic methods are quicker and simpler than biphasic methods and are therefore most suited for future automation.

P483 Vedolizumab serum drug levels are not associated with clinical outcomes or markers of disease activity in inflammatory bowel disease

Abstract Background Treatment options in Inflammatory Bowel Disease (IBD) include anti-TNFα and anti-integrin biologics. Therapeutic drug monitoring (TDM) is used to support clinical decision making and improve treatment outcomes with anti-TNFα drugs infliximab and adalimumab.1,2 It is unclear if TDM can offer similar benefits with vedolizumab (VDZ) and there are no clinical guidelines for using TDM with VDZ3. The aim of this study was to identify if drug levels (DL) are associated with clinical outcomes and markers of disease activity in patients treated with VDZ. Methods All VDZ DLs performed since introduction of testing at our unit in December 2018 were retrospectively identified. Target DLs of &amp;gt;30 μg/ml during induction (≤14 weeks since treatment initiation (TI)) and &amp;gt;10 μg/ml in maintenance (&amp;gt;14 weeks after TI) were agreed based on available published data. Dose information, timing of DL, lab results and disease activity scores were obtained from electronic patient records and paired with the DL dose. Calprotectin was included if recorded within 3 months of DL. Patients were classified as in remission or mild, moderate or severe active disease according to partial Mayo Score for ulcerative colitis and Harvey–Bradshaw Index for Crohn’s disease. Sub-analysis was undertaken according to timing of testing in relation to TI. Results Sixty pre-dose trough VDZ levels were identified from 41 patients. Median VDZ level was 25.7 μg/ml (&amp;lt;3.5–&amp;gt;70). Median time from TI to first VDL DL was 36 weeks (4.6–184). No relationship was identified between VDZ levels and biochemical markers of disease (Figure 1). Fourteen (23.3%) TDM were performed during induction. 6/14(42.8%) had subtherapeutic DLs; 3 in remission, 1 mild, 2 severe disease. The remaining 8/14(57.1%) had therapeutic DL; 3 mild, 3 moderate, 1 severe disease, 1 unknown. Forty-six (76.7%) TDM were performed during maintenance. Five out of 46(10.9%) had subtherapeutic DLs; 3 remission, 1 moderate disease, 1 unknown. The remaining 41/46(89.1%) had therapeutic DLs; 16 remission, 11 mild, 10 moderate, 3 severe disease, 1 unknown. For both sub-analysis groups, no relationship between disease state and drug level was observed. Conclusion The results from this small cohort do not suggest a relationship between serum VDZ levels and clinical outcomes. Further research in larger cohorts is needed to confirm or refute these findings. References

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

Crohn's Disease in Clinical Remission Is Marked by Systemic Oxidative Stress.

Introduction: Crohn’s disease (CD) is characterized by chronic and relapsing inflammation of the gastro-intestinal tract. It is assumed that oxidative stress contributes to CD pathogenesis, but systemic biomarkers for oxidative stress in CD are not yet identified. A reduction in free thiol groups in plasma proteins (“plasma free thiols”) reflects systemic oxidative stress since they are prime substrates for reactive oxygen species. Here, we determined the concentrations of plasma free thiols in CD patients and healthy controls and studied the putative correlation with disease parameters.Methods: Free thiols were quantified in plasma of patients with CD in clinical remission [according to the Harvey Bradshaw Index (HBI)] and healthy controls and adjusted for plasma albumin. Albumin-adjusted free thiol concentrations were analyzed for associations with clinical and biochemical disease markers.Results: Mean plasma free thiol concentrations were significantly lower in patients with CD (n = 51) compared to healthy controls (n = 27) (14.7 ± 2.4 vs. 17.9 ± 1.8 μmol/g albumin; P < 0.001). Patients with CD with above-average free thiols had significantly lower CRP levels (median 1.4 [interquartile range] [0.4; 2.6] vs. 3.6 [0.6; 7.0] mg/L; P < 0.05) and BMI (23.6 ± 4.8 vs. 27.1 ± 5.2 kg/m2; P < 0.05). Patients with CD having solely colonic disease demonstrated markedly reduced plasma free thiol concentrations compared to patients with ileocolonic involvement (13.2 ± 1.8 vs. 15.2 ± 2.2 μmol/g; P < 0.05). Finally, plasma free thiol concentrations negatively correlated with biomarkers of inflammation, including hsCRP, SAA, IL-17A (all P < 0.05), and VEGF.Conclusion: Plasma free thiols are reduced in patients with CD in clinical remission compared to healthy controls. Thus, subclinical CD disease activity is reflected by systemic oxidative stress and plasma free thiols may be a relevant therapeutic target and biomarker to monitor disease activity in CD.

Hypercholesterolemia and hypertriglyceridemia as biochemical markers of disease in companion rabbits.

Inflammation has important effects on lipid metabolism, but the relationship between hyperlipidemia, inflammation, and disease remains unknown in rabbits. While rabbits are sensitive to dietary hypercholesterolemia, the etiology of hyperlipidemia when fed non-atherogenic diets is uncertain. This study aimed to determine the association between hypercholesterolemia and patient characteristics, diseases, and select CBC and biochemistry analytes in rabbits, and to measure plasma lipoprotein lipid fractions in rabbits with inflammatory and other diseases. Complete blood count and plasma biochemistry data, including total cholesterol concentrations, were evaluated in 531 companion rabbits. Lipoprotein cholesterol fractions (non-high-density lipoprotein cholesterol [non-HDLc] and high-density lipoprotein [HDLc]) and triglycerides were measured using a colorimetric enzymatic assay in archived plasma from a subset of 267 rabbits. Rabbits were categorized by age, sex, spay/neuter status, breed, diet status (fed atherogenic dietary components or not), the organ system affected by disease, and the pathologic process. Cholesterol was associated with fibrinogen (P=0.01), globulins (P<0.01), and heterophil (P<0.01) concentrations. Adjusting for diet, rabbits with severe infection or sepsis (odds ratio [OR]=13.25, 95% CI=5.83-30.12), renal failure (OR=14.42, 95% CI=5.69-36.54), and hepatopathy (OR=8.55, 95% CI=3.55-20.62) had increased risks of hypercholesterolemia. Increased non-HDLc and triglyceride concentrations were also associated with these three disease states (P<0.05). Hyperlipidemia is associated with biochemical and CBC markers of inflammation, and with severe infection or sepsis, renal failure, and hepatopathy. Independent of diet, increased cholesterol, non-HDLc, and triglycerides are indicators of disease in companion rabbits.

Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe'sdisease).

Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a debilitating and always fatal pediatric neurodegenerative disease caused by a mutation in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC). In the absence of GALC, progressive loss of myelin and accumulation of a neurotoxic substrate lead to incapacitating loss of motor and cognitive function and death, typically by 2 years of age. Currently, there is no cure. Recent convincing evidence of the therapeutic potential of combining gene and cell therapies in the murine model of GLD has accelerated the requirement for validated markers of disease to evaluate therapeutic efficacy. Here we demonstrate clinically relevant and quantifiable measures of central (CNS) and peripheral (PNS) nervous system disease progression in the naturally occurring canine model of GLD. As measured by brainstem auditory-evoked response testing, GLD dogs demonstrated a significant increase in I-V interpeak latency and hearing threshold at all time points. Motor nerve conduction velocities (NCVs) in GLD dogs were significantly lower than normal by 12-16 weeks of age, and sensory NCV was significantly lower than normal by 8-12 weeks of age, serving as a sensitive indicator of peripheral nerve dysfunction. Post-mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and the PNS. Additionally, cerebrospinal fluid psychosine concentrations were significantly elevated in GLD dogs, demonstrating potential as a biochemical marker of disease. These data demonstrate that CNS and PNS disease progression can be quantified over time in the canine model of GLD with tools identical to those used to assess human patients. © 2016 Wiley Periodicals, Inc.

CSF complement 3 and factor H are staging biomarkers in Alzheimer's disease.

IntroductionCSF levels of established Alzheimer’s disease (AD) biomarkers remain stable despite disease progression, and non-amyloid non-tau biomarkers have the potential of informing disease stage and progression. We previously identified complement 3 (C3) to be decreased in AD dementia, but this change was not found by others in earlier AD stages. We hypothesized that levels of C3 and associated factor H (FH) can potentially distinguish between mild cognitive impairment (MCI) and dementia stages of AD, but we also found their levels to be influenced by age and disease status.ResultsWe developed a biochemical/bioinformatics pipeline to optimize the handling of complex interactions between variables in validating biochemical markers of disease. We used data from the Alzheimer’s Disease Neuro-imaging Initiative (ADNI, n = 230) to build parallel machine learning models, and objectively tested the models in a test cohort (n = 73) of MCI and mild AD patients independently recruited from Emory University. Whereas models incorporating age, gender, APOE ε4 status, and CSF amyloid and tau levels failed to reliably distinguish between MCI and mild AD in ADNI, introduction of CSF C3 and FH levels reproducibly improved the distinction between the two AD stages in ADNI (p < 0.05) and the Emory cohort (p = 0.014). Within each AD stage, the final model also distinguished between fast vs. slower decliners (p < 0.001 for MCI, p = 0.007 for mild AD), with lower C3 and FH levels associated with more advanced disease and faster progression.ConclusionsWe propose that CSF C3 and FH alterations may reflect stage-associated biomarker changes in AD, and can complement clinician diagnosis in diagnosing and staging AD using the publically available ADNI database as reference.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0277-8) contains supplementary material, which is available to authorized users.

Treatment of acromegaly in the era of personalized and predictive medicine.

Acromegaly is a chronic disorder usually diagnosed late in the disease evolution. Such delayed diagnosis, together with the inability to achieve the treatment goals of normalizing biochemical disease markers and controlling tumour mass may result in substantial morbidity and mortality. Somatostatin analogues (SSA) are accepted as first-line medical therapy or as second-line therapy in patients undergoing unsuccessful surgery and are considered a cornerstone in the treatment of acromegaly. However, because a high percentage of patients experience SSA medical treatment failure, the identification of biomarkers associated with a successful or unsuccessful response to all classes of medical therapy would help in the choice of treatment and potentially allow for a quicker normalization of biochemical parameters. The current treatment algorithms for acromegaly are based upon a "trial-and-error" approach with additional treatment options provided when disease is not controlled. In many other diseases, therapeutic algorithms have been evolving towards personalized treatment with the medication that best matches individual disease characteristics, using biomarkers that identify therapeutic response. Additionally, a personalized approach to complementary treatment of comorbidities present in the acromegalic patient is also required. This review will discuss the development of a potential treatment algorithm for acromegaly addressing the biochemical control of the disease as well of its associated comorbidities, under a personalized approach based upon markers of prognostic and predictive significance, such as tumour size, MRI adenoma signal, GH value after acute octreotide test, granular adenoma pattern, Ki-67, somatostatin receptor phenotype, aryl hydrocarbon-interacting protein expression, gsp mutations, RAF kinase activity, E-cadherin and beta-arrestin-1.

Surgical management of medullary thyroid cancer

Medullary Thyroid cancer is a rare malignancy with aggressive behaviour, which can be either sporadic or hereditary. Diagnosis is based on measuring the serum calcitonin levels of patients with thyroid nodules or on screening for RET gene mutations of the first degree relatives of patients with hereditary MTC. Treatment is surgical and involves total thyroidectomy and central lymph node dissection in all diagnosed cases. Further lateral LN dissection should be performed when indicated and is further analyzed throughout the article. Postoperative observation includes biochemical markers of disease (calcitonin and CEA) as well as imaging studies when indicated. Recurrence rates are high because of early lymphatic metastases. However, the overall 5-year survival rates are also high.

Use of early biomarkers in neonatal brain damage and sepsis: state of the art and future perspectives.

The identification of early noninvasive biochemical markers of disease is a crucial issue of the current scientific research, particularly during the first period of life, since it could provide useful and precocious diagnostic information when clinical and radiological signs are still silent. The ideal biomarker should be practical and sensitive in the precocious identification of at risk patients. An earlier diagnosis may lead to a larger therapeutic window and improve neonatal outcome. Brain damage and sepsis are common causes of severe morbidity with poor outcome and mortality during the perinatal period. A large number of potential biomarkers, including neuroproteins, calcium binding proteins, enzymes, oxidative stress markers, vasoactive agents, and inflammatory mediators, have been so far investigated. The aim of the present review was to provide a brief overview of some of the more commonly investigated biomarkers used in case of neonatal brain damage and sepsis.