Glucose response to exercise in the post-prandial period is independent of exercise intensity.

This study investigated the acute glucose response to low-intensity, moderate-intensity, and high-intensity interval exercise compared to no-exercise in healthy insufficiently active males using a four-arm, randomized, crossover design. Ten males (age: 37.3 ± 7.3 years, BMI: 29.3 ± 6.5 kg·m-2 ) completed four 30-minute interventions at weekly intervals comprising low-intensity exercise (LIE) at ~35% V˙O2 R, moderate-intensity exercise (MIE) at ~50% V˙O2 R, high-intensity interval exercise (HIIE) at ~80% V˙O2 R, and a no-exercise control. Participants performed cycle ergometer exercise 30 minutes after finishing breakfast. Glucose response was assessed using a continuous glucose monitor under free-living conditions with dietary intake replicated. A significant effect for intensity on energy expenditure was identified (P < .001) with similar energy cost in MIE (mean ± SD: 869 ± 148 kJ) and HIIE (806 ± 145 kJ), which were both greater than LIE (633 ± 129 kJ). The pattern of glucose response between the interventions over time was different (P = .02). Glucose was lower 25 minutes into each of the HIIE, MIE and LIE trials respectively (mean difference ± SD: -0.7 ± 1.1; -0.9 ± 1.1; -0.6 ± 0.9 mmol·L-1 ; P < .05) than in the no-exercise trial. Glucose response was not different between exercise intensities (P > .05). Twenty-four-hour AUC was not affected by exercise intensity (P = .75). There was a significant effect for exercise enjoyment (P = .02), with LIE (69 ± 4) preferred less than HIIE (mean ± SD: 84 ± 14; P = .02), MIE (73 ± 5; P = .03), and no-exercise (75 ± 4; P = .03). Exercise at any intensity 30 minutes after a meal affects glycemic regulation equally in insufficiently active males. Moderate to vigorous exercise intensities were preferred, and therefore, the exercise guidelines appear appropriate for the prevention of cardiometabolic disease.

Prefrontal gray matter volume mediates age effects on memory strategies.

Age differences in the strategies that individuals spontaneously use to learn new information have been shown to contribute to age differences in episodic memory. We investigated the role of prefrontal structure in observed age effects on self-initiated use of memory strategies. The relationships among age, prefrontal regional gray matter volumes, and semantic and serial clustering during free recall on the California Verbal Learning Test-II were examined across the adult lifespan. Semantic clustering was negatively correlated with age and positively correlated with gray matter volumes in bilateral middle and left inferior frontal regions across the adult lifespan. Gray matter volumes in these regions mediated the effects of age on semantic clustering. Forward serial clustering was also negatively correlated with age. However, forward serial clustering was not significantly positively correlated with gray matter volumes in any region of lateral prefrontal cortex. These results suggest that bilateral middle and left inferior frontal regions support self-initiated semantic memory strategy use across the adult lifespan. They also suggest that age differences in prefrontal gray matter volume are a significant contributor to age differences in self-initiated use of elaborative memory strategies.

Insulin sensitivity not modulated 24 to 78 h after acute resistance exercise in type 2 diabetes patients.

Resistance exercise is recommended as part of the exercise guidelines to prevent and manage type 2 diabetes (T2D), however, the frequency of exercise required to improve glycaemic control and insulin sensitivity is not clear. We recruited and tested 10 individuals with T2D by collecting a fasting blood sample immediately prior to, a whole-body moderate-high intensity resistance exercise session, and 24, 48 and 72 h afterwards. No changes to estimates of insulin sensitivity (HOMA2), glucose or insulin were observed using a repeated measures analysis of variance (p > 0.05). Further, there were no changes observed to markers of inflammation at 24 h following the resistance exercise session (p > 0.05). These findings suggest that insulin sensitivity is not acutely modified, positively or negatively, at 24, 48 or 72 h after a bout of resistance exercise. Nor are markers of inflammation altered during this time frame in a way that could cause transient insulin resistance.

Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer's Disease.

OBJECTIVE: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. METHODS: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of ß-amyloid (Aß42/Aß40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. RESULTS: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aß42/Aß40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. CONCLUSION: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology.

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Insulin sensitivity in response to a single resistance exercise session in apparently healthy individuals.

BACKGROUND: Regular resistance exercise completed for a number of weeks has been shown to increase insulin sensitivity and reduce the risk of diabetes-related complications. However, the acute responses to resistance exercise have not been adequately investigated in relation to training frequency. AIM: To investigate the changes to insulin sensitivity in apparently healthy individuals following a single session of unaccustomed resistance exercise. SUBJECTS AND METHODS: Ten sedentary, apparently healthy individuals performed a baseline oral glucose tolerance test and maximal strength testing. Participants then performed a single session of moderate-high intensity resistance exercise which was followed by 4 consecutive days of oral glucose tolerance testing, for which participants replicated their initial diet. Mean estimated insulin sensitivity change scores from baseline values and their 95% confidence intervals were compared to the previously determined values for a clinically meaningful change. RESULTS: Two participants were identified as having hyperinsulinemia and their data were therefore removed from the main analysis. There was a clinically meaningful increase in insulin response (mean >7237 pmol·l⁻¹·120 min⁻¹) on all days following the exercise session and a clinically meaningful increase in glucose response (mean >81 mmol·l⁻¹·120 min⁻¹) on only the 3rd day following exercise. These changes suggest a potentially adverse short-term effect. Additionally, the 2 individuals with hyperinsulinemia displayed more extreme results. CONCLUSION: These results suggest that insulin sensitivity may be impaired following a single session of unaccustomed resistance exercise for approximately 4 days in healthy untrained, older individuals. Further research is required for individuals with hyperinsulinemia.

Heteroallelic missense mutations of the galactosamine-6-sulfate sulfatase (GALNS) gene in a mild form of Morquio disease (MPS IVA).

Morquio disease (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Patients commonly present in early infancy with growth failure, spondyloepiphyseal dysplasia, corneal opacification, and keratan sulfaturia, but milder forms have been described. We report on a patient who grew normally until age 5 years. Her keratan sulfaturia was not detected until adolescence, and she now has changes restricted largely to the axial skeleton. She has experienced only mildly impaired vision. At age 22, thin-layer chromatography of purified glycosaminoglycans showed some keratan sulfaturia. GALNS activity in fibroblast homogenate supernatants was 20 +/- 5% of controls (as compared to 5 +/- 3% of controls in severe MPS IVA, P < .003). Kinetic analysis of residual fibroblast GALNS activity in patient and parents revealed decreased K(m) and increased Vmax in the mother and daughter, but not in the father, compatible with compound heterozygosity. GALNS exons were amplified from patient genomic DNA and screened by SSCP. Two missense mutations, a C to T transition at position 335 (predicting R94C) and a T to G transversion at position 344 (predicting F97V), were found on sequencing an abnormally migrating exon 3 amplicon. Digestion of the amplicon with FokI and AccI restriction enzymes (specific for the R94C and F97V mutations, respectively) confirmed heterozygosity. In fibroblast transfection experiments, heterozygous R94C and F97V mutants independently expressed as severe and mild GALNS deficiency, respectively. We interpret these findings to indicate that our patient bears heteroallelic GALNS missense mutations, leading to GALNS deficiency and mild MPS IVA. Our findings expand the clinical and biochemical phenotype of MPS IVA, but full delineation of the genotype-phenotype relationship requires further study of native and transfected mutant cell lines.

Ultrastructure of hepatic mitochondria in a child with hyperornithinemia, hyperammonemia, and homocitrullinuria.

Ultrastructural studies of hepatic tissue obtained at biopsy from a nine year old severely retarded boy with hyperornithinemia, hyperammonemia, and homocitrullinuria showed mitochondria of bizarre shapes and unusual internal features. Among the latter were tubules extending throughout the length of the large mitochondria that on cross section had a rosette-like arrangement; the presence of a periodic, approximately 300 A thick, sievelike membrane interposed between the tubules and the inner mitochondrial membrane; and "bulges" of mitochondrial matrix occasionally formed between these two membranes. Since to be metabolized ornithine must enter the mitochondria, the hyperornithinemia is regarded as a reflection of its inability to reach the mitochondrial interior. It is speculated that among other possible causes, the unusual sievelike membrane may be the barrier to ornithine's access to the mitochondrion.

Amino-acid metabolism and liver ultrastructure in hyperornithinemia with gyrate atrophy of the choroid and retina.

Three patients with the rare hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) syndrome were studied to elucidate the metabolic derangement and its pathologic concomitants. Tenfold elevations of blood ornithine levels, decreases in lysine levels, and hitherto unreported decreases in blood glutamate and glutamine concentration were observed. The output of ornithine from muscle kidney and splanchnic beds was curtailed or reversed after intravenous glucose. Levels of ornithine in venous blood declined after oral glucose, and rose after intravenous arginine. Increased amounts of 3-amino-2-piperidone were found in the urine, but these did not increase after the arginine-induced increase in ornithine levels. Liver biopsies in two patients revealed a marked alteration in mitochondrial ultrastructure. These studies extend the knowledge of the metabolic and pathologic derangements in HOGA. These findings are consistent with a disorder of ornithine-ketoacid transaminase, but such a disorder might not account for all the observations.

Defective expression of alpha-L-fucosidase by lymphoid cells of a fucosidosis patient.

Fucosidosis is an inherited lysosomal storage disease due to a deficiency of alpha-L-fucosidase activity. Exponentially growing lymphoid cell cultures from a fucosidosis patient (JH) had 16-fold lower extracellular alpha-L-fucosidase protein and 72-fold lower intracellular alpha-L-fucosidase protein with negligible catalytic activity as compared with the mean of 19 control cultures. The percentage of total alpha-L-fucosidase protein released extracellularly by JH cells was 71% as compared with 35% +/- 9% for control cells. During a 1.5 h pulse with 35S-methionine, alpha-L-fucosidase was synthesized by JH cells as an intracellular doublet with Mr of 58,000 and 56,000 and by control cells as an intracellular form with Mr = 58,000. During a subsequent 21 h chase with unlabeled methionine, JH alpha-L-fucosidase was entirely secreted. In contrast, only 25%-30% of control enzyme was secreted with the remainder retained intracellularly. Thus, JH lymphoid cells synthesized a reduced amount of alpha-L-fucosidase that was catalytically inefficient and was hypersecreted. Treatment of JH alpha-L-fucosidase with N-glycanase produced polypeptide chains with Mr of 52,000 and 54,000. Previously, treatment of control alpha-L-fucosidase with N-glycancase produced a single polypeptide chain with Mr of 52,000 (Biochem Genet 1988; 26: 401-20). The doublet polypeptide chains of alpha-L-fucosidase in JH cultures may represent expression of two distinct allelic forms of mutant alpha-L-fucosidase.

Ornithine methyl ester. An unusual metabolite encountered in the urine of patients with a urea cycle disorder characterized by hyperammonemia, hyperornithinemia and homocitrullinuria.

In the urine of six subjects with a urea cycle disorder characterized by hyperammonemia, hyperornithinemia and homocitrullinuria, an unusual ninhydrin-reaction compound was encountered. This unknown on hydrolysis yielded ornithine as the only amino acid and, on dansylation studied, yielded didansyl ornithine. The metabolite from urine has been shown to have the same chromatographic mobility as ornithine methyl ester on paper cellulose thin layer, and ion exchange chromatography. When trimethylsily derivatives were prepared the unknown and the ornithine methyl ester standard had similar mobility on gas chromatography. Identification of the unknown as the ornithine methyl ester was confirmed by gas chromatography-mass spectrometric analysis. In the patients' urines the concentration of methyl ornithine ranged from 70 to 368 microne moles/g creatinine.

Defective heparan sulfate metabolism in the Sanfilippo syndrome and assay of this defect in the assessment of the mucopolysaccharidoses patient.

The Sanifilippo syndrome is an inherited dementia caused by defective degradation of heparan sulfate. In the course of its catabolism the heparan sulfate polymer must be desulfated. Heparan sulfate sulfatase activity was demonstrated in homogenates of normal tissues and cultured skin fibroblasts, and in normal urine. This activity was found to be grossly depressed or absent in necropsy specimens of liver and spleen from two Sanfilippo patients. The heparan sulfate sulfatase activity was not demonstrable in urine from eleven, or cultured fibroblasts from four Sanfilippo patients. Activities of alpha-N-acetyl-glucosaminidase, the site of the metabolic defect in the Sanfilippo B variant were either normal or slightly elevated in the Sanfilippo tissues and cultured fibroblasts whereas the mean level in the urine of our Sanfilippo patients was about one-third of that encountered in control urines.

Ataxia in institutionalized patients with epilepsy.

Fifty-four per cent of 41 chronically institutionalized adult patients with epilepsy had ataxia of gait (wide mean stride width). None of the following correlated with stride width: serum phenytoin, previous phenytoin toxicity, seizure frequency, or status epilepticus. Seventeen of the 41 patients had computed tomographic head scans. Patients with radiological evidence of cerebellar atrophy had a wider mean stride width, later age of onset of seizures, greater peak serum concentrations of phenytoin than did those without cerebellar atrophy. Ataxia of gait was inconsistently associated with cerebellar atrophy. Elevated serum/plasma concentrations of phenytoin may be a risk factor for cerebellar atrophy, but seizure frequency or status epilepticus are not independently related to this complication.

Tay-Sachs disease: B1 variant.

This first child of non-Jewish parents had nystagmus at 4 months of age, bilateral cherry-red macular spots at 7 months of age, and hyperacusis at 8 months of age; the patient has deteriorated progressively following a clinical course typical of Tay-Sachs disease B variant. Total beta-N-acetylhexosaminidase assayed with 4-methylumbelliferyl-beta-glucosamine (4 MU GlcNAc) as substrate was within the normal range in plasma and cultured dermal fibroblasts and 2/3 the normal mean in leukocytes. The hexosaminidase A activity, assayed with the same substrate in plasma and cultured fibroblasts, approximated Tay-Sachs disease heterozygote levels; however, the activity of hexosaminidase A assayed with 4 MU Glc NAc-6-sulfate in the plasma, leukocytes, and cultured fibroblasts was less than 8, 2, and 1%, respectively of the control mean. This female infant with the B1 variant of Tay-Sachs disease demonstrated an earlier onset and more rapidly progressive course than was observed in 4 of the 5 previously reported patients with this Tay-Sachs disease variant.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)-syndrome. Ultrastructural changes of mitochondria in cultured dermal fibroblasts of three patients.

Mitochondria of fibroblasts cultured from the skin obtained at biopsy from three patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)-syndrome, one of the autosomal recessive, heritable urea cycle disorders, were studied with appropriate controls ultrastructurally. The patients were two severely retarded 10- and 12-year-old boys, and a 22-year-old sister of the former whose mental status was at the low normal range; she never had motor impairments or seizures. The mitochondria, similar in all three patients, were increased in number, very long, branching and/or "looping," and tortuous. "Spurs" or "buddings" extended from their lateral surfaces and the terminal segments were often bulbous. Other unusual configurations were also present. In addition, giant forms with large diameter contained innumerable closely-packed and parallel cristae which traversed the entire width of these mitochondria; at times they assumed a "whirled" pattern. The mitochondrial matrix was usually of high electron density. These changes were not a feature of fibroblastic mitochondria of controls. Several changes resembled those of hepatic mitochondria in this disorder. All features are interpreted as an attempt at expanding the mitochondrial volume (via structural substratum) to compensate for the metabolic incompetence of these organelles (a block in transmembranous transfer of ornithine from hyaloplasm into mitochondria for conversion to citrulline).

Ultrastructure and peroxidase of leucocytes in five patients with juvenile form of ceroid lipofuscinoses.

Peripheral leucocytes obtained from five patients with clinical histories and funduscopic findings typical of the juvenile form of the so-called neuronal ceroid lipofuscinosis (NCLF) (synonym: Spielmeyer-Vogt disease) were assayed for peroxidase activity and examined by electron microscopy. The peroxidase levels were considerably lower in three but normal in two patients. Ultrastructurally, the lymphocytes of all five patients showed the presence of tubulo-membranous cytosomes many displaying the fingerprint images at present regarded as being typical for the NCLF. The possible implications of the discrepancy between the morphological observations and the enzymatic findings are discussed.

Reproducibility of multiple repeated oral glucose tolerance tests.

We assessed the oral glucose tolerance test's (OGTT) ability to produce consistent results for estimating insulin sensitivity over four consecutive days. Individual coefficients of variation for OGIS and Stumvoll-ISI were 7.8% and 14.4% with no statistically significant difference between days. Thereby, indicating repeated OGTT's are reliable for estimating insulin sensitivity.