Trajectories in estimated glomerular filtration rate in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study

AimsWe sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes.MethodsWe assessed the direction of eGFR change at two visits (mean 6.6 years apart) in SEARCH, a longitudinal cohort study of youth-onset type 1 and type 2 diabetes. We used the CKiD_Cr-CysC equation to estimate GFR and categorized ‘rising’ and ‘declining’ eGFR as an annual change of ≥3 ml/min/1.73 m² in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR.ResultsEstimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index.ConclusionsOver the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.     

A ribozyme that ligates RNA to protein

We have used a combination of in vitro selection and rational design to generate ribozymes that form a stable phosphoamide bond between the 5' terminus of an RNA and a specific polypeptide. This reaction differs from that of previously identified ribozymes, although the product is analogous to the enzyme-nucleotidyl intermediates isolated during the reactions of certain proteinaceous enzymes, such as guanyltransferase, DNA ligase, and RNA ligase. Comparative sequence analysis of the isolated ribozymes revealed that they share a compact secondary structure containing six stems arranged in a four-helix junction and branched pseudoknot. An optimized version of the ribozyme reacts with substrate-fusion proteins, allowing it to be used to attach RNA tags to proteins both in vitro and within bacterial cells, suggesting a simple way to tag a specific protein with amplifiable information.     

Plasma-sulfated C21-steroids increase during the periovulatory period in female common wolffish and are influenced by temperature during vitellogenesis

Plasma concentrations of steroids during the periovulatory period were measured in female common wolffish reared at three different temperatures. Steroids were quantified by radioimmunoassay (RIA). Two "broad-spectrum specificity" RIAs-one which detects C21-steroids with a 17,20beta-dihydroxyl configuration (17,20beta-steroids) and the other which detects C21-steroids with a 5beta-reduced, 3alpha-hydroxyl configuration (5beta,3alpha-steroids)-picked up very large amounts of cross-reacting material (1.7 microg ml(-1) in one fish) in the sulfate fraction of plasma from ovulating females. Reverse-phase high-performance liquid chromatography and thin-layer chromatography revealed two major steroids: 5beta-pregnane-3alpha,17,20beta-triol (80%) and 5beta-pregnane-3beta,17,20beta-triol (20%). The sulfated forms of these steroids were elevated 4 to 6 days before and during ovulation, compared with those of females in vitellogenic and postspawning condition, in which concentrations were below 2.0 ng ml(-1). In the three groups of fish held at 4, 8, and 12 degrees C during vitellogenesis, but returned to 4 degrees C just prior to the spawning season, the mean concentrations of sulfated 17,20beta-steroids in ovulating females were 530, 635, and 325 ng ml(-1), respectively. The corresponding concentrations of free 17,20beta-dihydroxy-4-pregnen-3-one (17,20beta-P; the maturation-inducing steroid in many teleosts) were 0.88, 0.86, and 0.57 ng ml(-1), respectively. Only minute amounts of 17,20beta,21-P and its sulfated derivatives were detected. Significantly lower steroid concentrations in the 12 degrees C group indicate that steroid synthesis and/or metabolism during the periovulatory period are influenced by the temperature experienced during vitellogenesis. In male fish, plasma concentrations of both sulfated 17,20beta-steroids and free 17,20beta-P were low (< 2.0 ng ml(-1)) at all times.     

Automatic tracking of rolling leukocytes in vivo.

The analysis of instantaneous and average rolling leukocyte velocity is crucial to the study of inflammatory disease. In order to record features associated with leukocyte rolling, the leukocyte position must be tracked, typically by manual observation. Automated tracking of leukocytes is possible for in vitro studies, but not for recordings resulting from intravital experiments. Therefore, we have designed and implemented an image processing system for automated tracking of rolling leukocytes in vivo. The novel image processing techniques used in the tracking system successfully address the four major problems associated with tracking cells in vivo: background movement, severe image noise and clutter, cell deformation and contrast change, and occlusion of the target cell by other structures. We have tested the system in two experimental protocols in which leukocyte rolling is observed in venules of the mouse cremaster muscle with and without TNF-alpha treatment. The automated tracking system was validated by comparing automatically generated displacement and velocity data with data from the same recordings collected manually. The root mean squared error between the computed displacements and the manually measured displacements was less than 12% of the average displacement in TNF-alpha-treated venules. The average velocity error was also less than 12%. For untreated venules, the computed and measured displacements and velocities had an RMSE of less than 8%. The automated tracking system allows one, for the first time, to reliably track rolling leukocytes in vivo, thus eliminating possible investigator bias and increasing throughput.     

Rift Valley fever surveillance in mobile sheep flocks in the Nile Delta

Rift Valley fever (RVF) surveillance was carried out in the Nile Delta by monitoring mobile and stationary sheep flocks for antibodies to RVF virus. Sheep are known to be susceptible to RVF virus infection and experienced severe morbidity in 1977 and 1978 when RVF was epidemic in Egypt. Four hundred six sheep in 32 flocks were surveyed during 1984. Twenty-four sheep from 7 flocks had antibodies to RVF virus detected by hemagglutination inhibition and plaque reduction neutralization tests. Antibodies were found primarily in sheep greater than 3 years of age, although 1- and 2-year-old sheep were included in the sample. No seroconversion was observed among 177 seronegative sheep that were bled successively for a period of 10 months. These results indicate that epizootic RVF was probably not present in the Nile Delta during 1984.     

A mucopolysaccharide storage disease with involvement of the renal glomerular epithelium

A young child with severe mental retardation, skeletal abnormalities and the phenotypic appearance typical of a mucopolysaccharide disorder was found to have a previously unrecognized form of mucopolysaccharide storage disease. Mucopolysaccharide was found to accumulate in perichondrium, coronary arteries, aorta and the glomerular epithelial cells of the kidney; the reticuloendothelial system remained free of mucopolysaccharide. Lipid accumulation was observed in peripheral neurons but not in central neurons. Skin fibroblast cultures accumulated ³⁵SO₄ to an extent intermediate between normal cell lines and those from patients with classic mucopolysaccharide storage disorders.     

Classification of Heart Failure According to Ejection Fraction: JACC Review Topic of the Week

The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to “preserved” ejection fraction but referring to “below normal” ejection fraction as those most likely to benefit. This review summarizes the evolution of nomenclature in heart failure and examines evidence showing that patients with ejection fraction in the “mid range” may benefit from neurohormonal blockade similar to those with more severely reduced (<40%) ejection fraction. Furthermore, prominent sex differences have been observed wherein the benefit of neurohormonal blockade appears to extend to a higher ejection fraction range in women compared to men. Based on emerging evidence, revised nomenclature is proposed defining heart failure with “reduced” (<40%), “mildly reduced,” and “normal” (≥55% in men, ≥60% in women) ejection fraction. Such nomenclature signals consideration of potentially beneficial therapies in the largest group of patients with reduced or mildly reduced ejection fraction.