Deep mining of oxysterols and cholestenoic acids in human plasma and cerebrospinal fluid: Quantification using isotope dilution mass spectrometry

Both plasma and cerebrospinal fluid (CSF) are rich in cholesterol and its metabolites. Here we describe in detail a methodology for the identification and quantification of multiple sterols including oxysterols and sterol-acids found in these fluids. The method is translatable to any laboratory with access to liquid chromatography – tandem mass spectrometry. The method exploits isotope-dilution mass spectrometry for absolute quantification of target metabolites. The method is applicable for semi-quantification of other sterols for which isotope labelled surrogates are not available and approximate quantification of partially identified sterols. Values are reported for non-esterified sterols in the absence of saponification and total sterols following saponification. In this way absolute quantification data is reported for 17 sterols in the NIST SRM 1950 plasma along with semi-quantitative data for 8 additional sterols and approximate quantification for one further sterol. In a pooled (CSF) sample used for internal quality control, absolute quantification was performed on 10 sterols, semi-quantification on 9 sterols and approximate quantification on a further three partially identified sterols. The value of the method is illustrated by confirming the sterol phenotype of a patient suffering from ACOX2 deficiency, a rare disorder of bile acid biosynthesis, and in a plasma sample from a patient suffering from cerebrotendinous xanthomatosis, where cholesterol 27-hydroxylase is deficient

Growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula in infants with cow’s milk protein allergy

ObjectiveTo evaluate growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula (eHCF) in infants with cow’s milk protein allergy (CMPA).MethodsA total of 226 infants (mean ± SD age: 106.5 ± 39.5 days, 52.7% were girls) with CMPA who received eHCF comprising at least half of the daily dietary intake were included. Data on anthropometrics [weight for age (WFA), length for age (LFA) and weight for length (WFL) z-scores] were recorded at baseline (visit 1), while data on infant feeding and stool records, anthropometrics and Infant Feeding and Stool Patterns and Formula Satisfaction Questionnaires were recorded at visit 2 (on Days 15 ± 5) and visit 3 (on Days 30 ± 5).ResultsFrom baseline to visit 2 and visit 3, WFA z-scores (from −0.60 ± 1.13 to −0.54 ± 1.09 at visit 2, and to −0.44 ± 1.05 at visit 3, p < 0.001) and WFL z-scores (from −0.80 ± 1.30 to −0.71 ± 1.22 at visit 2, and to −0.64 ± 1.13 at visit 3, p = 0.002) were significantly increased. At least half of infants never experienced irritability or feeding refusal (55.7%) and spit-up after feeding (50.2%). The majority of mothers were satisfied with the study formula (93.2%), and wished to continue using it (92.2%).ConclusionsIn conclusion, eHCF was well-accepted and tolerated by an intended use population of infants  ≤ 6 months of age with CMPA and enabled adequate volume consumption and improved growth indices within 30 days of utilization alongside a favorable gastrointestinal tolerance and a high level of parental satisfaction

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22–24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0–4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22–24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22–24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients

Rare disorders can be an underlying cause of cyclic vomiting: Familial Mediterranean fever, Helicobacter pylori gastritis, and cavernous transformation of the portal vein

Background/Aims: Considering the etiology of cyclic vomiting syndrome (CVS) in childhood, a variety of underlying organic causes has been clearly identified in the literature. The aim of this study was to emphasize that endoscopic evaluation in the first step may help diagnosis and treatment in patients with CVS, unlike the CVS-related ``North American Society for Pediatric Gastroenterology, Hepatology and Nutrition{''} (NASPGHAN) consensus statement in 2008. Materials and Methods: The medical files of patients with vomiting complaints admitted to our tertiary center between the years 2007 and 2012 were analyzed retrospectively. Patients were identified according to the International Classification of Diseases (ICD) codes at their initial presentation, including vomiting. Results: A total of 815 patients with vomiting complaints were evaluated. Of the 379 patients who presented with vomiting only, 336 patients were already being followed for chronic vomiting. Cyclic vomiting was detected in 31 out of 336 patients. Conclusion: In our series, familial Mediterranean fever (FMF), cavernous transformation of the portal vein, and Helicobacter pylori (HP) gastritis presented with CVS for the first time in the pediatric age group. We emphasize that endoscopic evaluation in patients with CVS should be performed as the first step for appropriate diagnosis and treatment

Efficacy and Safety Outcomes With Odevixibat in Children With Progressive Familial Intrahepatic Cholestasis Due to Deficiencies in Multidrug Resistance Protein 3 (PFIC Type 3) or Myosin 5B (PFIC Type 6)

Hasan Özen1, Etienne Sokal2, Florence Lacaille3, Buket Dalgic4, Quanhong Ni5, Lise Kjems5, Patrick Horn5 1Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Université Catholique de Louvain, Cliniques Universitaires Saint Luc, Division of Paediatric Gastroenterology and Hepatology, Brussels, Belgium; 3Paediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France; 4Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey; 5Albireo Pharma, Inc., Boston, MA, USA Introduction/background: Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, inherited liver diseases. Initial descriptions of PFIC were primarily based on data from patients with PFIC type 1 (PFIC1) or 2 (PFIC2). However, additional forms of PFIC have been identified. The ongoing, phase 3 PEDFIC 2 study is assessing the effects of odevixibat, an ileal bile acid transporter inhibitor, in patients with any type of PFIC. Aim: As of a data cut-off date of 4 December 2020, 6 patients with PFIC types other than PFIC1 or PFIC2 had enrolled in PEDFIC 2. Here, we describe efficacy and safety outcomes in this subset of patients, which comprises 5 patients with PFIC type 3 (PFIC3) and 1 with PFIC type 6 (PFIC6). Subjects and methods: In PEDFIC 2, all patients receive open-label odevixibat 120 μg/kg/day. Assessments include change from baseline in serum bile acids (sBAs), pruritus, hepatic biochemical parameters, growth, and sleep. Patient pruritus and sleep were evaluated twice daily by caregivers using the validated PRUCISION scale. Pruritus responses range from 0 to 4, with higher scores indicating worse symptoms. Other outcomes included proportion with sBA response (ie, sBAs reduced ≥70% or levels ≤70 μmol/L), proportion of positive pruritus assessments (PPAs) at the patient level (ie, pruritus score ≤1 or a ≥1-point drop from baseline), and treatment-emergent adverse events (TEAEs). Results: Patients with PFIC3 ranged in age from 3.7–13.3 years, and the 1 patient with PFIC6 was 12.8 years old at screening. All 6 patients were ongoing in the study at the data cut-off. Mean (range) exposure was 41 (34−54) weeks for the 5 PFIC3 patients and 54 weeks for the 1 PFIC6 patient. From baseline to last assessment, all patients had reductions in sBAs and all but 1 patient (PFIC3) had reductions in pruritus score. Mean changes from baseline to week 36 in sBAs, pruritus score, growth, sleep parameters, and liver parameters are shown in the Table. Three patients, including 2 with PFIC3 and 1 with PFIC6, met criteria for sBA response at last assessment. Over the interval from weeks 0–36, PPAs in 5 patients with available data were ≥85%. Overall, 5 of 6 patients experienced any TEAE; no patients had serious TEAEs or TEAEs leading to discontinuation. Summary and conclusion: Patients with PFIC3 or PFIC6 experienced clinical benefits with odevixibat, including reductions in sBAs and improvement in pruritus symptoms, growth, and sleep parameters. Odevixibat treatment was generally well tolerate

Obstructive jaundice and severe pancreatitis due to the foramen of Winslow hernia with multiple anomalies

Internal hernia through the foramen of Winslow is a very rare condition, especially in children. Here we report a 16-month-old girl who presented with obstructive jaundice and elevation of pancreatic enzymes and was ultimately diagnosed with internal hernia and malrotation by radiologic investigation and open approach surgery. To the best of our knowledge, obstructive jaundice with pancreatitis and other congenital abnormalities in children with the foramen of Winslow hernia have not been reported previously in the literature

Investigating The Role of JAK/STAT Pathway upon Dasatinib Induced Apoptosis for CML Cell Model K562

WOS: 00037067630009