Persistently high glucose levels in young children with type 1 diabetes.

OBJECTIVES: The aim of the study was to characterize glucose levels and variability in young children with type 1 diabetes (T1D). METHODS: A total of 144 children of 4-10 yr old diagnosed with T1D prior to age 8 were recruited at five DirecNet centers. Participants used a continuous glucose monitor (CGM) every 3 months during an 18-month study. Among the 144 participants, 135 (mean age 7.0 yr, 47% female) had a minimum of 48 h of CGM data at more than five of seven visits and were included in analyses. CGM metrics for different times of day were analyzed. RESULTS: Mean hemoglobin A1c (HbA1c) at the beginning and end of the study was 7.9% (63 mmol/mol). Fifty percent of participants had glucose levels >180 mg/dL (10.0 mmol/L) for >12 h/d and >250 mg/dL (13.9 mmol/L) for >6 h/d. Median time <70 mg/dL (3.9 mmol/L) was 66 min/d and <60 mg/dL (3.3 mmol/L) was 39 min/d. Mean amplitude of glycemic excursions (MAGE) was lowest overnight (00:00-06:00 hours). The percent of CGM values 71-180 mg/dL (3.9-10.0 mmol/L) and the overall mean glucose correlated with HbA1c at all visits. There were no differences in CGM mean glucose or coefficient of variation between the age groups of 4 and <6, 6 and <8, and 8 and <10. CONCLUSIONS: Suboptimal glycemic control is common in young children with T1D as reflected by glucose levels in the hyperglycemic range for much of the day. New approaches to reduce postprandial glycemic excursions and increase time in the normal range for glucose in young children with T1D are critically needed. Glycemic targets in this age range should be revisited.

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson's-like gut pathology.

Deposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson's Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal αsyn pathology by upregulating machinery for complement-mediated engulfment. Pharmacologic depletion of ENS-macrophages or genetic deletion of C1q enhanced enteric neuropathology. Conversely, C1q deletion ameliorated gut dysfunction, indicating that complement partially mediates αsyn-induced gut dysfunction. Internalization of αsyn led to increased endo-lysosomal stress that resulted in macrophage exhaustion and temporally correlated with the progression of ENS pathology. These novel findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the earliest stages of PD in the periphery.

Satisfaction with continuous glucose monitoring in adults and youths with Type 1 diabetes.

AIMS: To describe satisfaction with continuous glucose monitoring in Type 1 diabetes; to correlate continuous glucose monitoring satisfaction scores with usage; and to identify common themes in perceived benefits and barriers of monitoring reported by adults, youths and the parents of youths in the Juvenile Diabetes Research Foundation continuous glucose monitoring trials. METHODS: The Continuous Glucose Monitoring Satisfaction Scale questionnaire was completed after 6 months of monitoring. Participants also answered open-ended queries of positive and negative attributes of continuous glucose monitoring. RESULTS: More frequent monitoring was associated with higher satisfaction for adults (n = 224), youths (n = 208) and parents of youths (n = 192) (all P < 0.001) in both the 'benefits' and 'hassles' sub-scales of the Continuous Glucose Monitoring Satisfaction Scale, but the greatest differences between the two groups involved scores on hassle items. Common barriers to monitoring use included insertion pain, system alarms and body issues; while common benefits included glucose trend data, opportunities to self-correct out-of-range glucose levels and to detect hypoglycaemia. CONCLUSIONS: As frequent use of continuous glucose monitoring is associated with improved glycaemic control without increased hypoglycaemia it is important to overcome barriers, reinforce benefits and set realistic expectations for this technology in order to promote its more consistent and frequent use in individuals with Type 1 diabetes.

ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway.

AChR-inducing activity (ARIA)/heregulin, a ligand for erbB receptor tyrosine kinases (RTKs), is likely to be one nerve-supplied signal that induces expression of acetylcholine receptor (AChR) genes at the developing neuromuscular junction. Since some RTKs act through Ras and phosphatidylinositol 3-kinase (PI3K), we investigated the role of these pathways in ARIA signaling. Expression of activated Ras or Raf mimicked ARIA-induction of AChR epsilon subunit genes in muscle cells; whereas dominant negative Ras or Raf blocked the effect of ARIA. ARIA rapidly activated erk1 and erk2 and inhibition of both erks also abolished the effect of ARIA. ARIA stimulated association of PI3K with erbB3, expression of an activated PI3K led to ARIA-independent AChR epsilon subunit expression, and inhibition of PI3K abolished the action of ARIA. Thus, synaptic induction of AChR genes requires activation of both Ras/MAPK and PI3K signal transduction pathways.

GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival.

The GDNF family ligands (GFLs: GDNF, neurturin, persephin, and artemin) signal through RET and a gly-cosyl-phosphatidylinositol (GPI)-anchored coreceptor (GFRalpha1-alpha4) that binds ligand with high affinity and provides specificity. The importance of the GPI anchor is not fully understood; however, GPI-linked proteins cluster into lipid rafts, structures that may represent highly specialized signaling organelles. Here, we report that GPI-anchored GFRalpha1 recruits RET to lipid rafts after GDNF stimulation and results in RET/Src association. Disruption of RET localization using either transmembrane-anchored or soluble GFRalpha1 results in RET phosphorylation, but GDNF-induced intracellular signaling events are markedly attenuated as are neuronal differentiation and survival responses. Therefore, proper membrane localization of RET via interaction with a raft-localized, GPI-linked coreceptor is of fundamental importance in GFL signaling.

TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret.

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) comprise a family of TGF-beta-related neurotrophic factors (TRNs), which have trophic influences on a variety of neuronal populations. A receptor complex comprised of TrnR1 (GDNFR alpha) and Ret was recently identified and found to be capable of mediating both GDNF and NTN signaling. We have identified a novel receptor based on homology to TrnR1, called TrnR2, that is 48% identical to TrnR1, and is located on the short arm of chromosome 8. TrnR2 is attached to the cell surface via a GPI-linkage, and can mediate both NTN and GDNF signaling through Ret in vitro. Fibroblasts expressing TrnR2 and Ret are approximately 30-fold more sensitive to NTN than to GDNF treatment, whereas those expressing TrnR1 and Ret respond equivalently to both factors, suggesting the TrnR2-Ret complex acts preferentially as a receptor for NTN. TrnR2 and Ret are expressed in neurons of the superior cervical and dorsal root ganglia, and in the adult brain. Comparative analysis of TrnR1, TrnR2, and Ret expression indicates that multiple receptor complexes, capable of mediating GDNF and NTN signaling, exist in vivo.

Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex.

The glial cell line-derived neurotrophic factor (GDNF) ligands (GDNF, Neurturin [NTN], and Persephin [PSP]) signal through a multicomponent receptor system composed of a high-affinity binding component (GFRalpha1-GFRalpha4) and a common signaling component (RET). Here, we report the identification of Artemin, a novel member of the GDNF family, and demonstrate that it is the ligand for the former orphan receptor GFRalpha3-RET. Artemin is a survival factor for sensory and sympathetic neurons in culture, and its expression pattern suggests that it also influences these neurons in vivo. Artemin can also activate the GFRalpha1-RET complex and supports the survival of dopaminergic midbrain neurons in culture, indicating that like GDNF (GFRalpha1-RET) and NTN (GFRalpha2-RET), Artemin has a preferred receptor (GFRalpha3-RET) but that alternative receptor interactions also occur.

Persephin, a novel neurotrophic factor related to GDNF and neurturin.

A novel neurotrophic factor named Persephin that is approximately 40% identical to glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) has been identified using degenerate PCR. Persephin, like GDNF and NTN, promotes the survival of ventral midbrain dopaminergic neurons in culture and prevents their degeneration after 6-hydroxydopamine treatment in vivo. Persephin also supports the survival of motor neurons in culture and in vivo after sciatic nerve axotomy and, like GDNF, promotes ureteric bud branching. However, in contrast to GDNF and NTN, persephin does not support any of the peripheral neurons that were examined. Fibroblasts transfected with Ret and one of the coreceptors GFRalpha-1 or GFRalpha-2 do not respond to persephin, suggesting that persephin utilizes additional, or different, receptor components than GDNF and NTN.

Congenital hypothyroidism with delayed thyroid-stimulating hormone elevation in premature infants born at less than 30 weeks gestation.

OBJECTIVE: Congenital hypothyroidism (CH) with delayed thyroid-stimulating hormone (TSH) elevation is a common form of thyroid dysfunction among premature infants. Routine newborn screening (NBS) may miss infants with CH with delayed TSH elevation. The objective of the study is to determine the prevalence of CH with delayed TSH elevation in premature infants and to identify associated risk factors. STUDY DESIGN: Retrospective analysis of serum thyroid function screening (TFS) at day of life 30 in premature infants <30 weeks gestation, admitted to University of Iowa Neonatal Intensive Care Unit between 1 July 2012 to 30 June 2015. Serum free thyroxine and TSH levels were obtained in premature infants <30 weeks gestation on day of life 30. Follow-up testing and pediatric endocrinology consultation were done according to the institutional protocol. RESULT: In total, 286 infants were included. All infants underwent routine NBS and 280 patients underwent TFS. Twenty-six patients (9.1%) were diagnosed with thyroid dysfunction. NBS identified only three patients. CH with delayed TSH elevation was diagnosed in 20 patients (6.9%) and was significantly associated with multiple gestation, lower birth weight, higher gestational age and lower 5 min APGAR score. CONCLUSION: Thyroid dysfunction is common among premature infants born before 30 weeks gestation. The majority of cases with thyroid dysfunction had CH with delayed TSH elevation, which was not detected by NBS. We recommend measurement of serum TSH and free T4 levels on day of life 30 in premature infants born at <30 weeks gestation to identify patients with CH with delayed TSH elevation.

LRRK2 levels in immune cells are increased in Parkinson's disease.

Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson's disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (p = 0.0095), T cells (p = 0.029), and CD16+ monocytes (p = 0.01) of Parkinson's disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson's disease patients compared to healthy controls. In addition, Parkinson's disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson's disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), was decreased in Parkinson's disease compared to HC in T cells (p = 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson's disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T-cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function.

Guiding practice development using the Tidal Commitments.

The Tidal Model of Mental Health Recovery has contributed to the transformation of nursing practice at the Royal Ottawa Hospital (ROH), a psychiatric and mental health facility in Ontario, Canada. Ten commitments affirm the core values of the Tidal Model. These commitments guide person-centred, collaborative, strength-based practice and they facilitate Tidal teaching. In this paper we illustrate fidelity to the values, principles and processes of the model and the commitments while implementing the model. We share how some of the commitments are realized in our Tidal teaching and provide examples of successes and challenges.

c-Src is required for glial cell line-derived neurotrophic factor (GDNF) family ligand-mediated neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)-dependent pathway.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), consisting of GDNF, neurturin, persephin, and artemin, signal via a multicomponent complex composed of Ret tyrosine kinase and the glycosyl-phosphatidylinositol (GPI)-anchored coreceptors GFRalpha1-alpha4. In previous work we have demonstrated that the localization of Ret to membrane microdomains known as lipid rafts is essential for GDNF-induced downstream signaling, differentiation, and neuronal survival. Moreover, we have found that Ret interacts with members of the Src family kinases (SFK) only when it is localized to these microdomains. In the present work we show by pharmacological and genetic approaches that Src activity was necessary to elicit optimal GDNF-mediated signaling, neurite outgrowth, and survival. In particular, p60Src, but not the other ubiquitous SFKs, Fyn and Yes, was responsible for the observed effects. Moreover, Src appeared to promote neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)-dependent pathway because the PI-3K inhibitor LY294002 prevented GFL-mediated neuronal survival and prevented activated Src-mediated neuronal survival. In contrast, the inhibition of Src activity had no effects on NGF-mediated survival, indicating that the requirement for Src was selective for GFL-mediated neuronal survival. These data confirm the importance of protein-protein interactions between Ret and raft-associated proteins in the signaling pathways elicited by GDNF, and the data implicate Src as one of the major signaling molecules involved in GDNF-mediated bioactivity.

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

BACKGROUND/OBJECTIVES: The common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson's disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD. METHODS: For immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD. RESULTS: Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses. CONCLUSIONS: In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression.

Okadaic acid uncouples myosin light chain phosphorylation and tension in smooth muscle.

Tracheal smooth muscle precontracted with carbachol relaxes upon the addition of 3 microM okadaic acid. Although cytosolic Ca2+ concentrations decrease, myosin light chain remains highly phosphorylated (50%). In smooth muscle treated with carbachol alone or carbachol plus okadaic acid 32P is incorporated into a single peptide on myosin light chain which corresponds to the site phosphorylated by myosin light chain kinase. Treatment with okadaic acid alone does not result in myosin light chain phosphorylation or tension development. These results suggest that a cellular mechanism other than myosin light chain phosphorylation can regulate contractile tension.

Sumatriptan in the acute treatment of migraine.

Sumatriptan is a selective 5-HT1-like agonist, which is effective in the treatment of migraine and cluster headache. It has been rigorously assessed in clinical trials involving over 7000 patients who have treated over 35,000 migraine attacks. Both subcutaneous and oral sumatriptan provide a high level of efficacy with 86% of patients obtaining relief after a single 6 mg injection (at 2 h) and 75% after 100 mg oral sumatriptan (4 h), compared with up to 37% in the placebo-treated group (P < 0.001). The onset of effect is rapid, occurring 10 min after injection and 30 min after the tablet. Oral sumatriptan (100 mg) has been evaluated against ergotamine, 2 mg, plus caffeine, 200 mg (as Cafergot); and against aspirin, 900 mg, plus metoclopramide, 10 mg. Headache relief was superior in sumatriptan-treated patients; 66% obtaining relief at 2 h, compared with 48% on Cafergot (P < 0.001). The percentage of patients obtaining complete relief of headache (Grade 0, no pain) was significantly higher with sumatriptan (40%) than with Cafergot (14%) at 2 h. Associated symptoms such as nausea, vomiting and photophobia are effectively relieved by sumatriptan, whereas Cafergot provoked nausea and vomiting in a proportion of patients. Headache relief with sumatriptan was also superior to that seen with aspirin plus metoclopramide. Sumatriptan was as effective in the relief of accompanying nausea and vomiting as aspirin plus metoclopramide. The efficacy of sumatriptan is maintained after repeated long-term use; over a six-month period efficacy was comparable in the first and last attacks, regardless of how many attacks were treated.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers.

The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.

A simple and a complex tic (Gilles de la Tourette's syndrome): their response to EEG sensorimotor rhythm biofeedback training.

This study presents a clinical treatment regime for the treatment of tic manifestation, both simple and complex. The response of a case of simple tic and a case of complex tic (Gilles de la Tourette's syndrome) to EEG sensorimotor rhythm biofeedback training are presented. Specifically, the simple and the complex tic, both of long duration, were eliminated via this EEG biofeedback training procedure. It is hypothesized that this exercising of the sensorimotor cortex resulted in increased activation of this cerebrocortical subsystem and was reflected in increased voluntary muscle control and a heightened threshold for random motor discharge, resulting in the elimination of both tics as in the response of cases of epilepsy with motor involvement to EEG sensorimotor rhythm biofeedback training. The additional psychophysiologic sequelae of the complex tic--attention deficit disorder--remediated in the manner of the response of learning-disabled to EEG sensorimotor rhythm biofeedback training.

EEG sensorimotor rhythm biofeedback training: some effects on the neurologic precursors of learning disabilities.

This study presents a clinical treatment regime for pathological interhemispheric dysfunction with respect to a population of learning disabled boys. The results obtained replicate and extend earlier findings with respect to operantly conditioned increases in amplitude of sensorimotor transactions and its positive effect on learning disability. Specifically, the biofeedback, and subsequent conditioning, of increased 14 Hz neural discharge patterns (sensorimotor rhythm-SMR) over the central Rolandic cortex, appeared to increase bilateral sensorimotor transactions resulting in substantive reduction/remediation in the learning disabilities of the recipients of such EEG biofeedback training.

The response of a case of petit mal epilepsy to EEG sensorimotor rhythm biofeedback training.

A 14-year-old girl, with a long history of absence seizures, sudden rages, spatial disorientation, and academic difficulties received long-term (33 sessions) EEG sensorimotor rhythm biofeedback training. Operantly conditioned increases in the average amplitude of the 14 Hz neural discharge rhythm, over the central Rolandic cortex and cerebrolongitudinal fissure, resulted in a total cessation of her absence seizures; which had, prior to the EEG sensorimotor rhythm biofeedback training, occurred at the rate of 4-5 absences per hour. Concurrently, her sudden rages, spatial disorientation, and academic functioning all evidenced significant remediation.

Brainwave signatures--an index reflective of the brain's functional neuroanatomy: further findings on the effect of EEG sensorimotor rhythm biofeedback training on the neurologic precursors of learning disabilities.

Eight boys, ages 7 years 11 months to 15 years 3 months, were provided with long-term--symptom duration--sensorimotor rhythm biofeedback training for the remediation of their learning disabilities. Concurrently, the simultaneous recording of five frequency bands of brainwave activity (5 Hz, 7 Hz, 10 Hz, 12 Hz and 14 Hz), from one active electrode equidistant from reference and ground, was intended to provide a glimpse of the 'brainwave signature' reflective of the dynamic and synergistic processes involved in such cerebro-neural activation and the brain's global response to such an alteration in the sensorimotor subnetwork. Overall, the main effect of this procedure, for the biofeedback and subsequent conditioning of increased 14 Hz neural discharge patterns over the central Rolandic cortex in a clinical office setting, seems to be to increase bilateral sensorimotor transactions resulting in substantive remediation of the learning disabilities of the recipients of such training--by way of internally exercising of, and/or recruitment of additional neural activation within, the sensorimotor subnetwork/matrix. Observation of the changing brainwave signatures showed a tendency for decreased slow wave activity concomitant with increases in fast wave activity, for cases with a Full Scale I.Q. within the range of 76 and 85; with those cases with a Full Scale I.Q. within the range of 102 and 116 exhibiting increased amplitudes over most of the monitored bands, but with the increases being much less at the slower frequencies. It is noteworthy that those four subjects with either a significant Verbal greater than Performance, or Performance greater than Verbal, I.Q. Score discrepancy exhibited no less than a 40% greater increase in the lower of the two I.Q. scores; indicating that this SMR training procedure also resulted in an increased symmetry in the interhemispheric interactions reflective of the higher cortical functions for these no longer learning disabled boys.