Metabolomics Signature in Prediabetes and Diabetes: Insights From Tandem Mass Spectrometry Analysis.

OBJECTIVE: This study investigates the metabolic differences between normal, prediabetic and diabetic patients with good and poor glycaemic control (GGC and PGC). DESIGN: In this study, 1102 individuals were included, and 50 metabolites were analysed using tandem mass spectrometry. The diabetes diagnosis and treatment standards of the American Diabetes Association (ADA) were used to classify patients. METHODS: The nearest neighbour method was used to match controls and cases in each group on the basis of age, sex and BMI. Factor analysis was used to reduce the number of variables and find influential underlying factors. Finally, Pearson's correlation coefficient was used to check the correlation between both glucose and HbAc1 as independent factors with binary classes. RESULTS: Amino acids such as glycine, serine and proline, and acylcarnitines (AcylCs) such as C16 and C18 showed significant differences between the prediabetes and normal groups. Additionally, several metabolites, including C0, C5, C8 and C16, showed significant differences between the diabetes and normal groups. Moreover, the study found that several metabolites significantly differed between the GGC and PGC diabetes groups, such as C2, C6, C10, C16 and C18. The correlation analysis revealed that glucose and HbA1c levels significantly correlated with several metabolites, including glycine, serine and C16, in both the prediabetes and diabetes groups. Additionally, the correlation analysis showed that HbA1c significantly correlated with several metabolites, such as C2, C5 and C18, in the controlled and uncontrolled diabetes groups. CONCLUSIONS: These findings could help identify new biomarkers or underlying markers for the early detection and management of diabetes.

Investigation of catalytic activity of metal doped nanocages (Ni-C72 and Ni-Al36P36) for ozone decomposition to oxygen molecules.

CONTEXT: The potential of Ni-C72 and Ni-Al36P36 as effective catalysts for O3 decomposition is examined by LH and ER mechanisms. The activation barrier energy and Gibbs free energy of reaction steps for O3 decomposition on Ni-C72 and Ni-Al36P36 are calculated. The ∆Eformation of Ni-C72 and Ni-Al36P36 are negative values and these structures are stable nano-catalysts. The Ni atoms are catalytic positions to adsorb the O3 and other important species of O3 decomposition by LH and ER mechanisms. The Ni-Al36P36 for O3 decomposition has lower Eacivation and more negative ∆Greaction than Ni-C72. The Eacivation value of rate-determining step for O3 decomposition by LH mechanism is lower than ER mechanism. The Ni-C72 and Ni-Al36P36 can catalyze the reaction steps of O3 decomposition by LH and ER mechanisms. METHODS: The structures of Ni-C72 and Ni-Al36P36 nanocages and their complexes with O3 and other important species of are optimized by PW91PW91/6-311 + G (2d, 2p) model and M06-2X/cc-pVQZ model in GAMESS software. The strcutures of nanocages and their complexes with important species of O3 decomposition by LH and ER mechanisms are optimized and their frequencies are calculated in order to demonstrate that these structures are real minima on the potential energy surface.

Radiation-induced myofibroblastoma within the nasal sinus requiring maxillectomy and ethmoidectomy: A case report and literature review.

We report a case of radiation-induced myofibroblastoma of the right nasal cavity in a patient with a remote history of radiotherapy for pediatric retinoblastoma. The patient required maxillectomy and ethmoidectomy. To our knowledge, a rare number of cases have been reported in this location.

Pathogenic Novel Heterozygous Variant c.1076c>T p. (Ser359Phe) chr1: 120512166 in NOTCH2 Gene, Type 2 Alagille Syndrome Causing Neonatal Cholestasis: A Case Report.

BACKGROUND Alagille syndrome (ALGS) is a multisystem hereditary illness with a dominant pattern and partial penetrance. Multiple organ abnormalities can be caused by mutations in the Jagged canonical Notch ligand 1 (JAG1) gene. Notch receptor 2 (NOTCH2) gene mutations are also uncommon. ALGS is also characterized by deformed or narrowed bile ducts and is notoriously difficult to diagnose due to the wide range of symptoms and absence of unambiguous genotype-phenotype connections. Little is known about ALGS patients who have NOTCH2 mutations. We present a patient who developed progressive liver failure due to a unique pathogenic heterozygous variation of the NOTCH2 gene, c.1076c>T p. (Ser359Phe) chr1: 120512166, resulting in type 2 ALGS. CASE REPORT A Saudi Arabian newborn with bilateral hazy eyes, ectropion, dry ichthyic skin, normal male genitalia, and bilateral undescended testes was born at 31 weeks. Previous miscarriages, pregnancy-induced maternal cholestasis, fatty liver, or neonatal jaundice were not reported in the family history. He had developed worsening cholestatic jaundice by the third week of hospitalization. The extensive work-up for metabolic, infectious, and other relevant etiologies was negative. Following gram-negative sepsis, he died of multiorgan failure. A NOTCH2 gene mutation explained the phenotypic difference in our situation. Another intriguing observation was the presence of ichthysis and craniosynostosis in ALGS with a NOTCH2 mutation. CONCLUSIONS Cholestasis in newborns can be difficult to diagnose. Next-generation sequencing detects 112 copy number variants in the cholestasis gene panel blood test. More research is needed to understand why NOTCH2 mutations are relatively rare in ALGS.

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13.

BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.

Impact of serum soluble programed death ligand 1 on end of treatment metabolic response of diffuse large B cell lymphoma patients.

Programmed death ligand-1 (PD-L1) plays an important role in the immune evasion of cancer cells and, in turn, can influence the outcome of many malignancies. The serum soluble PD-L1 (sPD-L1) levels were measured in diffuse large B cell lymphoma (DLBCL) patients at diagnosis and at end of treatment. Their impact on end of treatment metabolic response was analyzed. Serum sPD-L1 level was significantly elevated in DLBCL patients at diagnosis than in controls (P < 0.001). Also, serum sPD-L1 level at diagnosis was significantly higher than that at end of treatment (P < 0.001). Patients who achieved partial response (PR) had significantly higher serum sPD-L1 level at end of treatment than controls (P < 0.001). In contrast, all patients especially those who achieved complete response (CR) had insignificantly different serum sPD-L1 level at end of treatment than controls (P = 0.354 and P = 0.090, respectively). There was a significant difference between serum sPD-L1 level at diagnosis and that at end of treatment in patients who achieved PR and CR (P = 0.023 and P < 0.001, respectively). On univariate analysis, presence of comorbidities, Ann Arbor stage IV, high serum sPD-L1 level at diagnosis and high serum sPD-L1 level at end of treatment were significantly associated with achievement of PR (P = 0.018 and P = 0.043, P = 0.045 and P < 0.001, respectively). On multivariate analysis, serum sPD-L1 levels at diagnosis and at end of treatment were still influencing metabolic response significantly (P = 0.014 and P = 0.007, respectively). Serum sPD-L1 is a predictor for metabolic response to immunochemotherapy in DLBCL patients.

Identification of a novel genetic locus underlying tremor and dystonia.

BACKGROUND: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants. RESULTS: Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5'UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM_001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5'UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition. CONCLUSIONS: Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.

Is early intervention using Mansoura-VV uterine compression sutures an effective procedure in the management of primary atonic postpartum hemorrhage? : a prospective study.

BACKGROUND: Postpartum hemorrhage is the leading cause of maternal death, uterine atony accounts for 75-90% of primary postpartum hemorrhage. The efficacy of the Uterine compression suture in the treatment of atonic postpartum hemorrhage is time-tested and can be said to be almost established.The aim of this study was to assess the role of the Mansoura-VV uterine compression suture as an early intervention in the management of primary atonic postpartum hemorrhage. METHODS: This prospective observational study included 108 women with primary atonic PPH over a period of 44 months. Uterine atony was diagnosed when the uterus was soft and failed to respond to ordinary ecbolics. Early intervention by Mansoura-VV uterine compression sutures was carried out within 15 min of the second dose of ecobolics and before progressing to any further surgical procedure. RESULTS: Following the Mansoura-VV uterine compression sutures, uterine bleeding was controlled in all except one patient (107/108 cases; 99.07%) who required additional bilateral uterine vessels ligation. Another case (0.93%) was subjected to re-laparotomy due to intraperitoneal hemorrhage. Packed RBC transfusion was needed in 10 cases (9.25%). Admission to ICU was needed in 9 cases (8.33%) because of associated medical conditions. One week following the procedure, 1 case (0.93%) was diagnosed with haematometra. CONCLUSION: Early intervention in cases of primary atonic PPH using the Mansoura-VV uterine compression sutures is an easy, rapid and effective method in controlling PPH in low resource settings. TRIAL REGISTRATION: The study was registered at clinicaltrial.gov , Identifiers: NCT03117647 "retrospectively registererd" registered at April 7, 2017.