Clinical correlates of cerebellar injury in preterm infants with surgical necrotizing enterocolitis.

BACKGROUND: The preterm infants are at risk of cerebellar injury and the risk factors for necrotizing enterocolitis (NEC) associated cerebellar injury are not fully understood. AIM: Determine the risk factors of cerebellar injury in infants with surgical necrotizing enterocolitis (NEC). METHODS: Retrospective study compared clinical/pathological information between surgical NEC infants with and those without cerebellar injury detected on brain MRI obtained at term equivalent age. Cerebellar Injury patterns that we identified on MRI brain were cerebellar hemorrhage, siderosis and/or cerebellar volume loss. RESULTS: Cerebellar injury (21/65, 32.3%) in preterm infants with NEC was associated with patent ductus arteriosus (PDA) (18/21(85.7%) vs. 25/44(56.8%); p = 0.021), blood culture positive sepsis (13/21 (61.9%) vs. 11/44 (25%); p = 0.004) following NEC, predominantly grew gram positive bacteria (9/21(42.9%) vs. 4/44(9.1%); p = 0.001), greater red cell transfusion, higher rates of cholestasis following NEC and differences in intestinal histopathology (more hemorrhagic and reparative lesions) on univariate analysis. Those with cerebellar injury had higher grade white matter injury (14/21 (66.7%) vs. 4/44(9.1%) p = 0.0005) and higher-grade ROP (70.6% vs. 38.5%; p = 0.027) than those without cerebellar injury.On multilogistic regression, the positive blood culture sepsis (OR 3.9, CI 1.1-13.7, p = 0.03), PDA (OR 4.5, CI 1.0-19.9, p = 0.04) and severe intestinal pathological hemorrhage (grade 3-4) (OR 16.9, CI 2.1-135.5, p = 0.007) were independently associated with higher risk of cerebellar injury. CONCLUSION: Preterm infants with surgical NEC with positive blood culture sepsis, PDA, and severe intestinal hemorrhagic lesions (grade 3-4) appear at greater risk for cerebellar injury.

Risk factors for postoperative complications in preterm infants with surgical necrotizing enterocolitis and associated outcomes.

BACKGROUND: We aim to determine clinical risk factors for postoperative complications in preterm infants with surgical necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). METHODS: A retrospective cohort study of preterm infants with surgical NEC or SIP to compare clinical factors between those with and without postoperative complications. RESULTS: 78/109 (71.5%) infants had any complication following surgical NEC. Adhesions (20/35, 57.1%) and wound infection (6/35, 17.1%) were the most common single surgical complications. Patients with a single surgical complication (35/66, 53%) were significantly less likely to be exposed to antenatal steroids, more frequently had a jejunostomy, needed a central line longer, and had a longer length of stay than those without any surgical complication. Infants with > 1 surgical complication (43/71, 60.5%) included mainly females, and had AKI more frequently at NEC onset, lower weight z-scores and lower weight for length z- scores at 36 weeks PMA than those without any complications.On multinomial logistic regression, antenatal steroids exposure (OR 0.23 [CI 0.06, 0.84]; p = 0.027) was independently associated with lower risk and jejunostomy 4.81 (1.29, 17.9) was independently associated with higher risk of developing a single complication. AKI following disease onset (OR 5.33 (1.38, 20.6), P = 0.015) was independently associated with > 1 complication in surgical NEC/SIP infants. CONCLUSION: Infants with postoperative complications following surgical NEC were more likely to be female, have additional morbidities, and demonstrate growth failure at 36 weeks PMA than those without surgical complications. There was no difference in mortality between those with and without surgical complications.

Similar efficacy and safety of once-weekly dulaglutide in patients with type 2 diabetes aged ≥65 and <65 years.

AIMS: To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in elderly patients (aged ≥65 years) with type 2 diabetes (T2D) in six phase III clinical trials. METHODS: Patients were grouped into two age groups: ≥65 and <65 years. Pooled analysis for glycated haemoglobin (HbA1c) change from baseline, percentage of patients achieving HbA1c targets, and gastrointestinal tolerability were evaluated at 26 weeks for each dulaglutide dose. Change in weight from baseline and rates of hypoglycaemia were evaluated for each individual study. RESULTS: A total of 958 of 5171 (18.5%) patients were aged ≥65 years. The reductions in HbA1c were similar between age groups for dulaglutide 1.5 mg-treated patients {least squares [LS] mean for patients aged ≥65 years: -1.24 [95% confidence interval (CI) -1.36, -1.12] and for patients aged <65 years: -1.29 [95% CI -1.38, -1.20]} and for dulaglutide 0.75 mg-treated patients [LS mean for patients aged ≥65 years: -1.16 (95% CI -1.29, -1.03) and for patients aged <65 years: -1.10 (95% CI -1.19, -1.01)] at 26 weeks. The percentages of patients who achieved HbA1c targets of <7, <8 or <9% were also similar in the two groups with both dulaglutide doses. Patients aged ≥65 years had similar weight change to patients aged <65 years. Severe hypoglycaemic events were infrequent. A similar incidence of gastrointestinal adverse events was observed in each age group with both dulaglutide doses. CONCLUSION: Both dulaglutide doses were well tolerated, with similar efficacy in patients with T2D aged ≥65 years to those aged <65 years. Dulaglutide can be considered a safe and effective treatment option for use in older adults.

Maintenance of the B-chain beta-turn in [GlyB24] insulin mutants: a steady-state fluorescence anisotropy study.

[GlyB24]insulin is a novel insulin analog which maintains nearly full biological activity [Mirmira, R. G., & Tager, H. S. (1989) J. Biol. Chem. 264, 6349-6354] even though its structure, as determined by 2D NMR, shows complete loss of the characteristic B-chain beta-turn [Hua, Q. X., Shoelson, S. E., Kochoyan, M., & Weiss, M. A. (1991) Nature 354, 238-241], which in native insulin allows the extended B-chain C-terminal region to fold against the central B-chain helix. In these studies, steady-state anisotropy measurements and fluorescence quenching analysis of the tryptophan-substituted analogs [TrpB25]insulin and [GlyB24,TrpB25]insulin have been used to study the structure of the C-terminal region of the B-chain and have demonstrated that [GlyB24]insulin mutants maintain the normal B-chain conformation to a degree comparable to that of native (PheB24) insulin at neutral pH. The tryptophan-substituted, B-chain C-terminally truncated analogs [TrpB25-alpha-carboxamide]despentapeptide(B26-B30)-insulin (DPI) and [GlyB24,TrpB25-alpha-carboxamide]DPI also significantly retain the characteristic insulin B-chain fold in solution with [GlyB24,TrpB25-alpha-carboxamide]DPI being more tightly folded than its corresponding PheB24-analog ([TrpB25-alpha-carboxamide]DPI), as assessed by these methods. The results of anisotropy measurements are consistent with the existence of a correlation between the high-affinity receptor binding of [GlyB24]insulin and the partial maintenance of the B-chain beta-turn under physiologic conditions. Thus we conclude that only analogs which possess, or can readily assume, this oriented structure can form high-affinity binding complexes with insulin receptor.

A spectroscopic investigation of the conformational dynamics of insulin in solution.

A conformational change, termed the T --> R transition, which can be detected by visible, circular dichoric, and fluorescence spectroscopy, occurs in native insulin and tryptophan substituted insulin analogs ([TrpB25]-, [TrpB26]-, [GlyB24,TrpB25]-, and [GlyB24,TrpB26]insulin) upon binding specific alcohol ligands, including phenol and cyclohexanol. In these studies we have demonstrated that changes in the visible absorbance spectrum of an insulin6(Co2+)2 solution are not a definitive means of determining the occurrence of T --> R transitions in the presence of alcohol ligands. We also have presented evidence that fast protein liquid chromatography (FPLC) can be used to determine the aggregation state of insulin and that des-octapeptide(B23-30)insulin (DOI) forms Zn(2+)-coordinated hexamers that appear to be stabilized by the T --> R transformation. Using fluorescence spectroscopy, we have shown that in the presence of specific alcohol ligands the B-chain COOH-terminal residues, particularly position B25, of hexameric, as well as monomeric insulin undergo a conformational change which appears to be related to the T --> R transformation. Circular dichroic studies indicate that a conformation similar to the R-state of metal-coordinated hexameric insulin can be induced by binding cyclohexanol; however, this new conformational state (RI-state) exists independent of divalent metal ion coordination, and therefore of hexamer formation. We further show that monomeric insulin can be induced to assume the RI-state upon alcohol binding, therefore illustrating the first defined conformational change described for monomeric insulin. We suggest that this new conformation may be an intermediate state in the T --> R transformation in metal-coordinated hexameric insulin, such that T --> RI --> R. The model presented here of the structural adjustments undergone by insulin upon binding cyclohexanol provides further insight into the conformational flexibility of insulin in solution.