Managing diabetes in preschool children

This article is a new chapter in the ISPAD Clinical Practice Consensus Guidelines Compendium. The complete set of guidelines can be found for free download at www.ispad.org. The evidence grading system used in the ISPAD Guidelines is the same as that used by the American Diabetes Association

Phenotypic characteristics of early Wolfram syndrome

BACKGROUND: Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. METHODS: Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. RESULTS: Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. CONCLUSIONS: WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression

Strong bones and restless legs New data about bone remodeling in women with RLS

Disorders of bone metabolism are a common concern for older women, since there are known associations among bone loss, sex, and age.(1) Women with restless legs syndrome (RLS) who have not yet been treated with medication have signs of increased sympathetic nervous system activity.(2) The autonomic nervous system appears to be a major regulator of bone mineral density (BMD) through signals sent to osteoblasts, and increased sympathetic activity is associated with more osteoporosis in older women because of decreased osteoblast proliferation.(3) These observations created a plausible hypothesis that there would be a higher incidence of osteopenia or osteoporosis in drug-naive women with RLS. In a new study reported in this issue of Neurology (R), Cikrikcioglu et al.(4) examined this relationship and found no evidence to support this hypothesis. In fact, they discovered the opposite result in their case-control study: an increase in lumbar BMD in 78 women with RLS, compared to 78 age-matched and body mass index (BMI)-matched controls. There was a positive bivariate correlation between duration of RLS and lumbar BMD. They also studied 2 markers of bone resorption, c-telopeptide of type 1 collagen (CTX) and sclerosin, and found lower levels in women with RLS. There were negative bivariate correlations between the severity of RLS and bone resorption markers

Distinguishing Alzheimer’s Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis

It is important to develop minimally invasive biomarker platforms to help in the identification and monitoring of patients with Alzheimer’s disease (AD). Assisting in the understanding of biochemical mechanisms as well as identifying potential novel biomarkers and therapeutic targets would be an added benefit of such platforms. This study utilizes a simplified and novel serum profiling platform, using mass spectrometry (MS), to help distinguish AD patient groups (mild and moderate) and controls, as well as to aid in understanding of biochemical phenotypes and possible disease development. A comparison of discriminating sera mass peaks between AD patients and control individuals was performed using leave one [serum sample] out cross validation (LOOCV) combined with a novel peak classification valuation (PCV) procedure. LOOCV/PCV was able to distinguish significant sera mass peak differences between a group of mild AD patients and control individuals with a p value of 10−13. This value became non-significant (p = 0.09) when the same sera samples were randomly allocated between the two groups and reanalyzed by LOOCV/PCV. This is indicative of physiological group differences in the original true-pathology binary group comparison. Similarities and differences between AD patients and traumatic brain injury (TBI) patients were also discernable using this novel LOOCV/PCV platform. MS/MS peptide analysis was performed on serum mass peaks comparing mild AD patients with control individuals. Bioinformatics analysis suggested that cell pathways/biochemical phenotypes affected in AD include those involving neuronal cell death, vasculature, neurogenesis, and AD/dementia/amyloidosis. Inflammation, autoimmunity, autophagy, and blood–brain barrier pathways also appear to be relevant to AD. An impaired VWF/ADAMTS13 vasculature axis with connections to F8 (factor VIII) and LRP1 and NOTCH1 was indicated and is proposed to be important in AD development

Influence of stream size on ammonium and suspended particulate nitrogen processing

We used 15NH4 tracer additions to determine travel distances of ammonium (NH4 ) and suspended particulate organic nitrogen (SPON) in six streams ranging from second to fifth order located within a single watershed on the North Slope of Alaska. Based on the distribution of 15N stored in stream bottom compartments (primary producers or grazers), we estimated NH4 travel lengths. We used a two‐compartment model to estimate the travel length of SPON based on the distribution of source 15N on the stream bottom and SPO 15N in the water column. Both NH4 and SPON travel lengths (Sw and Sp, respectively) increased with discharge primarily due to changes in depth and velocity. Variation in the vertical mass transfer coefficient (vf) of both NH4 and SPON did occur among the streams but was not related to stream size and was relatively small compared to the change in physical characteristics. Thus, in the Kuparuk watershed, physical gradients outweighed biological or chemical changes as controls on NH4 and SPON travel length. The one exception was the Kuparuk fertilized reach, where phosphorus fertilization greatly increased biological activity and NH4 processing compared to unaltered streams. Longitudinal gradients in major biological driving variables such as litter inputs, debris dams, and shading are absent in the Arctic, perhaps explaining the relatively uniform NH4 ‐ vf. Watersheds in other biomes may show differing degrees of physical versus biological/chemical controls. A conceptual model is presented for comparing the relative strength of these controls among different watersheds. Strong relationships between discharge and travel length should greatly aid development of watershed models of nutrient dynamics

A Coupled Field and Modeling Approach for the Analysis of Nitrogen Cycling in Streams

The stable isotope stream tracer model (SISTM) calculates the expected 15N content in various stream ecosystem N compartments over distance and time during and after 15N additions to streams. SISTM is a steady state compartment model that predicts δ 15N values based on N stocks and fluxes and the experimental rate of 15N addition. Predicted δ 15N values are compared with observed δ 15N values from a field tracer addition to evaluate our understanding of the N cycle. We demonstrated the use of this tool with information collected from field measurements and a 6-wk 15N-NH4+ addition to the Kuparuk River, Alaska, during the summer of 1991. SISTM was used to run a series of model calibrations that reflected increased information as the experiment progressed. Results of an a priori calibration (using pre-1991 data) yielded a predicted NH4+ uptake length (Sw) of 5.2 km compared with the observed Sw of 0.84 km, and underestimated the δ 15N values of biota in all cases. When discharge and NH4+ concentrations measured during the 1991 experiment were added (model calibration Update 1), the predicted Sw dropped to 0.44 km, indicating that the modeled fluxes overestimated the rate of NH4+ removal by the stream bottom. Adding N stocks and fluxes measured during the tracer addition (Update 2) did not improve predicted Sw, indicating faulty assumptions in our a priori calibration. The observed isotope data were used to estimate the form (NH4+ vs NO3-) of N taken up by primary producers and to improve our representation of the epilithon compartment (Update 3). Including this information brought the predicted Sw to 0.71 km compared with the observed 0.84 km, and resulted in a reasonable correspondence between predicted and observed δ 15N values over the 6-wk addition. SISTM can be used as a framework to 1) summarize N-cycle information prior to a tracer addition, 2) generate testable predictions for field isotope studies, 3) improve our understanding of the N cycle using the field isotope data as constraints on flux estimates, and 4) explore hypothetical N-cycle characteristics. The combined modeling and field tracer experiment approach efficiently provided a synoptic view of the N cycle in streams and rivers