Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel, often result in neonatal diabetes. Patients with this mutation have been successfully transitioned from insulin to sulfonylurea (SU) therapy without compromise in their glycemic control. Among patients with neonatal diabetes due to KCNJ11 mutations, approximately 25% have neurological findings including developmental delay, motor dysfunction, and epilepsy, known as DEND syndrome. There have been rare cases of juvenile patients with intermediate DEND syndrome (iDEND) reporting variable improvement in neurological function following transition from insulin to SU treatment. We describe the response to glyburide in a 15-yr-old boy with severe global developmental delays resulting from the KCNJ11 mutation V59M. The patient was discovered to have diabetes mellitus at 11.5 months of age, making this the oldest age at diagnosis of a KCNJ11 mutation-related case of neonatal diabetes. Because consensus has been to screen patients for this mutation only if younger than 6 months at the time of diagnosis, we suggest that all patients under the age of 12 months at diagnosis should receive genetic testing for monogenic causes of diabetes.

Growth hormone (GH) deficiency (GHD) causes somatic growth impairment. GH has a very short half-life and therefore it has to be administered by daily subcutaneous injections. Adeno-associated viral (AAV) vectors have been used to deliver genes to animals, and recently developed double stranded (ds)–AAV vectors provide widespread and stable transgene expression. In the present study we tested whether an intramuscular injection of ds-AAV vector expressing GH under the control of an M-creatine kinase regulatory cassette would assure sufficient systemic GH delivery in conjunction with muscle-specific expression. Virus-injected GHD mice showed a significant (p<0.05) increase in body length and body weight, without reaching full normalization, and significant (p<0.05) reduction in absolute and relative visceral fat. Quantitative RT-PCR showed preferential GH expression in skeletal muscles that was confirmed by qualitative fluorescence analysis in mice injected with a similar virus expressing GFP. The present study shows that systemic GH delivery to GHD animals is possible via a single intramuscular injection of dsAAV carrying a muscle-specific GH-expressing regulatory cassette.

No abstract

The synthesis, photophysical properties and kinetic stability of a series of water-soluble, highly emissive Tb(III) and Eu(III) complexes featuring triethylenetetraamine hexaacetic acid (TTHA) and cyclohexyl triethylenetetraamine hexaacetic acid (cyTTHA) chelator scaffolds and carbostyril sensitizers are reported. The unique and modular design of the chelators gives rise to striking quantum yields of emission in aqueous solutions (up to 54%) as well as the characteristic lanthanides’ photophysical properties (long excited state lifetimes, large effective Stokes shifts, and narrow emission peaks). Furthermore, the pre-organized chelators (L3, L4 and L6) bind metal within minutes at ambient temperature yet exhibit substantial resistance to transchelation in the presence of a challenge solution (EDTA, 1 mM). Moreover, the Eu(III) complex of L4 remains stably luminescent in HeLa cells over hours, demonstrating the suitability of these compounds for live cell imaging applications. Representative chelators suitable for derivatization and protein bioconjugation were also prepared that were functionalized with clickable azide and alkyne moieties, biotin and trimethoprim (TMP). With exceptional long-wavelength brightness, enhanced kinetic inertness, and an adaptable synthetic route, the reported lanthanide complexes are promising probes and labels for time-gated bioanalysis, biosensing and optical microscopy.