Gymnastics participation is associated with skeletal benefits in the distal forearm: a 6-month study using peripheral Quantitative Computed Tomography.

OBJECTIVES: Musculoskeletal development of the upper limbs during exposure to weight-bearing loading is under-researched during early pubescent growth. The purpose was to assess the changes in upper body musculoskeletal strength in young girls following 6 months of non-elite gymnastics participation. METHODS: Eighty-four girls, 6-12 years were divided into groups based on gymnastics participation: high-training (HGYM, 6-16 hr/wk), low-training (LGYM, 1-5 hr/wk), and non-gymnasts (NONGYM). Volumetric BMD, bone geometry, estimated bone strength and muscle size were assessed at the non-dominant forearm (4% and 66% radius and ulna) with pQCT. DXA assessed aBMD and body composition. Tests for explosive power, muscle strength, and endurance were also performed. RESULTS: Interaction effects were observed in all variables at the 4% radius. At the 66% ulna, HGYM and LGYM had greater bone mass, size and bone strength than NONGYM, furthermore a dose-response relationship was observed at this location. Body composition was better for HGYM than LGYM and NONGYM, however muscle function was better for HGYM and LGYM than NONGYM. CONCLUSION: The greatest changes were obtained with more than one gymnastics class per week. Separating gymnastics participation-related changes from those associated with normal growth and development remains difficult, particularly at the 4% radius.

Bone health of apprentice jockeys using peripheral quantitative computed tomography.

Our aim was to use Peripheral Quantitative Computed Tomography (pQCT) to assess the bone health of male and female apprentice jockeys and age- and sex-matched peers. 2 groups of 25 young adults (n=50) (age range 15-38 years) were comprised of male and female apprentice jockeys, and male and female controls. We used pQCT to measure the distal tibia and distal radius. After covarying for weight and limb length, apprentice jockeys displayed less tibial cortical area and lower strength strain index at 14% distal shaft, 38% mid shaft and 66% proximal sites measured distally than controls (p=0.001). No between group differences were found in cortical density, trabecular area, and trabecular density at the tibia. Compared with controls, apprentice jockeys displayed greater trabecular density at the distal radial site (p=0.001), greater strength strain index at 66% proximal site measured distally (p=0.01), and a lower strength strain index at the distal radius (p=0.006). In conclusion, only trabecular density at the distal radius and strength strain index at the proximal radius were greater in apprentice jockeys than controls. Strategies to increase bone density and bone strength in apprentice jockeys should be considered by relevant industry stakeholders and their health providers.

Non-elite gymnastics participation is associated with greater bone strength, muscle size, and function in pre- and early pubertal girls.

UNLABELLED: Recent reports indicate an increase in forearm fractures in children. Bone geometric properties are an important determinant of bone strength and therefore fracture risk. Participation in non-elite gymnastics appears to contribute to improving young girls' musculoskeletal health, more specifically in the upper body. INTRODUCTION: The primary aim of this study was to determine the association between non-elite gymnastics participation and upper limb bone mass, geometry, and strength in addition to muscle size and function in young girls. METHODS: Eighty-eight pre- and early pubertal girls (30 high-training gymnasts [HGYM, 6-16 hr/ wk], 29 low-training gymnasts [LGYM, 1-5 h r/wk] and 29 non-gymnasts [NONGYM]), aged 6-11 years were recruited. Upper limb lean mass, BMD and BMC were derived from a whole body DXA scan. Forearm volumetric BMD, bone geometry, estimated strength, and muscle CSA were determined using peripheral QCT. Upper body muscle function was investigated with muscle strength, explosive power, and muscle endurance tasks. RESULTS: HGYM showed greater forearm bone strength compared with NGYM, as well as greater arm lean mass, BMC, and muscle function (+5% to +103%, p < 0.05). LGYM displayed greater arm lean mass, BMC, muscle power, and endurance than NGYM (+4% to +46%, p < 0.05); however, the difference in bone strength did not reach significance. Estimated fracture risk at the distal radius, which accounted for body weight, was lower in both groups of gymnasts. Compared with NONGYM, HGYM tended to show larger skeletal differences than LGYM; yet, the two groups of gymnasts only differed for arm lean mass and muscle CSA. CONCLUSION: Non-elite gymnastics participation was associated with musculoskeletal benefits in upper limb bone geometry, strength and muscle function. Differences between the two gymnastic groups emerged for arm lean mass and muscle CSA, but not for bone strength.

Calcium and vitamin-D supplementation on bone structural properties in peripubertal female identical twins: a randomised controlled trial.

UNLABELLED: A randomised controlled trial was used in assessing the impact of 6 months of daily calcium and vitamin-D supplementation on trabecular and cortical bone acquisition at distal tibial and radial sites using peripheral quantitative computed tomography (pQCT). Daily supplementation was associated with increased bone density and bone strength at the distal tibia and radius. INTRODUCTION: pQCT has not been used to assess bone responses to calcium and vitamin-D supplementation on peripubertal children. This randomised controlled trial aimed to assess the impact of a 6-month daily calcium and vitamin-D supplementation on trabecular and cortical bone acquisition at distal tibial and radial sites using pQCT. METHODS: Twenty pairs of peripubertal female identical twins, aged 9 to 13 years, were randomly assigned to receive either 800 mg of calcium and 400 IU of vitamin D3, or a matched placebo. Bone structural properties at the distal tibia and distal radius were acquired at baseline and 6 months. RESULTS: The calcium-supplemented group showed greater gains in trabecular density, trabecular area and strength strain index at the 4% of distal tibial and radial sites compared with the placebo group (p=0.001). Greater gains in cortical area at the 38% and 66% of tibial sites were also found in twins receiving the calcium supplement (p=0.001). CONCLUSIONS: Daily supplementation for a period of 6 months was associated with increased trabecular area, trabecular density and strength strain index at the ultra-distal tibia and radius and increased cortical area at tibial mid-shaft.

Skeletal differences at the ulna and radius between pre-pubertal non-elite female gymnasts and non-gymnasts.

OBJECTIVE: To compare skeletal parameters between the ulna and radius in pre-pubertal non-elite gymnasts and non-gymnasts. METHODS: Fifty-eight non-elite artistic gymnasts, aged 6-11 years, were compared with 28 non-gymnasts for bone mineral content (BMC), total and cortical bone area (ToA, CoA), trabecular and cortical volumetric density (TrD, CoD) and estimated bone strength (BSI and SSIp), obtained by pQCT at the distal and proximal forearm. RESULTS: Gymnasts had greater estimated bone strength than non-gymnasts at both sites of the forearm. At the distal forearm, the gymnastics-induced skeletal benefits were greater at the radius than ulna (Z-scores for BMC, TrD and BSI +0.40 to +0.61 SD, p<0.05 vs. +0.15 to +0.48 SD, NS). At the proximal forearm, the skeletal benefits were greater at the ulna than the radius (Z-scores for BMC, ToA, CoA and SSIp +0.59 to +0.82 SD, p<0.01 vs. +0.35 (ToA) and +0.43 SD (SSIp), p<0.01). CONCLUSION: Skeletal benefits at the distal and proximal forearm emerged in young non-elite gymnasts. Benefits were larger when considering skeletal parameters at both the ulna and radius, than the radius alone as traditionally performed with pQCT. These findings suggest the ulna is worth investigating in future studies aiming to accurately quantify exercise-induced skeletal adaptations.

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

Nerve conduction impairment in experimental diabetes has been empirically but not mechanistically linked to altered nerve myo-inositol metabolism. The phospholipid-dependent membrane-bound sodium-potassium ATPase provides a potential mechanism to relate defects in diabetic peripheral nerve myo-inositol-phospholipid metabolism, impulse conduction, and energy utilization. Therefore, the effect of streptozocin-induced diabetes mellitus and dietary myo-inositol supplementation on rat sciatic nerve sodium-potassium ATPase was studied. ATPase activity was measured enzymatically in sciatic nerve homogenates from 4-wk streptozocin diabetic rats and age-matched controls either fed a standard or 1% myo-inositol supplemented diet. The sodium-potassium ATPase components were assessed by ouabain inhibition or the omission of sodium and potassium ions. Diabetes reduced the composite ATPase activity recovered in crude homogenates of sciatic nerve. The 40% reduction in the sodium-potassium ATPase was selectively prevented by 1% myo-inositol supplementation (which preserved normal nerve conduction). Thus, in diabetic peripheral nerve, abnormal myo-inositol metabolism is associated with abnormal sodium-potassium ATPase activity. The mechanism of the effect of dietary myo-inositol to correct diabetic nerve conduction may be through changes in a sodium-potassium ATPase, possibly via changes in myo-inositol-containing phospholipids.

Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect.

Experimental diabetes consistently reduces the concentration of free myo-inositol in peripheral nerve, which usually exceeds that of plasma by 90-100-fold. This phenomenon has been explicitly linked to the impairment of nerve conduction in the acutely diabetic streptozocin-treated rat. However, the mechanism by which acute experimental diabetes lowers nerve myo-inositol content and presumably alters nerve myo-inositol content and presumably alters nerve myo-inositol metabolism is unknown. Therefore, the effects of insulin and elevated medium glucose concentration of 2-[3H]myo-inositol uptake were studied in a metabolically-defined in vitro peripheral nerve tissue preparation derived from rabbit sciatic nerve, whose free myo-inositol content is reduced by experimental diabetes. The results demonstrate that myo-inositol uptake occurs by at least two distinct transport systems in the normal endoneurial preparation. A sodium- and energy-dependent saturable transport system is responsible for at least 94% of the measured uptake at medium myo-inositol concentrations approximating that present in plasma. This carrier-mediated transport system has a high affinity for myo-inositol (Kt = 63 microM), and is not influenced acutely by physiological concentrations of insulin; it is, however, inhibited by hyperglycemic concentrations of glucose added to the incubation medium in a primarily competitive fashion. Thus, competitive inhibition of peripheral nerve myo-inositol uptake by glucose may constitute a mechanism by which diabetes produces physiologically significant alterations in peripheral nerve myo-inositol metabolism.

Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy.

Altered sorbitol and myo-inositol metabolism, (Na,K)-ATPase function, electrochemical sodium gradients, axonal swelling, and distortion and disruption of the node of Ranvier ("axo-glial dysjunction") directly implicate hyperglycemia in the pathogenesis of neuropathy in diabetic rats, but the relevance of this sequence to clinical neuropathy in heterogeneous groups of diabetic patients remains to be established. Fascicular sural nerve morphometry in 11 patients with neuropathy complicating insulin-dependent diabetes revealed a pattern of interrelated structural changes strikingly similar to that of the diabetic rat when compared to age-matched controls. 17 older non-insulin-dependent diabetic patients with comparable duration and severity of hyperglycemia and severity of neuropathy, displayed similar nerve fiber loss, paranodal demyelination, paranodal remyelination and segmental demyelination compared to age-matched controls, but axo-glial dysjunction was replaced by Wallerian degeneration as the primary manifestation of fiber damage, and fiber loss occurred in a spatial pattern consistent with an ischemic component. The mechanistic model developed from the diabetic rat does indeed appear to apply to human diabetic neuropathy, but superimposed hormonal, metabolic, vascular, and/or age-related effects alter the morphologic expression of the neuropathy in non-insulin dependent diabetes.

Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat.

Biochemical abnormalities in peripheral nerve are thought to precede and condition the development of diabetic neuropathy, but metabolic intervention in chronic diabetic neuropathy produces only limited acute clinical response. The residual, metabolically unresponsive neurological deficits have never been rigorously defined in terms of either persistent metabolic derangements or irreversible structural defects because human nerve tissue is rarely accessible for anatomical and biochemical study and experimentally diabetic animals do not develop the structural hallmarks of human diabetic neuropathy. Detailed neuroanatomical-functional-biochemical correlation was therefore undertaken in long-term spontaneously diabetic BB-Wistar rats that functionally and structurally model human diabetic neuropathy. Vigorous insulin replacement in chronically diabetic BB rats essentially normalized both the sural nerve fiber caliber spectrum and the decreased sciatic nerve myo-inositol and (Na,K)-ATPase levels generally associated with conduction slowing in diabetic animals; yet, nerve conduction was only partially restored toward normal. Morphometric analysis revealed a striking disappearance of paranodal axo-glial junctional complexes that was not corrected by insulin replacement. Loss of these strategic junctional complexes, which are thought to limit lateral migration of axolemmal Na channels away from nodes of Ranvier, correlates with and can account for the diminished nodal Na permeability and resultant nodal conduction delay characteristic of chronic diabetic neuropathy in this animal model.

Altered aldose reductase gene regulation in cultured human retinal pigment epithelial cells.

Aldose reductase (AR2), a putative "hypertonicity stress protein" whose gene is induced by hyperosmolarity, protects renal medullary cells against the interstitial hyperosmolarity of antidiuresis by catalyzing the synthesis of millimolar concentrations of intracellular sorbitol from glucose. Although AR2 gene induction has been noted in a variety of renal and nonrenal cells subjected to hypertonic stress in vitro, the functional significance of AR2 gene expression in cells not normally exposed to a hyperosmolar milieu is not fully understood. The physiological impact of basal AR2 expression in such cells may be limited to hyperglycemic states in which AR2 promotes pathological polyol accumulation, a mechanism invoked in the pathogenesis of diabetic complications. Since AR2 overexpression in the retinal pigment epithelium has been associated with diabetic retinopathy, the regulation of AR2 gene expression and associated changes in sorbitol and myo-inositol were studied in human retinal pigment epithelial cells in culture. The relative abundance of aldehyde reductase (AR1) and AR2 mRNA was quantitated by filter hybridization of RNA from several human retinal pigment epithelial cell lines exposed to hyperglycemic and hyperosmolar conditions in vitro. AR2 but not AR1 mRNA was significantly increased some 11- to 18-fold by hyperosmolarity in several retinal pigment epithelial cell lines. A single cell line with a 15-fold higher basal level of AR2 mRNA than other cell lines tested demonstrated no significant increase in AR2 mRNA in response to hypertonic stress. This cell line demonstrated accelerated and exaggerated production of sorbitol and depletion of myo-inositol upon exposure to 20 mM glucose. Therefore, abnormal AR2 expression may enhance the sensitivity of cells to the biochemical consequences of hyperglycemia potentiating the development of diabetic complications.

Role of sorbitol accumulation and myo-inositol depletion in paranodal swelling of large myelinated nerve fibers in the insulin-deficient spontaneously diabetic bio-breeding rat. Reversal by insulin replacement, an aldose reductase inhibitor, and myo-inositol.

Axo-glial dysjunction refers to the disruption of important junctional complexes that anchor terminal loops of myelin to the paranodal axolemma in diabetic human and animal peripheral nerve. Neither axo-glial dysjunction nor the preceeding acute localized paranodal swelling has been specifically attributed to discrete metabolic consequences of insulin deficiency or hyperglycemia. Two metabolic sequelae of hyperglycemia in diabetic nerve, sorbitol accumulation via aldose reductase, and (Na,K)-ATPase deficiency related to myo-inositol depletion, were explored as possible underlying causes of acute paranodal swelling in the spontaneously diabetic bio-breeding rat. 3 wk of insulin replacement, or therapy with an aldose reductase inhibitor or myo-inositol completely reversed paranodal swelling in sural nerve fibers after 3 wk of untreated insulin deficiency. These observations suggest that insulin deficiency and hyperglycemia cause reversible paranodal swelling, and ultimately poorly reversible axo-glial dysjunction, via the myo-inositol-related (Na,K)-ATPase defect rather than by the osmotic effects of sorbitol accumulation within nerve fibers.

Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes.

The factors influencing the development of impaired sciatic motor nerve conduction velocity (MNCV) in acute experimental diabetes were examined. Decreased MNCV developed by the 14th day after streptozotocin administration but only in rats which became hyperglycemic. Insulin treatment, begun on day 3, failed to prevent imparied MNCV in diabetic rats in which improved or normal weight gain and a decreased degree of hyperglycemia was induced. However, insulin treatment prevented the development of impaired MNCV in a group of diabetic rats in which the tail vein plasma glucose concentration was never found to exceed 160 mg/dl during days 6 through 14, andin which the mean plus or minus SEM of the average plasma glucose concentration for each animal during the same period was 75 plus or minus 18 mg/dl. In normal rats fed diets containing 0.011% or 0.069% free myoinositol (a presumably normal range), sciatic nerve free myoinositol concentrations were 90- and 60-fold higher than those in plasma. On these diets the development of impaired MNCV in the diabetics was associated with a decrease in nerve free myoinositol as compared with nerves from normals fed the same diet, despite similar plasma levels in the normals and diabetics. Plasma and nerve free myoinositol increased with increasing dietary myoinositol content in both normals and diabetics, and nerve myoinositol content could be acutely increased by an i.p. myoinositol load. By supplementing the diets with 1.0% myoinositol, the difference in nerve myoinositol in normal and diabetic rats on day 14 was abolished; on this diet the development of impaired MNCV in the diabetics was moderated or totally prevented, despite persistent hyperglycemia and elevated nerve sorbitol and fructose concentrations. Insulin treatment that prevented impaired MNCV prevented a decrease in nerve myoinositol in diabetics. These studies suggest that insulin deficiency, and possibly hyperglycemia, are primary factors in the development of imparied MNCV in acute experimental diabetes. However, the development of impaired MNCV appears to be related in some manner to a derangement in the regulation of nerve free myoinositol content, which appears to be subject to modification by increases in plasma myoinositol concentration over a critical range.

Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat.

To test the hypothesis that aldose reductase inhibition may prevent or delay the development of functional and structural neuropathy in the insulin-deficient diabetic Bio-Breeding rat (BB-rat), hyperglycemic rats were begun on the aldose reductase inhibitor (ARI) ponalrestat 25 mg/kg body wt soon after the onset of diabetes and followed for 4 or 6 mo. Ponalrestat treatment completely prevented the characteristic nerve conduction slowing and structural abnormalities of the node of Ranvier for 4 mo despite only partial preservation of axonal integrity. Ponalrestat treatment for 6 mo achieved a partial but significant prevention of nerve conduction slowing, axoglial dysjunction, and axonal degenerative changes. This incomplete but significant prevention of neuropathy by ponalrestat suggests that additional mechanisms besides polyol-pathway activation may be of importance in the pathogenesis of diabetic neuropathy. Alternatively, the dosage used in the present study may not have been sufficient to achieve a complete prevention. Despite the only partial protective effect of ARI treatment on degenerative peripheral nerve changes in hyperglycemic BB-rats, 6 mo of treatment resulted in a more than threefold increase in regenerating nerve fibers. These data suggest that prophylactic ARI treatment may be efficacious in delaying the development of diabetic neuropathy.

Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat.

The abnormalities underlying diabetic neuropathy appear to be multiple and involve metabolic neuronal and vasomediated defects. The accumulation of long-chain fatty acids and impaired beta-oxidation due to deficiencies in carnitine and/or its esterified derivatives, such as acetyl-L-carnitine, may have deleterious effects. In the present study, we examined, in the diabetic bio-breeding Worcester rat, the short- and long-term effects of acetyl-L-carnitine administration on peripheral nerve polyols, myoinositol, Na+/K+ -ATPase, vasoactive prostaglandins, nerve conduction velocity, and pathologic changes. Short-term prevention (4 mo) with acetyl-L-carnitine had no effects on nerve polyols, but corrected the Na+/K+ -ATPase defect and was associated with 63% prevention of the nerve conduction defect and complete prevention of structural changes. Long-term prevention (8 mo) and intervention (from 4 to 8 mo) with acetyl-L-carnitine treatment normalized nerve PGE(1) whereas 6-keto PGF(1-alpha) and PGE(2) were unaffected. In the prevention study, the conduction defect was 73% prevented and structural abnormalities attenuated. Intervention with acetyl-L-carnitine resulted in 76% recovery of the conduction defect and corrected neuropathologic changes characteristic of 4-mo diabetic rats. Acetyl-L-carnitine treatment promoted nerve fiber regeneration, which was increased two-fold compared to nontreated diabetic rats. These results demonstrate that acetyl-L-carnitine has a preventive effect on the acute Na+/- K+_ATPase defect and a preventive and corrective effect on PGE1 in chronically diabetic nerve associated with improvements of nerve conduction velocity and pathologic changes.

A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake.

Effects of glucose on sorbitol pathway activation, cellular redox, and metabolism of myo-inositol, phosphoinositide, and diacylglycerol in cultured human retinal pigment epithelial cells.

Sorbitol (aldose reductase) pathway flux in diabetes perturbs intracellular metabolism by two putative mechanisms: reciprocal osmoregulatory depletion of other organic osmolytes e.g., myo-inositol, and alterations in NADPH/NADP+ and/or NADH/NAD+. The "osmolyte" and "redox" hypotheses predict secondary elevations in CDP-diglyceride, the rate-limiting precursor for phosphatidylinositol synthesis, but through different mechanisms: the "osmolyte" hypothesis via depletion of intracellular myo-inositol (the cosubstrate for phosphatidylinositol-synthase) and the "redox" hypothesis through enhanced de novo synthesis from triose phosphates. The osmolyte hypothesis predicts diminished phosphoinositide-derived arachidonyl-diacylglycerol, while the redox hypothesis predicts increased total diacylglycerol and phosphatidic acid. In high aldose reductase expressing retinal pigment epithelial cells, glucose-induced, aldose reductase inhibitor-sensitive CDP-diglyceride accumulation and inhibition of 32P-incorporation into phosphatidylinositol paralleled myo-inositol depletion (but not cytoplasmic redox, that was unaffected by glucose) and depletion of arachidonyl-diacylglycerol. 3 mM pyruvate added to the culture medium left cellular redox unaltered, but stimulated Na(+)-dependent myo-inositol uptake, accumulation, and incorporation into phosphatidylinositol. These results favor myo-inositol depletion rather than altered redox as the primary cause of glucose-induced aldose reductase-related defects in phospholipid metabolism in cultured retinal pigment epithelial cells.

Modulation of basal nitric oxide-dependent cyclic-GMP production by ambient glucose, myo-inositol, and protein kinase C in SH-SY5Y human neuroblastoma cells.

Defective tissue perfusion and nitric oxide production and altered myo-inositol metabolism and protein kinase C activation have been invoked in the pathogenesis of diabetic complications including neuropathy. The precise cellular compartmentalization and mechanistic interrelationships of these abnormalities remain obscure, and nitric oxide possesses both neurotransmitter and vasodilator activity. Therefore the effects of ambient glucose and myo-inositol on nitric oxide-dependent cGMP production and protein kinase C activity were studied in SH-SY5Y human neuroblastoma cells, a cell culture model for peripheral cholinergic neurons. D-Glucose lowered cellular myo-inositol content, phosphatidylinositol synthesis, and phosphorylation of an endogenous protein kinase C substrate, and specifically reduced nitric oxide-dependent cGMP production a time- and dose-dependent manner with an apparent IC50 of approximately 30 mM. The near maximal decrease in cGMP induced by 50 mM D-glucose was corrected by the addition of protein kinase C agonists or 500 microM myo-inositol to the culture medium, and was reproduced by protein kinase C inhibition or downregulation, or by myo-inositol deficient medium. Sodium nitroprusside increased cGMP in a dose-dependent fashion, with low concentrations (1 microM) counteracting the effects of 50 mM D-glucose or protein kinase C inhibition. The demonstration that elevated D-glucose diminishes basal nitric oxide-dependent cGMP production by myo-inositol depletion and protein kinase C inhibition in peripheral cholinergic neurons provides a potential metabolic basis for impaired nitric oxide production, nerve blood flow, and nerve impulse conduction in diabetes.

The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat.

Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis.

A challenge to fitness testing in primary schools.

We challenge the tradition of fitness testing in schools on the basis of purpose, procedures and outcomes. A number of assumptions about validity of selected tests are raised. The need to be able to track fitness through childhood into adulthood is challenged with limited scientific evidence of longitudinal tracking. Supporters of wide-scale fitness testing of children in schools include researchers whose intention is to promote public health awareness and policy. But a variety of confounding factors can affect field-based testing and lower the confidence in intra and inter group comparisons. Confounders include variability in motivation, familiarisation, external conditions, group dynamics, self-efficacy in testing, and perceived value of testing and likely outcomes. With acknowledged limitations, a more appropriate context for fitness testing for young people who have a strong commitment to physical activity may lie more in a professionally delivered sports-specific setting rather than in large-scale school-based testing. Given the less than desirable participation in activity outside of school and the distressing prevalence of childhood overweight and obesity, it is unlikely that fitness testing experiences will provide children with much needed positive encouragement for lifelong physical activity. Alternative strategies for school-based assessment of the promotion of child health through physical activity are proposed.

Assessment of bone strength at differentially-loaded skeletal regions in adolescent middle-distance runners.

Bone adaptations to loading extend beyond mineral accrual to geometric markers of bone strength. Available technology and regional differences in cortical bone dictate how bone strength is reported. Examination of bone strength at two differentially-loaded skeletal sites using hip structure analysis (HSA) and bone strength index (BSI) is under-explored in adolescent sporting populations. The purpose of this study was to compare HSA at the femoral neck and BSI at the distal tibia in adolescent middle-distance runners and age- and gender-matched controls. Four groups of 20 adolescents aged 14-18 years were composed of male and female middle-distance runners, and male and female controls. Distal tibial BSI was calculated using data from dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Calculations for femoral neck strength were acquired from DXA-derived HSA software. Female athletes displayed greater distal tibial BSI than controls t(38)=3.4, p=0.002, but femoral neck bone measures did not differ. In males, no group differences were found at either the distal tibia or femoral neck. In conclusion, exposure to similar high training loads may advantage female adolescent athletes more than male adolescent athletes compared with less active peers in bone strength at the distal tibia.