[Show abstract][Hide abstract] ABSTRACT: Background: Exercise stimulates bone remodeling and improves insulin sensitivity (Si), even without associated weight loss. Osteocalcin (OCN), a bone-derived protein, is associated with improved Si. Purpose: We examined how daily physical activity is associated with OCN and Si. Methods: Physical activity was measured through questionnaires completed in Minneapolis from 2010 to 2012. A physical activity score (PAQsum) was calculated to quantify physical activity (range 1-5). OCN and bone specific alkaline phosphatase (BAP) were measured by ELISA. Si was measured by the insulin modified frequently sampled IV glucose tolerance test. Results: The mean PAQsum value was 2.4 ± 0.8 in 47 participants (12-17.9. years old). PAQsum was positively associated with OCN (p = 0.006). Participants with PAQsum < 2 had significantly lower OCN levels compared to participants with PAQsum > 2 (p. <. 0.02). Obesity did not modify the association between PAQsum and OCN. There was no statistically significant association between PAQsum and Si or between OCN and Si, even after adjustment for percent body fat. Conclusions: OCN is higher in more physically active individuals. More research is needed to clarify the relationship between OCN, physical activity and Si.
Case Reports in Clinical Medicine 12/2015; 2:568-571. DOI:10.1016/j.pmedr.2015.06.017
[Show abstract][Hide abstract] ABSTRACT: Purpose:
This study analyzed the characteristics of responders vs. nonresponders in people with stroke receiving a novel form of repetitive transcranial magnetic stimulation (rTMS) to improve hand function.
Twelve people with stroke received five treatments of 6-Hz primed low-frequency rTMS to the contralesional primary motor area. We compared demographic factors, clinical features, and the ipsilesional/contralesional volume ratio of selected brain regions in those who improved hand performance (N = 7) on the single-hand component of the Test Évaluant la performance des Membres supérieurs des Personnes Âgées (TEMPA) and those who showed no improvement (N = 5).
Responders showed significantly greater baseline paretic hand function on the TEMPA, greater preservation volume of the ipsilesional posterior limb of the internal capsule (PLIC), and lower scores (i.e., less depression) on the Beck Depression Inventory than nonresponders. There were no differences in age, sex, stroke duration, paretic side, stroke hemisphere, baseline resting motor threshold for ipsilesional primary motor area (M1), NIH Stroke Scale, Upper Extremity Fugl-Meyer, Mini-Mental State Examination, or preservation volume of M1, primary somatosensory area, premotor cortex, or supplementary motor area.
Our results support that preserved PLIC volume is an important influential factor affecting responsiveness to rTMS.
[Show abstract][Hide abstract] ABSTRACT: Objective
To describe serum 25(OH)D changes after Roux-en-Y gastric bypass (RYGB) and to determine if fat mass (FM) loss and vitamin D intake are associated with changes in serum levels.
We investigated the relationship between serum 25(OH)D and 1) FM, 2) weight, 3) % excess weight loss (EWL), and 4) BMI, after controlling for potential confounders using a mixed effects linear model in 20 women before and up to 1-year post-RYGB. Subcutaneous (SAT) and visceral adipose tissue (VAT) vitamin D concentrations at time of RYGB were also evaluated.
Weight and FM decreased 1-year after surgery by 45±1kg and 37±1kg, respectively while 25(OH)D increased by 10±2 ng/mL. Weight, FM, BMI, and %EWL changes were associated with 25(OH)D change. VAT had on average 21% more vitamin D per gram than SAT and concentrations were highly correlated.
Although weight loss may lead to increased serum 25(OH)D after RYGB, low levels remain a concern in some patients 1-year post-surgery. Additional research is needed to clarify the relationship between adipose storage of vitamin D and serum 25(OH)D in obesity, and how that relationship might change after surgery. This could lead to improved clinical management of vitamin D in this ever-growing clinical population.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the feasibility and efficacy of five treatments of 6 Hz primed, low-frequency, repetitive transcranial magnetic stimulation (rTMS) combined with constraint-induced movement therapy (CIMT) to promote recovery of the paretic hand in children with congenital hemiparesis.
Nineteen children with congenital hemiparesis aged between 8 and 17 years (10 males, nine females; mean age 10 years 10 months, SD 2 years 10 months; Manual Ability Classification Scale levels I-III) underwent five sessions of either real rTMS (n=10) or sham rTMS (n=9) alternated daily with CIMT. CIMT consisted of 13 days of continuous long-arm casting with five skin-check sessions. Each child received a total of 10 hours of one-to-one therapy. The primary outcome measure was the Assisting Hand Assessment (AHA) and the secondary outcome variables were the Canadian Occupational Performance Measure (COPM) and stereognosis. A Wilcoxon signed-rank sum test was used to analyze differences between pre- and post-test scores within the groups. Analysis of covariance was used to compute mean differences between groups adjusting for baseline. Fisher's exact test was used to compare individual change in AHA raw scores with the smallest detectable difference (SDD) of 4 points.
All participants receiving treatment finished the study. Improvement in AHA differed significantly between groups (p=0.007). No significant differences in the secondary outcome measures were found. Eight out of 10 participants in the rTMS/CIMT group showed improvement greater than the SDD, but only two out of nine in the sham rTMS/CIMT group showed such improvement (p=0.023). No serious adverse events occurred.
Primed, low-frequency rTMS combined with CIMT appears to be safe, feasible, and efficacious in pediatric hemiparesis. Larger clinical trials are now indicated.
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis has been described in animal models of mucopolysaccharidosis (MPS). Whether clinically significant osteoporosis is common among children with MPS is unknown. Therefore, cross-sectional data from whole body (WB; excluding head) and lumbar spine (LS) bone mineral density (BMD) compared with sex-, chronologic age-, and ethnicity-matched healthy individuals (Zage), height-for-age (HAZ) Z-score (ZHAZ) and bone mineral content (BMC) measured by dual-energy X-ray absorptiometry (DXA) in 40 children with MPS were analyzed. A subset of these children (n=24) was matched 1:3 by age and sex to a group of healthy children (n=72) for comparison of BMC adjusted for Tanner stage, race, lean body mass, height, and bone area. Low BMD Z-score was defined as Z-score of -2 or less. In children with MPS, 15% had low WB Zage and 48% had low LS Zage; 0% and 6% had low WB ZHAZ and low LS ZHAZ, respectively. Adjusted WB BMC was lower in MPS participants (p=0.009). In conclusion, children with MPS had deficits in WB BMC after adjustments for stature and bone area. HAZ adjustment underestimated bone deficits (i.e., overestimated WB BMD Z-scores) in children with MPS likely owing to their abnormal bone shape. The influence of severe short stature and bone geometry on DXA measurements must be considered in children with MPS to avoid unnecessary exposure to antiresorptive treatments.
[Show abstract][Hide abstract] ABSTRACT: Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10-13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy ((1)H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N = 9; SCA2, N = 7; SCA6, N = 5) or cerebellar multiple system atrophy (MSA-C, N = 5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N-acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected p < 0.05). The best MRS predictors were selected by a tree classification procedure and lead to 89% accurate classification of all subjects while the SARA scores overlapped considerably between patient groups. Therefore, this study demonstrated multiple neurochemical alterations in SCAs and MSA-C relative to controls and the potential for these neurochemical levels to differentiate ataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers.
The Cerebellum 06/2011; 10(2):208-17. DOI:10.1007/s12311-010-0213-6 · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Roux-en-Y gastric bypass (RYGB) imparts long-term weight loss, the mechanisms for which are not well understood. Changes in leptin and gastrointestinal (GI) hormones, including glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin, may contribute to the relative success of RYGB compared with conventional weight loss methods. This study evaluated changes in GI hormones and leptin post-RYGB. The study also evaluated whether GI hormones differed after a short-term dose of protein or fat.
GLP-1, PYY, ghrelin, and leptin were assessed in 16 women before RYGB and up to 1 year after RYGB. Plasma was collected before and at several times after a short-term equicaloric dose of protein or fat.
GLP-1 area under the curve (AUC) increased at week 6 and 1 year in the fat beverage (FAT-BEV) group compared with baseline. PYY AUC remained elevated at 1 year in the FAT-BEV group. Ghrelin AUC decreased at week 2, week 6, and 1 year in the protein beverage (PRO-BEV) group compared with baseline. Ghrelin AUC was lower in the PRO-BEV group compared with the FAT-BEV group at week 6. Fasted leptin decreased at all visits in both groups and was lower in the FAT-BEV group compared with the PRO-BEV group at 1 year.
Changes from baseline were evident for all GI hormones and leptin; some differences were evident soon after surgery (ghrelin, leptin), whereas others were maintained long term (GLP-1, PYY, ghrelin, leptin). In response to a short-term stimulus, protein suppressed ghrelin and fat potently stimulated GLP-1 and PYY. Future work in this area is warranted.
Journal of Parenteral and Enteral Nutrition 03/2011; 35(2):169-80. DOI:10.1177/0148607110381403 · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Female carriers of X-linked Alport syndrome (XLAS) demonstrate variability in clinical phenotype that, unlike males, cannot be correlated with genotype. X-inactivation, the method by which females (XX) silence transcription from one X chromosome in order to achieve gene dosage parity with males (XY), likely modifies the carrier phenotype, but this hypothesis has not been tested directly.
Using a genetically defined mouse model of XLAS, we generated two groups of Alport female (Col4a5(+/-)) carriers that differed only in the X-controlling element (Xce) allele regulating X-inactivation. We followed the groups as far as 6 months of age comparing survival and surrogate outcome measures of urine protein and plasma urea nitrogen.
Preferential inactivation of the mutant Col4a5 gene improved survival and surrogate outcome measures of urine protein and plasma urea nitrogen. In studies of surviving mice, we found that X-inactivation in kidney, measured by allele-specific mRNA expression assays, correlated with surrogate outcomes.
Our findings establish X-inactivation as a major modifier of the carrier phenotype in X-linked Alport syndrome. Thus, X-inactivation patterns may offer prognostic information and point to possible treatment strategies for symptomatic carriers.
[Show abstract][Hide abstract] ABSTRACT: Children with Hurler syndrome experience progressive growth failure after hematopoietic cell transplantation (HCT). The goal of this study was to review the safety and efficacy of growth hormone (GH) in eight children with Hurler syndrome who were treated at our institution with GH for short stature or GH deficiency between 2005 and 2008. The age at initiation of treatment with GH was 9.6+/-2.3 years and time since HCT was 7.5+/-1.5 years. Mean GH dose was 0.32 mg/kg/week. Baseline growth velocity was 3.5+/-1.5 cm/year (-2.6+/-1.9 s.d.), and it increased to 5.2+/-3.0 cm/year (-0.1+/-3.6 s.d.) after 1 year of treatment. Of the six patients with radiographic data, there was one progression of scoliosis, one progression of kyphosis and one progression of genu valgum. No patient discontinued treatment due to progression of skeletal disease. One patient discontinued GH due to slipped capital femoral epiphysis. Preliminary data suggest that 1-year GH treatment may modestly improve growth velocity in children with Hurler syndrome.
Bone marrow transplantation 04/2009; 44(5):279-85. DOI:10.1038/bmt.2009.31 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the relationship of fatigue severity to other clinical features in primary Sjögren's syndrome (SS) and to identify factors contributing to the physical and mental aspects of fatigue.
We identified 94 subjects who met the American-European Consensus Group criteria for the classification of primary SS. Fatigue was assessed with a visual analog scale, the Fatigue Severity Scale (FSS), and the Profile of Fatigue (ProF). Associations with fatigue were compared using multivariate regression.
Abnormal fatigue, defined as an FSS score >or=4, was present in 67% of the subjects. Pain, helplessness, and depression were the strongest predictors of fatigue according to the FSS and the somatic fatigue domain of the ProF (ProF-S), both with and without adjustment for physiologic and serologic characteristics. Depression was associated with higher levels of fatigue; however, the majority of subjects with abnormal fatigue were not depressed. Anti-Ro/SSA-positive subjects were no more likely to report fatigue than seronegative subjects. The regression models explained 62% of the variance in FSS and 78% of the variance in ProF-S scores. Mental fatigue was correlated with depression and helplessness, but the model predicted only 54% of the variance in mental fatigue scores.
Psychosocial variables are determinants of fatigue, but only partially account for it. Although fatigue is associated with depression, depression is not the primary cause of fatigue in primary SS. Investigation of the pathophysiologic correlates of physical and mental aspects of fatigue is needed to guide the development of more effective interventions.
[Show abstract][Hide abstract] ABSTRACT: Long-standing type 1 diabetes is associated with deficits on neurocognitive testing that suggest central white matter dysfunction. This study investigated whether diffusion tensor imaging (DTI), a type of magnetic resonance imaging that measures white matter integrity quantitatively, could identify white matter microstructural deficits in patients with long-standing type 1 diabetes and whether these differences would be associated with deficits found by neurocognitive tests.
Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects completed DTI on a 3.0 Tesla scanner and a battery of neurocognitive tests. Fractional anisotropy was calculated for the major white matter tracts of the brain.
Diabetic subjects had significantly lower mean fractional anisotropy than control subjects in the posterior corona radiata and the optic radiation (P < 0.002). In type 1 diabetic subjects, reduced fractional anisotropy correlated with poorer performance on the copy portion of the Rey-Osterreith Complex Figure Drawing Test and the Grooved Peg Board Test, both of which are believed to assess white matter function. Reduced fractional anisotropy also correlated with duration of diabetes and increased A1C. A history of severe hypoglycemia did not correlate with fractional anisotropy.
DTI can detect white matter microstructural deficits in subjects with long-standing type 1 diabetes. These deficits correlate with poorer performance on selected neurocognitive tests of white matter function.
[Show abstract][Hide abstract] ABSTRACT: Mechanisms responsible for hypoglycemia unawareness remain unknown. Previously, we found that patients with type 1 diabetes and hypoglycemia unawareness had increased brain glucose concentrations as measured by (1)H-magnetic resonance spectroscopy (MRS) compared with controls measured under the same metabolic condition, suggesting that an alteration in brain glucose transport and/or metabolism may play a role in the pathogenesis of hypoglycemia unawareness. To determine whether the brain glucose concentration is altered in normal subjects subjected to recurrent hypoglycemia, we compared the brain glucose concentrations measured in healthy subjects after three episodes of hypoglycemia to blunt the counterregulatory response over 24 hr and compared this value with that measured at a time remote from the antecedent hypoglycemia protocol. Sixteen subjects (9 M/7 F, age 36 +/- 10 years, mean +/- SD) underwent three hypoglycemic clamps for 30 min at 8 AM (0 hr), 5 PM (9 hr), and 7 AM (24 hr). After the third hypoglycemic clamp, subjects underwent a hyperglycemic clamp during which brain glucose concentration was measured by MRS at 4 T. Brain glucose concentration after repeated hypoglycemia was not different from the brain glucose concentration measured in the same subjects during a control study (5.1 +/- 0.8 vs. 4.5 +/- 0.5 mumol/g wet weight, respectively, P = 0.05). These observations suggest that brain glucose transport or metabolism is not altered following short episodes of recurrent hypoglycemia in healthy human volunteers.
Journal of Neuroscience Research 11/2005; 82(4):525-30. DOI:10.1002/jnr.20654 · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the brain remains poorly defined, but some animal data suggest that chronic hyperglycemia reduces rates of brain glucose transport and/or metabolism. To address this question in human beings, we measured glucose in the occipital cortex of patients with poorly controlled diabetes and healthy volunteers at the same levels of plasma glucose using proton magnetic resonance spectroscopy. Fourteen patients with poorly controlled diabetes (hemoglobin A 1c = 9.8% +/- 1.7%, mean +/- SD) and 14 healthy volunteers similar with respect to age, sex, and body mass index were studied at a plasma glucose of 300 mg/dL. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects (4.7 +/- 0.9 vs 5.3 +/- 1.1 micromol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 micromol/g wet wt. We conclude that chronic hyperglycemia in diabetes does not alter brain glucose concentrations in human subjects.
[Show abstract][Hide abstract] ABSTRACT: Although it is well established that recurrent hypoglycemia leads to hypoglycemia unawareness, the mechanisms responsible for this are unknown. One hypothesis is that recurrent hypoglycemia alters brain glucose transport or metabolism. We measured steady-state brain glucose concentrations during a glucose clamp to determine whether subjects with type 1 diabetes and hypoglycemia unawareness may have altered cerebral glucose transport or metabolism after exposure to recurrent hypoglycemia. We compared 14 subjects with diabetes and hypoglycemia unawareness to 27 healthy control subjects. Brain glucose concentrations were measured under similar metabolic conditions using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 4 Tesla during a hyperglycemic clamp (plasma glucose = 16.7 mmol/l) with somatostatin and insulin. Subjects with type 1 diabetes and hypoglycemia unawareness had significantly higher brain glucose concentrations compared to that in controls under the same conditions (5.5 +/- 0.3 vs. 4.7 +/- 0.1 micromol/g wet weight, P = 0.016). These data suggest that changes in brain glucose transport or metabolism may occur as a result of recurrent hypoglycemia.
Journal of Neuroscience Research 01/2005; 79(1-2):42-7. DOI:10.1002/jnr.20296 · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for alpha5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With alpha5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.
Journal of the American Society of Nephrology 07/2004; 15(6):1466-74. DOI:10.1097/01.ASN.0000130562.90255.8F · 9.34 Impact Factor