OBJECTIVEThis randomized, controlled noninferiority trial aimed to compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) (both with prandial insulin aspart) in pregnant women with type 1 diabetes.RESEARCH DESIGN AND METHODSPatients were randomized and exposed to IDet or NPH up to 12 months before pregnancy or at 8–12 weeks gestation. The primary analysis aimed to demonstrate noninferiority of IDet to NPH with respect to A1C at 36 gestational weeks (GWs) (margin of 0.4%). The data were analyzed using linear regression, taking several baseline factors and covariates into account.RESULTSA total of 310 type 1 diabetic women were randomized and exposed to IDet (n = 152) or NPH (n = 158) up to 12 months before pregnancy (48%) or during pregnancy at 8–12 weeks (52%). The estimated A1C at 36 GWs was 6.27% for IDet and 6.33% for NPH in the full analysis set (FAS). IDet was declared noninferior to NPH (FAS, –0.06% [95% CI –0.21 to 0.08]; per protocol, –0.15% [–0.34 to 0.04]). Fasting plasma glucose (FPG) was significantly lower with IDet versus NPH at both 24 GWs (96.8 vs. 113.8 mg/dL, P = 0.012) and 36 GWs (85.7 vs. 97.4 mg/dL, P = 0.017). Major and minor hypoglycemia rates during pregnancy were similar between groups.CONCLUSIONSTreatment with IDet resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin. Rates of hypoglycemia were comparable.

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The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) are activated by the neuroprotective and neurotrophic cytokines, erythropoietin (EPO) and growth hormone (GH). Here, we show a dissociation of the intracellular pathway mediating the protective effect of EPO against glutamate toxicity from that needed for its neurotrophic activity using hippocampal neuronal cultures from Stat5a/b-knockout (Stat5 À/À ) mouse fetuses. Both pretreatment and post-treatment with EPO counteracted glutamate-induced cell death in Stat5 þ / þ and Stat5 À/À neurons. Acute pharmacological inhibition of Janus kinase 2 (JAK2)/Stat signalling had no effect on EPO neuroprotection, whereas inhibition of phosphatidylinositol-3 0 kinase (PI3K)/Akt pathway abolished the protective effect of EPO in both Stat5 þ / þ and Stat5 À/À neurons. GH effectively protected Stat5 þ / þ cells against glutamate toxicity but had no effect in Stat5 À/À neurons or in Stat5 þ / þ neurons treated with JAK2/Stat or PI3K inhibitor. EPO and GH stimulated neurite outgrowth and branching of Stat5 þ / þ neurons by activating PI3K/Akt signalling but had no trophic effect in Stat5 À/À cells. We conclude that in hippocampal neurons, Stat5 is not required for neuroprotection by EPO but is together with Akt essential for its neurotrophic activity. Both Stat5 and Akt are needed for neuroprotective and neurotrophic signalling of GH in neurons. The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) control cell fate decisions such as differentiation, proliferation and apoptosis. 1 Stat5 mediates cellular response to cytokines, growth factors and hormones. 1 Upon binding to their membrane receptors, growth factors such as erythropoietin (EPO) and growth hormone (GH) activate Janus kinase 2 (JAK2), causing activation of Stat5 by its phosphorylation, dimerization and translocation to the nucleus, where Stat5 induces expression of various antiapoptotic genes. 1 Indicative of an impaired functioning of EPO and GH receptor-associated signalling, Stat5a/b-knockout mice (Stat5 À/À ) are severely anaemic and growth retarded and the vast majority die perinatally. 2 Stat5 is expressed in the developing nervous system. 3,4 Recent studies suggest a role for Stat5 in neuronal migration and axon guidance in the developing brain 3 and a novel therapeutic potential for constitutively active Stat5 in reducing axonal outgrowth defects in spinal muscular atrophy-like motor neurons. 5 Since activation of Stat5 in neurons accompanies the antiapoptotic and neuroprotective effects of EPO in vitro and in vivo, 6-12 Stat5 has been suggested to mediate the protective effects of EPO in neuronal cells. Nevertheless, the molecular mechanisms of EPO receptor (EPOR) activation in neurons are complex, as multiple neuroprotective signalling pathways are activated downstream of EPOR/JAK2. In addition to Stat5, best characterized from these are the phosphatidylinositol-3 0 kinase (PI3K)/ Akt, nuclear factor-kB and Ras/mitogen-activated p...

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The exercise programme had a beneficial effect on the severity of lumbopelvic pain in pregnancy, reducing the intensity of pain and the level of disability experienced as a result.