Adrenergic regulation of carbohydrate metabolism during exercise

1. This series of studies was undertaken to examine the adrenergic regulation of carbohydrate metabolism during exercise. Recreationally active males were tested during moderate to intense exercise on a stationary cycle ergometer. Venous and arterial plasma obtained from indwelling catheters was analysed for hormonal and metabolite responses, and hepatic glucose production and glucose uptake were measured using the tracer-dilution method with stable isotopes. Muscle samples were obtained by the needle biopsy technique to examine muscle glycogen utilisation and the flux of related muscle metabolites using enzymatic, fluorometric and radioisotopic techniques. 2. During moderate exercise adrenaline infusion induced a marked hyperglycemia and this was due to reduced glucose uptake rather than enhanced hepatic glucose production. The reduction in glucose uptake was most likely mediated by a decrease in glucose phosphorylation, as indicated by the accumulation of glucose 6-phosphate with adrenaline infusion. 3. The hyperglycemic response to intense exercise was prevented by the administration of α- and β-adrenergic antagonists. Adrenergic blockade was without effect on hepatic glucose production whereas glucose uptake was enhanced when compared with control subjects. These data support the notion that adrenergic mechanisms are more important in restraining glucose uptake than enhancing hepatic glucose production during intense exercise. Other glucoregulatory factors are responsible for the increase in glucose production during intense exercise. 4. Elevated plasma adrenaline levels during moderate exercise in untrained men increases skeletal muscle glycogen breakdown and PDH activation which results

Interrelations between ceruloplasmin and Fe status during human pregnancy

It is well established that Fe and ceruloplasmin interact in animals and in in vitro models. However, Fe-mediated regulation of ceruloplasmin has never been investigated in humans. In an observational study, 53 pregnant women aged 19-39 yr (29.8±0.7 yr, mean ± SEM) were recruited at the Aberdeen Antenatal Clinic, Aberdeen Maternity Hospital, UK. All requirements for local ethical committees were followed. Venous blood samples were taken from each woman at 34 wk gestation for measurement of Fe status and ceruloplasmin. Various parameters were used to test for Fe status. The most sensitive one appeared to be soluble transferrin receptor, which increased with parity. In the population studied, there was no relationship between hemoglobin or ferritin and serum ceruloplasmin. However, using soluble transferrin receptor (sTfR) levels, we were able to demonstrate an inverse linear relationship (r=0.37, p=0.021, n=41) between Fe status and ceruloplasmin. Fe supplementation, number of previous pregnancies, and smoking habits did not affect this relationship. Our data support in vitro results showing regulation of ceruloplasmin by Fe and also suggest that the interactions between Fe and ceruloplasmin should be considered when Fe supplementation is given.

Chronic disease risk factors in rural Australia : results from the Greater Green Triangle risk factor surveys

The aim of this article was to assess the level and prevalence of major chronic disease risk factors among rural adults. Two cross-sectional surveys were carried out in 2004 and 2005 in the southeast of South Australia and the southwest of Victoria. Altogether 891 randomly selected persons aged 25 to 74 years participated in the studies. Surveys included a self-administered questionnaire, physical measurements, and a venous blood specimen for lipid analyses. Two thirds of participants had cholesterol levels ≥5.0 mmol/L. The prevalence of high diastolic blood pressure (≥90 mm Hg) was 22% for men and 10% for women in southeast of South Australia, and less than 10% for both sexes in southwest of Victoria. Two thirds of participants were overweight or obese (body mass index ≥25 kg/m2). About 15% of men and slightly less women were daily smokers. The abnormal risk factor levels underline the need for targeted prevention activities in the Greater Green Triangle region. Continuing surveillance of levels and patterns of risk factors is fundamentally important for planning and evaluating preventive activities.

Impaired muscle Ca2+ and K+ regulation contribute to poor exercise performance post-lung transplantation

Lung transplant recipients (LTx) exhibit marked peripheral limitations to exercise. We investigated whether skeletal muscle Ca2+ and K+ regulation might be abnormal in eight LTx and eight healthy controls. Peak oxygen consumption and arterialized venous plasma [K+] (where brackets denote concentration) were measured during incremental exercise. Vastus lateralis muscle was biopsied at rest and analyzed for sarcoplasmic reticulum Ca2+ release, Ca2+ uptake, and Ca2+-ATPase activity rates; fiber composition; Na+-K+-ATPase (K+-stimulated 3-O-methylfluorescein phosphatase) activity and content ([3H]ouabain binding sites); as well as for [H+] and H+-buffering capacity. Peak oxygen consumption was 47% less in LTx (P < 0.05). LTx had lower Ca2+ release (34%), Ca2+ uptake (31%), and Ca2+-ATPase activity (25%) than controls (P < 0.05), despite their higher type II fiber proportion (LTx, 75.0 ± 5.8%; controls, 43.5 ± 2.1%). Muscle [H+] was elevated in LTx (P < 0.01), but buffering capacity was similar to controls. Muscle 3-O-methylfluorescein phosphatase activity was 31% higher in LTx (P < 0.05), but [3H]ouabain binding content did not differ significantly. However, during exercise, the rise in plasma [K+]-to-work ratio was 2.6-fold greater in LTx (P < 0.05), indicating impaired K+ regulation. Thus grossly subnormal muscle calcium regulation, with impaired potassium regulation, may contribute to poor muscular performance in LTx.

The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion

Retinal vein occlusion (RVO) is associated with hyperhomocysteinaemia and the antiphospholipid syndrome—disorders known to contribute to both arterial and venous thrombosis. In both of these conditions and RVO, platelet activation occurs. Aspirin, not warfarin, is the most effective antithrombotic agent in RVO and, taken together, these observations suggest an important role for platelets in this common ocular thrombotic condition. Platelet glycoprotein Ia/IIa (GpIa/IIa) is an adhesion molecule mediating platelet–collagen interactions and is key to the initiation of thrombosis. Recently, the cellular density of this molecule was shown to be determined by two silent, linked polymorphisms (C807T/G873A) within the GpIa/IIa gene. There is evidence that some of the resulting genotypes are associated with thrombo-embolic disease. This study therefore aimed to establish the prevalence of the GpIa/IIa polymorphisms and the three commonest hereditary thrombophilic disorders (prothrombin gene G20210A (PT) mutation, Factor V Leiden (FVL), and the thermolabile methylene tetrahydrofolate reductase C677T (MTHFR) mutation) in patients with RVO and normal controls. The GpIa/IIa polymorphisms and thrombophilic abnormalities were all identified using the polymerase chain reaction.

Our results show that the frequency of the GpIa/IIa polymorphisms was similar in our normal control population to previously published series. Patients with RVO, however, had only a 10% (4/40) frequency of the lowest risk subtype (CC/GG) compared to 37.5% (15/40) in the control group—P 0.0039. The incidence of the PT, FVL, and MTHFR thrombophilic mutations was not different between the two groups, but interestingly none of the 7/40 RVO cases with a PT, FVL, or MTHFR mutation had the low-risk GpIa/IIa genotype while all but one of the controls did—P<0.05. Thus, 17.5% of RVO patients harboured more than one prothrombotic abnormality. The principal difference between the RVO and control group was the very high incidence of the intermediate-risk GpIa/IIa subtype (CT/GA)—82.5 vs 50%, P<0.05.

These results suggest a major role for GpIa/IIa polymorphisms in the pathogenesis of RVO.

The neuronal noradrenaline transporter, anxiety and cardiovascular disease

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses.

The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients.

Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic ‘co-morbidity’ perhaps underlies the clinical concordance.

Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

The resident assessment instrument-minimum data set 2.0 quality indicators : a systematic review

Background
The Resident Assessment Instrument-Minimum Data Set (RAI-MDS) 2.0 is designed to collect the minimum amount of data to guide care planning and monitoring for residents in long-term care settings. These data have been used to compute indicators of care quality. Use of the quality indicators to inform quality improvement initiatives is contingent upon the validity and reliability of the indicators. The purpose of this review was to systematically examine published and grey research reports in order to assess the state of the science regarding the validity and reliability of the RAI-MDS 2.0 Quality Indicators (QIs).

Methods
We systematically reviewed the evidence for the validity and reliability of the RAI-MDS 2.0 QIs. A comprehensive literature search identified relevant original research published, in English, prior to December 2008. Fourteen articles and one report examining the validity and/or reliability of the RAI-MDS 2.0 QIs were included.

Results
The studies fell into two broad categories, those that examined individual quality indicators and those that examined multiple indicators. All studies were conducted in the United States and included from one to a total of 209 facilities. The number of residents included in the studies ranged from 109 to 5758. One study conducted under research conditions examined 38 chronic care QIs, of which strong evidence for the validity of 12 of the QIs was found. In response to these findings, the 12 QIs were recommended for public reporting purposes. However, a number of observational studies (n=13), conducted in "real world" conditions, have tested the validity and/or reliability of individual QIs, with mixed results. Ten QIs have been studied in this manner, including falls, depression, depression without treatment, urinary incontinence, urinary tract infections, weight loss, bedfast, restraint, pressure ulcer, and pain. These studies have revealed the potential for systematic bias in reporting, with under-reporting of some indicators and over-reporting of others.

Conclusion
Evidence for the reliability and validity of the RAI-MDS QIs remains inconclusive. The QIs provide a useful tool for quality monitoring and to inform quality improvement programs and initiatives. However, caution should be exercised when interpreting the QI results and other sources of evidence of the quality of care processes should be considered in conjunction with QI results.

Implementation of a management guideline aimed at minimizing the severity of primary graft dysfunction after lung transplant

Objective
Primary graft dysfunction, a severe form of lung injury that occurs in the first 72 hours after lung transplant, is associated with morbidity and mortality. We sought to assess the impact of an evidence-based guideline as a protocol for respiratory and hemodynamic management.

Methods
Preoperative and postoperative data for patients treated per the guideline (n = 56) were compared with those of a historical control group (n = 53). Patient data such as ratio of arterial Po2 to inspired oxygen fraction, central venous pressure, cumulative fluid balance, vasopressor dose, and serum urea and creatinine were measured and documented at specific times. Primary outcome was severity of primary graft dysfunction within the first 72 hours.

Results
Primary graft dysfunction grade was progressively lower in patients treated after introduction of the guideline (P = .01). Lower postoperative fluid balances (P = .01) and vasopressor doses (P = .007) were seen, with no associated renal dysfunction. There were no differences in duration of mechanical ventilation or mortality. Nonadherence to the guideline occurred in 10 cases (18%).

Conclusions
Implementation of an evidence-based guideline for managing respiratory and hemodynamic status is feasible and safe and was associated with reduction in severity of primary graft dysfunction. Further studies are required to determine whether such a guideline would lead to a consistent reduction in severity of primary graft dysfunction at other institutions. Creation of a protocol for postoperative care provides a template for further studies of novel therapies or management strategies for primary graft dysfunction.

Modulating the interaction of CXCR4 and CXCL12 by low-molecular-weight heparin inhibits hepatic metastasis of colon cancer

Liver metastasis is the major obstacle for prolonging the survival of colon cancer patients. Low-molecular-weight heparin (LMWH), a common drug for venous thromboembolism, has displayed beneficial effects in improving the survival of cancer patients, though the mechanism remains unclear. This study aimed to investigate the effects of LMWH on hepatic metastasis of colon cancer and its underlying molecular mechanism by targeting the interaction of the chemokine receptor CXCR4 and its ligand CXCL12 (formerly known as stromal cell-derived factor 1α, SDF-1α), as the CXCR4-CXCL12 axis has been shown to regulate the interaction of cancer cells and stroma. Experimental results revealed that LMWH (Enoxaparin, 3500-5500 Da) inhibited the CXCL12-stimulated proliferation, adhesion and colony formation of human colon cancer HCT-116 cells that highly expressed CXCR4. Interestingly, LMWH or an anti-CXCR4 blocking antibody diminished the migrating and invading abilities of HCT116 cells stimulated by the recombinant CXCL12 protein or liver homogenates which contained endogenous CXCL12 protein. Although LMWH did not significantly inhibit the growth of subcutaneous colon tumors, it significantly suppressed the formation of hepatic metastasis established by intrasplenic injection of colon cancer cells in nude Balb/c mice and also downregulated the expression of CXCL12 in hepatic sinusoidal endothelial cells. The results suggest that LMWH inhibits the formation of hepatic metastasis of colon cancer by disrupting the interaction of CXCR4 and CXCL12, supporting that perioperative administration of LMWH may help to prevent the seeding and subsequent growth of hepatic metastases of colon cancer cells.

Forearm blood flow in individuals with CHF and age-matched healthy volunteers : a study and historical review

This study examined forearm blood flow (FBF) in individuals with chronic heart failure (CHF) at rest, moderate exercise, and following limb occlusion. FBF was measured by venous occlusion plethysmography in CHF patients (n = 43) and healthy age-matched volunteers (n = 8) at rest and during exercise consisting of intermittent isometric hand squeezing at 15, 30, and 45% of maximum voluntary contraction (MVC). Peak vasodilatory capacity was also determined following the release of an occluding arm cuff. FBF was lower in CHF patients during exercise and during peak reactive hyperemia (PRH) compared to healthy volunteers, but there was no significant difference between groups at rest. Peak vasodilatory capacity was significantly higher in healthy volunteers than the CHF group ((30.6 ± 8.6 ml±100 mL^-1±min^-1 and 18.3 ± 6.9 ml±100 mL^-1±min^-1, respectively). Local blood flow stimulation in response to exercise or limb occlusion is reduced in individuals with CHF, however, there was no difference in resting flows between the two groups, suggesting vasodilatory medication may restore resting blood flow to healthy values.

Alkalosis increases muscle K+ release, but lowers plasma [K+] and delays fatigue during dynamic forearm exercise

Alkalosis enhances human exercise performance, and reduces K⁺ loss in contracting rat muscle. We investigated alkalosis effects on K⁺ regulation, ionic regulation and fatigue during intense exercise in nine untrained volunteers. Concentric finger flexions were conducted at 75% peak work rate (-3 W) until fatigue, under alkalosis (Alk, NaHCO₃, 0.3 g kg⁻¹) and control (Con, CaCO₃) conditions, 1 month apart in a randomised, double-blind, crossover design. Deep antecubital venous (v) and radial arterial (a) blood was drawn at rest, during exercise and recovery, to determine arterio-venous differences for electrolytes, fluid shifts, acid–base and gas exchange. Finger flexion exercise barely perturbed arterial plasma ions and acid–base status, but induced marked arterio-venous changes. Alk elevated [HCO₃⁻] and P^CO2, and lowered [H+] (P < 0.05). Time to fatigue increased substantially during Alk (25 ± 8%, P < 0.05), whilst both [K⁺]_a and [K⁺]_v were reduced (P < 0.01) and [K⁺]_a-v during exercise tended to be greater (P= 0.056, n= 8). Muscle K⁺ efflux at fatigue was greater in Alk (21.2 ± 7.6 µmol min⁻¹, 32 ± 7%, P < 0.05, n= 6), but peak K⁺ uptake rate was elevated during recovery (15 ± 7%, P < 0.05) suggesting increased muscle Na⁺,K^+-ATPase activity. Alk induced greater [Na⁺]_a, [Cl⁻]_v, muscle Cl⁻ influx and muscle lactate concentration ([Lac⁻]) efflux during exercise and recovery (P < 0.05). The lower circulating [K⁺] and greater muscle K⁺ uptake, Na⁺ delivery and Cl⁻ uptake with Alk, are all consistent with preservation of membrane excitability during exercise. This suggests that lesser exercise-induced membrane depolarization may be an important mechanism underlying enhanced exercise performance with Alk. Thus Alk was associated with improved regulation of K⁺, Na⁺, Cl⁻ and Lac⁻.

Short-term bone biochemical response to a single bout of high-impact exercise

Bone response to a single bout of exercise can be observed with biochemical markers of bone formation and resorption. The purpose of this study was to examine the response of bone biochemical markers to a single bout of exhaustive high-impact exercise. 15 physically active young subjects volunteered to participate. The subjects performed continuous bilateral jumping with the ankle plantarflexors at 65 % of maximal ground reaction force (GRF) until exhaustion. Loading was characterized by analyzing the GRF recorded for the duration of the exercise. Venous blood samples were taken at baseline, immediately after, 2h and on day 1 and day 2 after the exercise. Procollagen type I amino terminal propeptide (P1NP, marker of bone formation) and carboxyterminal crosslinked telopeptide (CTx, marker of bone resorption) were analyzed from the blood samples. CTx increased significantly (32 %, p = 0.015) two days after the exercise and there was a tendensy towards increase seen in P1NP (p = 0.053) one day after the exercise. A significant positive correlation (r = 0.49 to 0.69, p ≤ 0.038) was observed between change in P1NP from baseline to day 1 and exercise variables (maximal slope of acceleration, body weight (BW) adjusted maximal GRF, BW adjusted GRF exercise intensity and osteogenic index). Based on the two biochemical bone turnover markers, it can be concluded that bone turnover is increased in response to a very

Three-month bilateral hopping intervention is ineffective in initiating bone biomarker response in healthy elderly men.

In animal studies, bone adaptation has been initiated successfully without the transient force spike associated with high impact exercises. Consequently, a 12-week bilateral hopping on the balls of the feet intervention was conducted. 25 elderly men (age 72(SD4) years, height 171(6) cm, weight 75(9) kg) were randomly assigned into exercise and control groups. Ten subjects in each group completed the study. Carboxyterminal propeptide of type I collagen (CICP), bone-specific alkaline phosphatase (bALP) and carboxyterminal telopeptide of type I collagen (CTx) were measured from venous blood samples at baseline, at 2 weeks and at the end of the intervention. Maximal ground reaction force (GRF), osteogenic index (OI) and jump height (JH) were determined from bilateral hopping test and balance was assessed with velocity of center of pressure (COPvelocity) while standing on the preferred leg with eyes open. The intervention consisted of 5–7 sets of 10 s timed bilateral hopping exercise at 75–90% intensity three times/week. There was no significant group 9 time interaction for GRF, OI and JH (P = 0.065). GRF (11% change from baseline vs. 4%), OI (15 vs. 6%) and COPvelocity (-10 vs. -1%) were not influenced by the intervention (P[0.170), while the control group improved JH (P = 0.031) (2 vs. 18%). For the biomarkers, no effect was observed in MANOVA (P = 0.536) or in univariate analyses (P = 0.082 to P = 0.820) (CICP -2 vs. -3%, CTx 8 vs. -12%, bALP 0 vs. -3.7%). Allowing transient impact force spikes may be necessary to initiate a bone response in elderly men as the intervention was ineffective.

Use of an arginine-enriched oral nutrition supplement in the healing of pressure ulcers in patients with spinal cord injuries : an observational study

Aim: Pressure ulcers are a serious secondary consequence of spinal cord injuries. The objective of the present study was to determine whether an arginine-containing nutritional supplement can reduce the healing time of pressure ulcers in people with spinal cord injuries compared with those not consuming the supplement until full wound healing.

Methods: Thirty-four spinal cord injured patients with a grade 2, 3 or 4 pressure ulcer were prescribed two 237 mL tetrapaks/day of a supplement containing additional protein, arginine, zinc and vitamin C. Pressure ulcer healing was assessed with the Pressure Ulcer Scale for Healing tool.

Results: Twenty patients consumed the nutritional supplement until full pressure ulcer healing had occurred, while 14 patients ceased consuming the supplement before full healing occurred because of intolerance, compliance or taste issues. A 2.5-fold greater rate of healing was observed in patients consuming the supplement until full healing compared with those who ceased taking the supplement (8.5 ± 1.1 weeks vs 20.9 ± 7.0 weeks respectively; P = 0.04). There were no significant differences in age, nutritional status, gender or reason for admission between groups. Comparison of healing rates in the group consuming the supplement to full wound healing against expected rates derived from the medical literature showed a significantly shorter time-to-healing (grade 3 pressure ulcer: 6.5 ± 0.8 weeks vs 18.2 weeks; grade 4: 11.4 ± 2.0 weeks vs 22.1 weeks; P < 0.001).

Conclusion: The present small-scale study demonstrated the potential for specialised wound healing nutritional supplements to shorten the time to pressure ulcer healing in spinal cord injured patients.

Risk factors for Mycobacterium ulcerans infection, southeastern Australia

Buruli/Bairnsdale ulcer (BU) is a severe skin and soft tissue disease caused by Mycobacterium ulcerans. To better understand how BU is acquired, we conducted a case-control study during a sustained outbreak in temperate southeastern Australia. We recruited 49 adult patients with BU and 609 control participants from a newly recognized BU-endemic area in southeastern Australia. Participants were asked about their lifestyle and insect exposure. Odds ratios were calculated by using logistic regression and were adjusted for age and location of residence. Odds of having BU were at least halved for those who frequently used insect repellent, wore long trousers outdoors, and immediately washed minor skin wounds; odds were at least doubled for those who received mosquito bites on the lower legs or lower arms. This study provides new circumstantial evidence that implicates mosquitoes in the transmission of M. ulcerans in southeastern Australia.