Assessment from Functional Perspectives: Using Sensorimotor Control in the Hand as an Outcome Indicator in the Surgical Treatment of Carpal Tunnel Syndrome

To investigate whether sensorimotor control of the hand could be an outcome indicator after carpal tunnel release (CTR), this work examined changes in the results of patients’ manual tactile test (MTT), pinch-holding-up activity (PHUA), two-point discrimination (2PD) and Semmes-Weinstein monofilament (SWM) tests. Participants included 30 predominantly sensory neuropathy CTS patients, as confirmed by a nerve conduction study. The MTT, precision pinch performance in PHUA and traditional sensibility (2PD and SWM) tests were used to examine different aspects of sensory status at the time-points of two weeks before operation and one month post-operation, with a single-blind design. The results showed significant improvements in the sensory function as detected by the 2PD and SWM tests (p<0.001) and sensorimotor function as detected by the MTT (p<0.001) and PHUA test (p<0.05) for patients receiving CTR. The responsiveness of the SWM, MTT and PHUA tests (effect size>0.5, p<0.01) are better than that of two-point discrimination test (effect size<0.5, p<0.001). However, pinch strength saw a decline compared to baseline with a moderate effect sizes (effect size = 0.7, p<0.001). This cohort study found that the MTT and PHUA test can both meet all the statistical criteria with regard to assessing treatment outcomes for patients with CTS. In addition, the results of this work provide clinicians with the information that the sensorimotor functions of the hands, as assessed by MTT and PHUA, are responsive to clinical changes due to CTR.     

A Passive Heat Maintenance Strategy Implemented during a Simulated Half-Time Improves Lower Body Power Output and Repeated Sprint Ability in Professional Rugby Union Players

Reduced physical performance has been observed following the half-time period in team sports players, likely due to a decrease in muscle temperature during this period. We examined the effects of a passive heat maintenance strategy employed between successive exercise bouts on core temperature (T_core) and subsequent exercise performance. Eighteen professional Rugby Union players completed this randomised and counter-balanced study. After a standardised warm-up (WU) and 15 min of rest, players completed a repeated sprint test (RSSA 1) and countermovement jumps (CMJ). Thereafter, in normal training attire (Control) or a survival jacket (Passive), players rested for a further 15 min (simulating a typical half-time) before performing a second RSSA (RSSA 2) and CMJ’s. Measurements of T_core were taken at baseline, post-WU, pre-RSSA 1, post-RSSA 1 and pre-RSSA 2. Peak power output (PPO) and repeated sprint ability was assessed before and after the simulated half-time. Similar T_core responses were observed between conditions at baseline (Control: 37.06±0.05°C; Passive: 37.03±0.05°C) and for all other T_core measurements taken before half-time. After the simulated half-time, the decline in T_core was lower (-0.74±0.08% vs. -1.54±0.06%, p<0.001) and PPO was higher (5610±105 W vs. 5440±105 W, p<0.001) in the Passive versus Control condition. The decline in PPO over half-time was related to the decline in T_core (r = 0.632, p = 0.005). In RSSA 2, best, mean and total sprint times were 1.39±0.17% (p<0.001), 0.55±0.06% (p<0.001) and 0.55±0.06% (p<0.001) faster for Passive versus Control. Passive heat maintenance reduced declines in T_core that were observed during a simulated half-time period and improved subsequent PPO and repeated sprint ability in professional Rugby Union players.     

Pulmonary and Cardiac Function in Asymptomatic Obese Subjects and Changes following a Structured Weight Reduction Program: A Prospective Observational Study

Background

The prevalence of obesity is rising. Obesity can lead to cardiovascular and ventilatory complications through multiple mechanisms. Cardiac and pulmonary function in asymptomatic subjects and the effect of structured dietary programs on cardiac and pulmonary function is unclear.

Objective

To determine lung and cardiac function in asymptomatic obese adults and to evaluate whether weight loss positively affects functional parameters.

Methods

We prospectively evaluated bodyplethysmographic and echocardiographic data in asymptomatic subjects undergoing a structured one-year weight reduction program.

Results

74 subjects (32 male, 42 female; mean age 42±12 years) with an average BMI 42.5±7.9, body weight 123.7±24.9 kg were enrolled. Body weight correlated negatively with vital capacity (R = −0.42, p<0.001), FEV1 (R = −0.497, p<0.001) and positively with P 0.1 (R = 0.32, p = 0.02) and myocardial mass (R = 0.419, p = 0.002). After 4 months the study subjects had significantly reduced their body weight (−26.0±11.8 kg) and BMI (−8.9±3.8) associated with a significant improvement of lung function (absolute changes: vital capacity +5.5±7.5% pred., p<0.001; FEV1+9.8±8.3% pred., p<0.001, ITGV+16.4±16.0% pred., p<0.001, SR tot −17.4±41.5% pred., p<0.01). Moreover, P0.1/Pimax decreased to 47.7% (p<0.01) indicating a decreased respiratory load. The change of FEV1 correlated significantly with the change of body weight (R = −0.31, p = 0.03). Echocardiography demonstrated reduced myocardial wall thickness (−0.08±0.2 cm, p = 0.02) and improved left ventricular myocardial performance index (−0.16±0.35, p = 0.02). Mitral annular plane systolic excursion (+0.14, p = 0.03) and pulmonary outflow acceleration time (AT +26.65±41.3 ms, p = 0.001) increased.

Conclusion

Even in asymptomatic individuals obesity is associated with abnormalities in pulmonary and cardiac function and increased myocardial mass. All the abnormalities can be reversed by a weight reduction program.     

Incomplete Restoration of Angiotensin II - Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats

Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p<0.001) and proteinuria (51.4 ± 6.3 vs. 14.7 ± 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 ± 0.5 vs. 4.9 ± 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 ± 4.8 vs. 3.6 ± 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 ± 0.4 vs. 2.2 ± 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.     

Increased Circulating ANG II and TNF-α Represents Important Risk Factors in Obese Saudi Adults with Hypertension Irrespective of Diabetic Status and BMI

Central adiposity is a significant determinant of obesity-related hypertension risk, which may arise due to the pathogenic inflammatory nature of the abdominal fat depot. However, the influence of pro-inflammatory adipokines on blood pressure in the obese hypertensive phenotype has not been well established in Saudi subjects. As such, our study investigated whether inflammatory factors may represent useful biomarkers to delineate hypertension risk in a Saudi cohort with and without hypertension and/or diabetes mellitus type 2 (DMT2). Subjects were subdivided into four groups: healthy lean controls (age: 47.9±5.1 yr; BMI: 22.9±2.1 Kg/m²), non-hypertensive obese (age: 46.1±5.0 yr; BMI: 33.7±4.2 Kg/m²), hypertensive obese (age: 48.6±6.1 yr; BMI: 36.5±7.7 Kg/m²) and hypertensive obese with DMT2 (age: 50.8±6.0 yr; BMI: 35.3±6.7 Kg/m²). Anthropometric data were collected from all subjects and fasting blood samples were utilized for biochemical analysis. Serum angiotensin II (ANG II) levels were elevated in hypertensive obese (p<0.05) and hypertensive obese with DMT2 (p<0.001) compared with normotensive controls. Systolic blood pressure was positively associated with BMI (p<0.001), glucose (p<0.001), insulin (p<0.05), HOMA-IR (p<0.001), leptin (p<0.01), TNF-α (p<0.001) and ANG II (p<0.05). Associations between ANG II and TNF-α with systolic blood pressure remained significant after controlling for BMI. Additionally CRP (p<0.05), leptin (p<0.001) and leptin/adiponectin ratio (p<0.001) were also significantly associated with the hypertension phenotype. In conclusion our data suggests that circulating pro-inflammatory adipokines, particularly ANG II and, TNF-α, represent important factors associated with a hypertension phenotype and may directly contribute to predicting and exacerbating hypertension risk.     

Gender Differences in In-Hospital Clinical Outcomes after Percutaneous Coronary Interventions: An Insight from a Japanese Multicenter Registry

Background

Gender differences in clinical outcomes after percutaneous coronary intervention (PCI) among different age groups are controversial in the era of drug-eluting stents, especially among the Asian population who are at higher risk for bleeding complications.

Methods and Results

We analyzed data from 10,220 patients who underwent PCI procedures performed at 14 Japanese hospitals from September 2008 to April 2013. A total of 2,106 (20.6%) patients were women. Women were older (72.7±9.7 vs 66.6±10.8 years, p<0.001), and had a lower body mass index (23.4±4.0 vs 24.3±3.5, p<0.001), with a higher prevalence of hypertension (p<0.001), hyperlipidemia (p<0.001), insulin-dependent diabetes (p<0.001), renal failure (p<0.001), and heart failure (p<0.001) compared with men. Men tended to have more bifurcation lesions (p = 0.003) and chronic totally occluded lesions (p<0.001) than women. Crude overall complications (14.8% vs 9.5%, p<0.001) and the rate of bleeding complications (5.3% vs 2.8%, p<0.001) were significantly higher in women than in men. On multivariate analysis in the total cohort, female sex was an independent predictor of overall complications (OR, 1.47; 95% CI, 1.26–1.71; p<0.001) and bleeding complications (OR, 1.74; 95% CI, 1.36–2.24; p<0.001) after adjustment for confounding variables. A similar trend was observed across the middle-aged group (≥55 and <75 years) and old age group (≥75 years).

Conclusions

Women are at higher risk than men for post-procedural complications after PCI, regardless of age.     

Inhibition of Platelet Activation and Thrombus Formation by Adenosine and Inosine: Studies on Their Relative Contribution and Molecular Modeling

Background

The inhibitory effect of adenosine on platelet aggregation is abrogated after the addition of adenosine-deaminase. Inosine is a naturally occurring nucleoside degraded from adenosine.

Objectives

The mechanisms of antiplatelet action of adenosine and inosine in vitro and in vivo, and their differential biological effects by molecular modeling were investigated.

Results

Adenosine (0.5, 1 and 2 mmol/L) inhibited phosphatidylserine exposure from 52±4% in the control group to 44±4 (p<0.05), 29±2 (p<0.01) and 20±3% (p<0.001). P-selectin expression in the presence of adenosine 0.5, 1 and 2 mmol/L was inhibited from 32±4 to 27±2 (p<0.05), 14±3 (p<0.01) and 9±3% (p<0.001), respectively. At the concentrations tested, only inosine to 4 mmol/L had effect on platelet P-selectin expression (p<0.05). Adenosine and inosine inhibited platelet aggregation and ATP release stimulated by ADP and collagen. Adenosine and inosine reduced collagen-induced platelet adhesion and aggregate formation under flow. At the same concentrations adenosine inhibited platelet aggregation, decreased the levels of sCD40L and increased intraplatelet cAMP. In addition, SQ22536 (an adenylate cyclase inhibitor) and ZM241385 (a potent adenosine receptor A_2A antagonist) attenuated the effect of adenosine on platelet aggregation induced by ADP and intraplatelet level of cAMP. Adenosine and inosine significantly inhibited thrombosis formation in vivo (62±2% occlusion at 60 min [n = 6, p<0.01] and 72±1.9% occlusion at 60 min, [n = 6, p<0.05], respectively) compared with the control (98±2% occlusion at 60 min, n = 6). A_2A is the adenosine receptor present in platelets; it is known that inosine is not an A_2A ligand. Docking of adenosine and inosine inside A_2A showed that the main difference is the formation by adenosine of an additional hydrogen bond between the NH₂ of the adenine group and the residues Asn253 in H6 and Glu169 in EL2 of the A_2A receptor.

Conclusion

Therefore, adenosine and inosine may represent novel agents lowering the risk of arterial thrombosis.     

Total Beta-Adrenoceptor Knockout Slows Conduction and Reduces Inducible Arrhythmias in the Mouse Heart

Introduction

Beta-adrenoceptors (β-AR) play an important role in the neurohumoral regulation of cardiac function. Three β-AR subtypes (β₁, β₂, β₃) have been described so far. Total deficiency of these adrenoceptors (TKO) results in cardiac hypotrophy and negative inotropy. TKO represents a unique mouse model mimicking total unselective medical β-blocker therapy in men. Electrophysiological characteristics of TKO have not yet been investigated in an animal model.

Methods

In vivo electrophysiological studies using right heart catheterisation were performed in 10 TKO mice and 10 129SV wild type control mice (WT) at the age of 15 weeks. Standard surface ECG, intracardiac and electrophysiological parameters, and arrhythmia inducibility were analyzed.

Results

The surface ECG of TKO mice revealed a reduced heart rate (359.2±20.9 bpm vs. 461.1±33.3 bpm; p<0.001), prolonged P wave (17.5±3.0 ms vs. 15.1±1.2 ms; p = 0.019) and PQ time (40.8±2.4 ms vs. 37.3±3.0 ms; p = 0.013) compared to WT. Intracardiac ECG showed a significantly prolonged infra-Hisian conductance (HV-interval: 12.9±1.4 ms vs. 6.8±1.0 ms; p<0.001). Functional testing showed prolonged atrial and ventricular refractory periods in TKO (40.5±15.5 ms vs. 21.3±5.8 ms; p = 0.004; and 41.0±9.7 ms vs. 28.3±6.6 ms; p = 0.004, respectively). In TKO both the probability of induction of atrial fibrillation (12% vs. 24%; p<0.001) and of ventricular tachycardias (0% vs. 26%; p<0.001) were significantly reduced.

Conclusion

TKO results in significant prolongations of cardiac conduction times and refractory periods. This was accompanied by a highly significant reduction of atrial and ventricular arrhythmias. Our finding confirms the importance of β-AR in arrhythmogenesis and the potential role of unspecific beta-receptor-blockade as therapeutic target.     

BMI as a Mediator of the Relationship between Muscular Fitness and Cardiometabolic Risk in Children: A Mediation Analysis

Objective

Muscular fitness levels have been associated with cardiometabolic risk in children, although whether body weight acts as a confounder or as an intermediate variable in this relationship remains controversial. The aim of this study was to examine whether the association between muscular fitness and cardiometabolic risk factors is mediated by body mass index (BMI).

Design and Methods

Cross-sectional study using a sample of 1158 schoolchildren aged 8-11 years from the province of Cuenca, Spain. We measured anthropometrics and biochemical variables and we calculated a muscular fitness index as the sum of z-scores of handgrip dynamometry/weight and standing long jump, and we estimated a previously validated cardiometabolic risk index (CMRI). Linear regression models were fitted for mediation analysis to assess whether the association between muscular fitness and cardiometabolic risk was mediated by BMI.

Results

Children with normal weight (NW) had a better cardiometabolic risk profile than their overweight (OW) or obese (OB) peers after controlling for muscular fitness. Marginal estimated mean±SE values for NW, OW and OB categories of CMRI were -0.75±0.06<0.84±0.10<2.18±0.16 in boys and -0.73±0.06<0.96±0.10<2.71±0.17 in girls, both p<0.001. Children with higher levels of muscular fitness had a better cardiometabolic risk profile (CMRI marginal estimated mean±SE 1.04±0.13>0.05±0.09>-1.16±0.13 for lower, middle and upper quartiles of muscular fitness in boys and 1.01±0.16>0.10±0.09>-1.02±0.15 in girls, both p<0.001), but differences disappeared when controlling for BMI. BMI acted as a full mediator between muscular fitness and most cardiometabolic risk factors (Sobel test z=-11.44 for boys; z=-11.83 for girls; p<0.001 in CMRI mediation model) and as a partial mediator in the case of waist circumference (Sobel test z=-14.86 for boys; z=-14.51 for girls; p<0.001).

Conclusions

BMI mediates the association between muscular fitness and cardiometabolic risk in schoolchildren. Overall, good muscular fitness is associated with lower cardiometabolic risk, but particularly when accompanied by normal weight.     

Changes in Serum Free Amino Acids and Muscle Fatigue Experienced during a Half-Ironman Triathlon

The aim of this study was to investigate the relationship between changes in serum free amino acids, muscle fatigue and exercise-induced muscle damage during a half-ironman triathlon. Twenty-six experienced triathletes (age = 37.0 ± 6.8 yr; experience = 7.4 ± 3.0 yr) competed in a real half-ironman triathlon in which sector times and total race time were measured by means of chip timing. Before and after the race, a countermovement jump and a maximal isometric force test were performed, and blood samples were withdrawn to measure serum free amino acids concentrations, and serum creatine kinase levels as a blood marker of muscle damage. Total race time was 320 ± 37 min and jump height (-16.3 ± 15.2%, P < 0.001) and isometric force (-14.9 ± 9.8%; P = 0.007) were significantly reduced after the race in all participants. After the race, the serum concentration of creatine kinase increased by 368 ± 187% (P < 0.001). In contrast, the serum concentrations of essential (-27.1 ± 13.0%; P < 0.001) and non-essential amino acids (-24.4 ± 13.1%; P < 0.001) were significantly reduced after the race. The tryptophan/BCAA ratio increased by 42.7 ± 12.7% after the race. Pre-to-post changes in serum free amino acids did not correlate with muscle performance variables or post-race creatine kinase concentration. In summary, during a half-ironman triathlon, serum amino acids concentrations were reduced by > 20%. However, neither the changes in serum free amino acids nor the tryptophan/BCAA ratio were related muscle fatigue or muscle damage during the race.     

Role of Alveolar β2-Adrenergic Receptors on Lung Fluid Clearance and Exercise Ventilation in Healthy Humans

Background

In experimental conditions alveolar fluid clearance is controlled by alveolar β₂-adrenergic receptors. We hypothesized that if this occurs in humans, then non-selective β-blockers should reduce the membrane diffusing capacity (D_M), an index of lung interstitial fluid homeostasis. Moreover, we wondered whether this effect is potentiated by saline solution infusion, an intervention expected to cause interstitial lung edema. Since fluid retention within the lungs might trigger excessive ventilation during exercise, we also hypothesized that after the β₂-blockade ventilation increased in excess to CO₂ output and this was further enhanced by interstitial edema.

Methods and Results

22 healthy males took part in the study. On day 1, spirometry, lung diffusion for carbon monoxide (DLCO) including its subcomponents D_M and capillary volume (V_Cap), and cardiopulmonary exercise test were performed. On day 2, these tests were repeated after rapid 25 ml/kg saline infusion. Then, in random order 11 subjects were assigned to oral treatment with Carvedilol (CARV) and 11 to Bisoprolol (BISOPR). When heart rate fell at least by 10 beats·min⁻¹, the tests were repeated before (day 3) and after saline infusion (day 4). CARV but not BISOPR, decreased D_M (−13±7%, p = 0.001) and increased V_Cap (+20±22%, p = 0.016) and VE/VCO₂ slope (+12±8%, p<0.01). These changes further increased after saline: −18±13% for D_M (p<0.01), +44±28% for V_Cap (p<0.001), and +20±10% for VE/VCO₂ slope (p<0.001).

Conclusions

These findings support the hypothesis that in humans in vivo the β₂-alveolar receptors contribute to control alveolar fluid clearance and that interstitial lung fluid may trigger exercise hyperventilation.     

The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration

Introduction

We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS).

Methods

In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 μg/kg/h) or intratracheally (bolus, 25 μg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB.

Results

The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration.

Conclusion

Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of β2-agonists on clinical outcome in ARDS.     

The Effect of Two Speed Endurance Training Regimes on Performance of Soccer Players

In order to better understand the specificity of training adaptations, we compared the effects of two different anaerobic training regimes on various types of soccer-related exercise performances. During the last 3 weeks of the competitive season, thirteen young male professional soccer players (age 18.5±1 yr, height 179.5±6.5 cm, body mass 74.3±6.5 kg) reduced the training volume by ~20% and replaced their habitual fitness conditioning work with either speed endurance production (SEP; n = 6) or speed endurance maintenance (SEM; n = 7) training, three times per wk. SEP training consisted of 6–8 reps of 20-s all-out running bouts followed by 2 min of passive recovery, whereas SEM training was characterized by 6–8 x 20-s all-out efforts interspersed with 40 s of passive recovery. SEP training reduced (p<0.01) the total time in a repeated sprint ability test (RSA_t) by 2.5%. SEM training improved the 200-m sprint performance (from 26.59±0.70 to 26.02±0.62 s, p<0.01) and had a likely beneficial impact on the percentage decrement score of the RSA test (from 4.07±1.28 to 3.55±1.01%) but induced a very likely impairment in RSA_t (from 83.81±2.37 to 84.65±2.27 s). The distance covered in the Yo-Yo Intermittent Recovery test level 2 was 10.1% (p<0.001) and 3.8% (p<0.05) higher after SEP and SEM training, respectively, with possibly greater improvements following SEP compared to SEM. No differences were observed in the 20- and 40-m sprint performances. In conclusion, these two training strategies target different determinants of soccer-related physical performance. SEP improved repeated sprint and high-intensity intermittent exercise performance, whereas SEM increased muscles’ ability to maximize fatigue tolerance and maintain speed development during both repeated all-out and continuous short-duration maximal exercises. These results provide new insight into the precise nature of a stimulus necessary to improve specific types of athletic performance in trained young soccer players.     

Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis

The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (r_s = 0.69; p<0.05) and C3c/C3 activation ratio (r_s = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation.     

Phenolic Acid Composition,Antiatherogenic and Anticancer Potential of Honeys Derived from Various Regions in Greece

The phenolic acid profile of honey depends greatly on its botanical and geographical origin. In this study, we carried out a quantitative analysis of phenolic acids in the ethyl acetate extract of 12 honeys collected from various regions in Greece. Our findings indicate that protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, caffeic acid and p-coumaric acid are the major phenolic acids of the honeys examined. Conifer tree honey (from pine and fir) contained significantly higher concentrations of protocatechuic and caffeic acid (mean: 6640 and 397 µg/kg honey respectively) than thyme and citrus honey (mean of protocatechuic and caffeic acid: 437.6 and 116 µg/kg honey respectively). p-Hydroxybenzoic acid was the dominant compound in thyme honeys (mean: 1252.5 µg/kg honey). We further examined the antioxidant potential (ORAC assay) of the extracts, their ability to influence viability of prostate cancer (PC-3) and breast cancer (MCF-7) cells as well as their lowering effect on TNF- α-induced adhesion molecule expression in endothelial cells (HAEC). ORAC values of Greek honeys ranged from 415 to 2129 µmol Trolox equivalent/kg honey and correlated significantly with their content in protocatechuic acid (p<0.001), p-hydroxybenzoic acid (p<0.01), vanillic acid (p<0.05), caffeic acid (p<0.01), p-coumaric acid (p<0.001) and their total phenolic content (p<0.001). Honey extracts reduced significantly the viability of PC-3 and MCF-7 cells as well as the expression of adhesion molecules in HAEC. Importantly, vanillic acid content correlated significantly with anticancer activity in PC-3 and MCF-7 cells (p<0.01, p<0.05 respectively). Protocatechuic acid, vanillic acid and total phenolic content correlated significantly with the inhibition of VCAM-1 expression (p<0.05, p<0.05 and p<0.01 respectively). In conclusion, Greek honeys are rich in phenolic acids, in particular protocatechuic and p-hydroxybenzoic acid and exhibit significant antioxidant, anticancer and antiatherogenic activities which may be attributed, at least in part, to their phenolic acid content.     

The Role of Whole Blood Impedance Aggregometry and Its Utilisation in the Diagnosis and Prognosis of Patients with Systemic Inflammatory Response Syndrome and Sepsis in Acute Critical Illness

Objective

To assess the prognostic and diagnostic value of whole blood impedance aggregometry in patients with sepsis and SIRS and to compare with whole blood parameters (platelet count, haemoglobin, haematocrit and white cell count).

Methods

We performed an observational, prospective study in the acute setting. Platelet function was determined using whole blood impedance aggregometry (multiplate) on admission to the Emergency Department or Intensive Care Unit and at 6 and 24 hours post admission. Platelet count, haemoglobin, haematocrit and white cell count were also determined.

Results

106 adult patients that met SIRS and sepsis criteria were included. Platelet aggregation was significantly reduced in patients with severe sepsis/septic shock when compared to SIRS/uncomplicated sepsis (ADP: 90.7±37.6 vs 61.4±40.6; p<0.001, Arachadonic Acid 99.9±48.3 vs 66.3±50.2; p = 0.001, Collagen 102.6±33.0 vs 79.1±38.8; p = 0.001; SD ± mean)). Furthermore platelet aggregation was significantly reduced in the 28 day mortality group when compared with the survival group (Arachadonic Acid 58.8±47.7 vs 91.1±50.9; p<0.05, Collagen 36.6±36.6 vs 98.0±35.1; p = 0.001; SD ± mean)). However haemoglobin, haematocrit and platelet count were more effective at distinguishing between subgroups and were equally effective indicators of prognosis. Significant positive correlations were observed between whole blood impedance aggregometry and platelet count (ADP 0.588 p<0.0001, Arachadonic Acid 0.611 p<0.0001, Collagen 0.599 p<0.0001 (Pearson correlation)).

Conclusions

Reduced platelet aggregometry responses were not only significantly associated with morbidity and mortality in sepsis and SIRS patients, but also correlated with the different pathological groups. Whole blood aggregometry significantly correlated with platelet count, however, when we adjust for the different groups we investigated, the effect of platelet count appears to be non-significant.     

Measurement of Cooling Detection Thresholds for Identification of Diabetic Sensorimotor Polyneuropathy in Type 1 Diabetes

Objective

Compared to recently-studied novel morphological measures, conventional small nerve fiber functional tests have not been systematically studied for identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine and compare the diagnostic performance of cooling detection thresholds (CDT) in a cross-sectional type 1 diabetes cohort.

Research Design and Methods

136 subjects with type 1 diabetes and 52 healthy volunteers underwent clinical and electrophysiological examination for DSP classification concomitantly with the Toronto Clinical Neuropathy Score (TCNS) and three small fiber function tests: CDT, heart rate variability (HRV), and laser doppler imaging of axon-mediated neurogenic flare responses to cutaneous heating (LDI_FLARE). Area under the curve (AUC) and optimal thresholds were determined by receiver operating characteristic (ROC) curves in the type 1 diabetes cohort.

Results

Type 1 diabetes subjects were 42±17 years of age with mean HbA1c 7.9±1.7%. Fifty-nine (45%) met the case definition for DSP. CDT values were lowest in cases with DSP (18.3±8.4°C) compared to controls without DSP (28.4±3.5°C) and to healthy volunteers (29.6±1.8°C; p-value for both comparisons<0.0001). AUC_CDT was 0.863 which was similar to AUC_TCNS (0.858, p = 0.24) and AUC_HRV (0.788, p = 0.05), but exceeded AUC_LDIFLARE (0.750, p = 0.001). The threshold of <25.1°C was equivalent to the lower bound of the healthy volunteer 95% distribution [25.1, 30.8°C] and performed with 83% sensitivity and 82% specificity.

Conclusions

Akin to novel small fiber morphological measures, CDT is a functional test that identifies DSP with very good diagnostic performance. These findings support further research that revisits the role of CDT in early DSP detection.     

Cardiac Compression of Lung Lower Lobes after Coronary Artery Bypass Graft with Cardiopulmonary Bypass

Background

Atelectasis is a major cause of hypoxemia after coronary artery bypass grafting (CABG) and is commonly ascribed to general anesthesia, high inspiratory oxygen concentration and cardiopulmonary bypass (CPB). The objective of this study was to evaluate the role of heart-induced pulmonary compression after CABG with CPB.

Methods

Seventeen patients without pre-operative cardiac failure who were scheduled for coronary artery bypass graft underwent pre- and postoperative thoracic computed tomography. The cardiac mass, the pressure exerted on the lungs by the right and left heart and the fraction of collapsed lower lobe segments below and outside of the heart limits were evaluated on a computed tomography section 1 cm above the diaphragmatic cupola.

Results

In the postoperative period, cardiac mass increased by 32% (117±31 g versus 155±35 g, p<0.001), leading to an increase in the pressure that was exerted on the lungs by the right (2.2±0.6 g.cm⁻² versus 3.2±1.2 g.cm⁻², p<0.05) and left heart (2.4±0.7 g.cm⁻² versus 4.2±1.8 g.cm⁻², p<0.001). The proportion of collapsed lung segments beneath the heart markedly increased [from 6.7% to 32.9% on the right side (p<0.001) and from 6.2% to 29% on the left side (p<0.001)], whereas the proportion of collapsed lung segments outside of the heart limits slightly increased [from 0.7% to 10.8% on the right side (p<0.001) and from 1.5% to 12.6% on the left side (p<0.001)].

Conclusion

The pressure that is exerted by the heart on the lungs increased postoperatively and contributed to the collapse of subjacent pulmonary segments.     

Comparison of Retinal Nerve Fiber Layer Thickness In Vivo and Axonal Transport after Chronic Intraocular Pressure Elevation in Young versus Older Rats

Purpose

To compare in young and old rats longitudinal measurements of retinal nerve fiber layer thickness (RNFLT) and axonal transport 3-weeks after chronic IOP elevation.

Method

IOP was elevated unilaterally in 2- and 9.5-month-old Brown-Norway rats by intracameral injections of magnetic microbeads. RNFLT was measured by spectral domain optical coherence tomography. Anterograde axonal transport was assessed from confocal scanning laser ophthalmolscopy of superior colliculi (SC) after bilateral intravitreal injections of cholera toxin-B-488. Optic nerve sections were graded for damage.

Results

Mean IOP was elevated in both groups (young 37, old 38 mmHg, p = 0.95). RNFL in young rats exhibited 10% thickening at 1-week (50.9±8.1 µm, p<0.05) vs. baseline (46.4±2.4 µm), then 7% thinning at 2-weeks (43.0±7.2 µm, p>0.05) and 3-weeks (43.5±4.4 µm, p>0.05), representing 20% loss of dynamic range. RNFLT in old rats showed no significant change at 1-week (44.9±4.1 µm) vs. baseline (49.2±5.3 µm), but progression to 22% thinning at 2-weeks (38.0±3.7 µm, p<0.01) and 3-weeks (40.0±6.6 µm, p<0.05), representing 59% loss of dynamic range. Relative SC fluorescence intensity was reduced in both groups (p<0.001), representing 77–80% loss of dynamic range and a severe transport deficit. Optic nerves showed 75–95% damage (p<0.001). There was greater RNFL thinning in old rats (p<0.05), despite equivalent IOP insult, transport deficit and nerve damage between age groups (all p>0.05).

Conclusion

Chronic IOP elevation resulted in severely disrupted axonal transport and optic nerve axon damage in all rats, associated with mild RNFL loss in young rats but a moderate RNFL loss in old rats despite the similar IOP insult. Hence, the glaucomatous injury response within the RNFL depends on age.