The Effect of Carbohydrate Restriction on Lipids, Lipoproteins, and Nuclear Magnetic Resonance-Based Metabolites: CALIBER, a Randomised Parallel Trial.

Low-carbohydrate high-fat (LCHF) diets can be just as effective as high-carbohydrate, lower-fat (HCLF) diets for improving cardiovascular disease risk markers. Few studies have compared the effects of the UK HCLF dietary guidelines with an LCHF diet on lipids and lipoprotein metabolism using high-throughput NMR spectroscopy. This study aimed to explore the effect of an ad libitum 8-week LCHF diet compared to an HCLF diet on lipids and lipoprotein metabolism and CVD risk factors. For 8 weeks, n = 16 adults were randomly assigned to follow either an LCHF (n = 8, <50 g CHO p/day) or an HCLF diet (n = 8). Fasted blood samples at weeks 0, 4, and 8 were collected and analysed for lipids, lipoprotein subclasses, and energy-related metabolism markers via NMR spectroscopy. The LCHF diet increased (p < 0.05) very small VLDL, IDL, and large HDL cholesterol levels, whereas the HCLF diet increased (p < 0.05) IDL and large LDL cholesterol levels. Following the LCHF diet alone, triglycerides in VLDL and HDL lipoproteins significantly (p < 0.05) decreased, and HDL phospholipids significantly (p < 0.05) increased. Furthermore, the LCHF diet significantly (p < 0.05) increased the large and small HDL particle concentrations compared to the HCLF diet. In conclusion, the LCHF diet may reduce CVD risk factors by reducing triglyceride-rich lipoproteins and improving HDL functionality.

Neuromuscular fatigue and recovery after strenuous exercise depends on skeletal muscle size and stem cell characteristics.

Hamstring muscle injury is highly prevalent in sports involving repeated maximal sprinting. Although neuromuscular fatigue is thought to be a risk factor, the mechanisms underlying the fatigue response to repeated maximal sprints are unclear. Here, we show that repeated maximal sprints induce neuromuscular fatigue accompanied with a prolonged strength loss in hamstring muscles. The immediate hamstring strength loss was linked to both central and peripheral fatigue, while prolonged strength loss was associated with indicators of muscle damage. The kinematic changes immediately after sprinting likely protected fatigued hamstrings from excess elongation stress, while larger hamstring muscle physiological cross-sectional area and lower myoblast:fibroblast ratio appeared to protect against fatigue/damage and improve muscle recovery within the first 48 h after sprinting. We have therefore identified novel mechanisms that likely regulate the fatigue/damage response and initial recovery following repeated maximal sprinting in humans.

Short-term, but not acute, intake of New Zealand blackcurrant extract improves insulin sensitivity and free-living postprandial glucose excursions in individuals with overweight or obesity.

Impaired postprandial glucose handling and low-grade systemic inflammation are risk factors for developing insulin resistance in individuals with overweight or obesity. Acute ingestion of anthocyanins improves postprandial glucose responses to a single carbohydrate-rich meal under strictly controlled conditions. PURPOSE: Examine whether acute and short-term supplementation with anthocyanin-rich New Zealand blackcurrant (NZBC) extract can improve postprandial glucose responses to mixed-macronutrient meals. METHODS: Twenty-five overweight (BMI > 25 kg m2) sedentary individuals participated in one of the following double-blinded, randomised controlled trials: (1) ingestion of 600 mg NZBC extract or placebo prior to consumption of a high-carbohydrate, high-fat liquid meal (n = 12); (2) 8-days supplementation with NZBC extract (600 mg day-1) or placebo, with insulin sensitivity and markers of inflammation assessed on day-7, and free-living postprandial glucose (continuous glucose monitoring) assessed on day-8 (n = 13). RESULTS: A single dose of NZBC extract had no effect on 3 h postprandial glucose, insulin or triglyceride responses. However, in response to short-term NZBC extract supplementation insulin sensitivity was improved (+ 22%; P = 0.011), circulating C-reactive protein concentrations decreased (P = 0.008), and free-living postprandial glucose responses to both breakfast and lunch meals were reduced (- 9% and - 8%, respectively; P < 0.05), compared to placebo. CONCLUSION: These novel results indicate that repeated intake, rather than a single dose of NZBC extract, is required to induce beneficial effects on insulin sensitivity and postprandial glucose handling in individuals with overweight or obesity. Continuous glucose monitoring enabled an effect of NZBC extract to be observed under free-living conditions and highlights the potential of anthocyanin-rich supplements as a viable strategy to reduce insulin resistance.

DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

Stable C isotope data of southern mixed-grass prairie vegetation from Oklahoma, United States.

Stable carbon isotopic data (δ13C) of 41 individual plant species was collected from long-term grazed and ungrazed pastures in Oklahoma, USA. These data can serve as a library of stable carbon isotope values for Southern mixed-grass prairie species. Seventeen warm-season (C4) and twenty-four cool-season (C3) plants were identified and collected from the United States Department of Agriculture (USDA) Southern Plains Experimental Range (SPER). Plant samples were dried at 55°C, and ground finely. The δ13C isotopic compositions were determined using a Europa Scientific automated nitrogen carbon analyzer (ANCA/NT) with a Solid/Liquid Preparation Module (Dumas combustion sample preparation system) coupled to a Europa 20-20 Stable isotope analyzer continuous flow isotope ratio mass spectrometer (Sercon Ltd, formerly Europa Scientific Ltd., Crewe, England). These data can be used as end members in isotopic mixing models or in paleoecology to correlate soil ages with plant species composition. Data from plant species provides information about soil organic carbon sequestration and possible long-term climate change.

Intense noise exposure alters peripheral vestibular structures and physiology.

The otolith organs play a critical role in detecting linear acceleration and gravity to control posture and balance. Some afferents that innervate these structures can be activated by sound and are at risk for noise overstimulation. A previous report demonstrated that noise exposure can abolish vestibular short-latency evoked potential (VsEP) responses and damage calyceal terminals. However, the stimuli that were used to elicit responses were weaker than those established in previous studies and may have been insufficient to elicit VsEP responses in noise-exposed animals. The goal of this study was to determine the effect of an established noise exposure paradigm on VsEP responses using large head-jerk stimuli to determine if noise induces a stimulus threshold shift and/or if large head-jerks are capable of evoking VsEP responses in noise-exposed rats. An additional goal is to relate these measurements to the number of calyceal terminals and hair cells present in noise-exposed vs. non-noise-exposed tissue. Exposure to intense continuous noise significantly reduced VsEP responses to large stimuli and abolished VsEP responses to small stimuli. This finding confirms that while measurable VsEP responses can be elicited from noise-lesioned rat sacculi, larger head-jerk stimuli are required, suggesting a shift in the minimum stimulus necessary to evoke the VsEP. Additionally, a reduction in labeled calyx-only afferent terminals was observed without a concomitant reduction in the overall number of calyces or hair cells. This finding supports a critical role of calretinin-expressing calyceal-only afferents in the generation of a VsEP response.NEW & NOTEWORTHY This study identifies a change in the minimum stimulus necessary to evoke vestibular short-latency evoked potential (VsEP) responses after noise-induced damage to the vestibular periphery and reduced numbers of calretinin-labeled calyx-only afferent terminals in the striolar region of the sacculus. These data suggest that a single intense noise exposure may impact synaptic function in calyx-only terminals in the striolar region of the sacculus. Reduced calretinin immunolabeling may provide insight into the mechanism underlying noise-induced changes in VsEP responses.

Methylome of human skeletal muscle after acute & chronic resistance exercise training, detraining & retraining.

DNA methylation is an important epigenetic modification that can regulate gene expression following environmental encounters without changes to the genetic code. Using Infinium MethylationEPIC BeadChip Arrays (850,000 CpG sites) we analysed for the first time, DNA isolated from untrained human skeletal muscle biopsies (vastus lateralis) at baseline (rest) and immediately following an acute (single) bout of resistance exercise. In the same participants, we also analysed the methylome following a period of muscle growth (hypertrophy) evoked via chronic (repeated bouts-3 sessions/wk) resistance exercise (RE) (training) over 7-weeks, followed by complete exercise cessation for 7-weeks returning muscle back to baseline levels (detraining), and finally followed by a subsequent 7-week period of RE-induced hypertrophy (retraining). These valuable methylome data sets described in the present manuscript and deposited in an open-access repository can now be shared and re-used to enable the identification of epigenetically regulated genes/networks that are modified after acute anabolic stimuli and hypertrophy, and further investigate the phenomenon of epigenetic memory in skeletal muscle.

Variations of collagen-encoding genes are associated with exercise-induced muscle damage.

We investigated whether single nucleotide polymorphisms (SNPs) within genes encoding the alpha-1 chain of type I ( COL1A1, rs2249492 ; rs1800012 ), type II ( COL2A1, rs2070739 ), and type V (COL5A1, rs12722 ) collagen were associated with the variable response to exercise-induced muscle damage (EIMD). Knee extensor muscle strength and soreness were assessed pre-, post-, and 48 h post-EIMD (120 maximal eccentric knee extensor contractions) in 65 young healthy participants, who were genotyped for the aforementioned SNPs. We found that COL1A1 (minor) T-allele carriers ( rs1800012 ) and (major) T-allele homozygotes ( rs2249492 ) were generally weaker ( P ≤ 0.019); and (minor) A-allele carriers of COL2A1 ( P = 0.002) and (major) T-allele carriers of COL5A1 ( P = 0.004) SNPs reported greater muscle soreness, all compared with their respective major ( rs1800012 ; rs2070739 ) and minor ( rs2249492 ; rs12722 ) allele homozygote counterparts. To conclude, the risk alleles of these four SNPs appear to negatively influence muscle strength and post-EIMD recovery, possibly via a dysregulated collagen network affecting the muscle's mechanical properties.

TRIM63 (MuRF-1) gene polymorphism is associated with biomarkers of exercise-induced muscle damage.

Unaccustomed strenuous exercise can lead to muscle strength loss, inflammation and delayed-onset muscle soreness, which may be influenced by genetic variation. We investigated if a missense single nucleotide polymorphism (A>G, rs2275950 ) within the TRIM63 gene (encoding MuRF-1 and potentially affecting titin mechanical properties) was associated with the variable response to unaccustomed eccentric exercise. Sixty-five untrained, healthy participants (genotyped for rs2275950 : AA, AG, and GG) performed 120 maximal eccentric knee extensions (ECC) to induce muscle damage. Isometric and isokinetic maximal voluntary knee extension contractions (MVCs) and muscle soreness were assessed before, immediately after, and 48 h after ECC. AA homozygotes were consistently stronger [baseline isometric MVC: 3.23 ± 0.92 Nm/kg (AA) vs. 2.09 ± 0.67 Nm/kg (GG); P = 0.006] and demonstrated less muscle soreness over time ( P = 0.022) compared with GG homozygotes. This may be explained by greater titin stiffness in AA homozygotes, leading to intrinsically stronger muscle fibers that are more resistant to eccentric damaging contractions.

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

Growth hormone deficiency after childhood bone marrow transplantation with total body irradiation: interaction with adiposity and age.

OBJECTIVE: Bone marrow transplantation with total body irradiation (BMT/TBI) has adverse effects on growth, growth hormone status and adiposity. We investigated the GH-IGF-I axis in relation to adiposity. DESIGN: Cross-sectional case control study. PATIENTS: BMT/TBI survivors (n = 22) and short stature control participants (n = 19), all GH-naïve or off GH treatment >3 months. MEASUREMENTS: Auxology, DEXA scans and GH-IGF-I axis investigation: (i) 12-h overnight GH profiles; (ii) insulin tolerance test (ITT); and (iii) IGF-I generation test. ANALYSIS: auto-deconvolution of GH profile data and comparison of quantitative parameters using ANOVA. RESULTS: Eighty-two percent of BMT/TBI survivors had growth hormone deficiency (GHD) using ITT. GH profile area-under-the-curve (GH-AUC) was reduced in BMT/TBI survivors vs short stature control participants [geometric mean (range) 209 (21-825) vs 428 (64-1400) mcg/l/12 h, respectively, P = 0·007]. GHD was more marked in those who had additional cranial irradiation (CRT) [ITT peak 1·4 (0·2-3·0) vs TBI only 4·1 (1·1-14·8) mcg/l, P = 0·036]. GHD was more marked at the end of growth in BMT/TBI survivors vs short stature control participants (GH-AUC 551 (64-2474) vs 1369 (192-4197) mcg/l/12 h, respectively, P = 0·011) and more prevalent (9/11 vs 1/9, respectively, P = 0·005). GH profile data were consistent with ITT results in 80% of participants. IGF-I generation tests were normal. BMT/TBI survivors still demonstrated lower GH levels after adjustment for adiposity (fat-adjusted mean difference for GH-AUC 90·9 mcg/l/12 h, P = 0·025). CONCLUSIONS: GHD was more prevalent in BMT/TBI survivors than expected for the CRT dose in TBI, worsened with time and persisted into adulthood. GHD could not be explained by adiposity. There was no evidence of GH neurosecretory dysfunction or resistance after BMT/TBI.

The individual and combined influence of ACE and ACTN3 genotypes on muscle phenotypes before and after strength training.

Alternative measures of muscle size, strength, and power to those used in previous studies could help resolve the controversy surrounding associations between polymorphisms of the angiotensin-I converting enzyme (ACE) and α-actinin-3 (ACTN3) genes and skeletal muscle phenotypes, and the responses to resistance training (RT). To this end, we measured quadriceps femoris muscle volume (Vm), physiological cross-sectional area (PCSA), maximum isometric force (Ft), specific force (Ft per unit PCSA), maximum isoinertial strength (1-RM), and maximum power (Wmax ; n = 40) before and after 9-week knee extension RT in 51 previously untrained young men, who were genotyped for the ACE I/D and ACTN3 R577X polymorphisms. ACTN3 R-allele carriers had greater Vm, 1-RM, and Wmax than XX homozygotes at baseline (all P < 0.05), but responses to RT were independent of ACTN3 genotype (all P > 0.05). Muscle phenotypes were independent of ACE genotype before (all P > 0.05) and after RT (all P > 0.01). However, people with the "optimal" ACE+ACTN3 genotype combination had greater baseline 1-RM and Wmax compared to those with the "suboptimal" profile (both P < 0.0125). We show for the first time that the ACTN3 R577X polymorphism is associated with human Vm and (independently and in combination with the ACE I/D polymorphism) influences 1-RM and Wmax.

Impact of sildenafil on marital and sexual adjustment in patients and their wives after radiotherapy and short-term androgen suppression for prostate cancer: analysis of RTOG 0215.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives. METHODS: RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives. RESULTS: There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09). CONCLUSIONS: Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response.

Developmental influences, muscle morphology, and sarcopenia in community-dwelling older men.

BACKGROUND: Sarcopenia is associated with disability, morbidity, and mortality. Lower birth weight is associated with reduced muscle mass and strength in older people, suggesting that developmental influences are important in sarcopenia. However, underlying mechanisms are unknown. Our objective was to determine whether low birth weight is associated with altered skeletal muscle morphology in older men. METHODS: Ninety-nine men with historical records of birth weight (≤3.18 kg and ≥3.63 kg), aged 68-76 years, consented for detailed characterization of muscle, including a biopsy of the vastus lateralis. Tissue was processed for immunohistochemical studies and analyzed to determine myofibre density, area, and score. RESULTS: Muscle fibre score (fibres kilograms per square millimeter) was significantly reduced in those with lower birth weight: 1.5 × 10(3) vs 1.7 × 10(3), p = .04 unadjusted; p = .09 adjusted for age, height, and physical activity. In addition, there was a trend for reduced myofibre density (fibres per square millimeter) in those with lower birth weight: total fibre density: 176 vs 184, type I myofibre density: 77 vs 80, and type II myofibre density: 99 vs 105. Types I and II myofibre areas (square micrometers) were larger in those with lower birth weight: type I: 4903 vs 4643 and type II: 4046 vs 3859. However, none of these differences were statistically significant. CONCLUSIONS: This is the first study showing that lower birth weight is associated with a significant decrease in muscle fibre score, suggesting that developmental influences on muscle morphology may explain the widely reported associations between lower birth weight and sarcopenia. However, the study may have been underpowered and did not include women supporting replication in larger cohorts of older men and women.

Resistance training increases in vivo quadriceps femoris muscle specific tension in young men.

AIM: The present study investigated whether in vivo human quadriceps femoris (QF) muscle specific tension changed following strength training by systematically determining QF maximal force and physiological cross-sectional area (PCSA). METHODS: Seventeen untrained men (20 +/- 2 years) performed high-intensity leg-extension training three times a week for 9 weeks. Maximum tendon force (F(t)) was calculated from maximum voluntary contraction (MVC) torque, corrected for agonist and antagonist muscle activation, and moment arm length (d(PT)) before and after training. QF PCSA was calculated as the sum of the four component muscle volumes, each divided by its fascicle length. Dividing F(t) by the sum of the component muscle PCSAs, each multiplied by the cosine of the respective fascicle pennation angle, provided QF specific tension. RESULTS: MVC torque and QF activation increased by 31% (P < 0.01) and 3% (P < 0.05), respectively, but there was no change in antagonist co-activation or d(PT). Subsequently, F(t) increased by 27% (P < 0.01). QF volume increased by 6% but fascicle length did not change in any of the component muscles, leading to a 6% increase in QF PCSA (P < 0.05). Fascicle pennation angle increased by 5% (P < 0.01) but only in the vastus lateralis muscle. Consequently, QF specific tension increased by 20% (P < 0.01). CONCLUSION: An increase in human muscle specific tension appears to be a real consequence of resistance training rather than being an artefact of measuring errors but the underlying cause of this phenomenon remains to be determined.

Pharmacogenetic characterization of indacaterol, a novel beta 2-adrenoceptor agonist.

BACKGROUND AND PURPOSE: Indacaterol is a novel beta(2)-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human beta(2)-adrenoceptor and in human primary airway smooth muscle (ASM) cells. EXPERIMENTAL APPROACH: Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human beta(2)-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3',5'-cyclic-monophosphate production was used as an outcome measure. KEY RESULTS: In both the low- and high-expression recombinant GEVT 'wild type' cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the beta(2)-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3',5'-cyclic-monophosphate in response to beta(2)-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of beta(2)-adrenoceptors.

Characterization of the insulin-like growth factor axis and Wilms' tumour suppressor gene in hyperparathyroidism.

BACKGROUND: Genetic mutations and upregulation of growth factors are implicated in the pathogenesis of hyperparathyroidism. The aim of this study was to evaluate the role of Wilms' tumour suppressor gene (WT-1) and the insulin-like growth factor (IGF) axis in hyperparathyroidism. METHODS: The expression of WT-1 and IGF components was examined by immunohistochemistry, reverse transcriptase-polymerase chain reaction and western immunoblotting in a panel of parathyroid specimens from both primary and secondary hyperparathyroidism. A human parathyroid cell culture model was established to examine the parathyroid response to IGF stimulation. RESULTS: There was a significantly lower level of WT-1 expression in parathyroid tumours than in normal parathyroid glands. Most tumours expressed IGF-I and IGF-II receptors and responded to IGF stimulation. Only IGF-I was present in normal parathyroid glands, whereas IGF-II was expressed exclusively in parathyroid tumours. CONCLUSION: Abnormal expression of WT-1 and the IGF axis may play a role in the pathogenesis of hyperparathyroidism.

Apoptosis and the cardiac action of insulin-like growth factor I.

In both cardiac surgical and cardiological settings, clinical interventions used to reperfuse the ischemic heart are associated with myocardial damage that is likely to influence long-term functional recovery. Ischaemia and reperfusion trigger cardiomyocyte death by necrosis and apoptosis. Therefore identifying potent cardioprotective agents remains an important goal in cardiac research. In a variety of tissues, insulin-like growth factor I (IGF-I) stimulates cellular proliferation, somatic growth, and differentiation. In addition, IGF-I inhibits apoptotic cell death and therefore plays an important role as a cell survival factor. This characteristic would provide an opportunity to both protect (rescue) the cardiac myocytes during (after) cardiac insults. In this review, we shall (i) describe the characteristics of apoptotic cell death with particular emphasis on the heart, (ii) discuss the IGF system with emphasis on the cardiac actions of IGF-I under normal and pathological conditions, (iii) elaborate on the potential role of IGF-I in myocardial protection, and finally (iv) describe how an improved understanding of the cardiac actions of IGF-I may lead to better protective clinical strategies in the future. We discuss work by ourselves and others in these areas and also consider recent work describing the cellular signaling associated with the IGF-I receptor (IGF-IR) in the heart and its potential role in regulating excitation-contraction coupling.