Factor XII truncation accelerates activation in solution.

Essentials During contact system activation, factor XII is progressively cleaved by plasma kallikrein. We investigated the role of factor XII truncation in biochemical studies. Factor XII contains naturally occurring truncating cleavage sites for a variety of enzymes. Truncation of factor XII primes it for activation in solution through exposure of R353. SUMMARY: Background The contact activation system and innate immune system are interlinked in inflammatory pathology. Plasma kallikrein (PKa) is held responsible for the stepwise processing of factor XII (FXII). A first cleavage activates FXII (into FXIIa); subsequent cleavages truncate it. This truncation eliminates its surface-binding domains, which negatively regulates surface-dependent coagulation. Objectives To investigate the influence of FXII truncation on its activation and downstream kallikrein-kinin system activation. Methods We study activation of recombinant FXII variants by chromogenic assays, by FXIIa ELISA and western blotting. Results We demonstrate that FXII truncation primes it for activation by PKa in solution. We demonstrate this phenomenon in three settings. (i) Truncation at a naturally occurring PKa-sensitive cleavage site, R334, accelerates FXIIa formation in solution. A site-directed mutant FXII-R334A displays ~50% reduced activity when exposed to PKa. (ii) A pathogenic mutation in FXII that causes hereditary angioedema, introduces an additional plasmin-sensitive cleavage site. Truncation at this site synergistically accelerates FXII activation in solution. (iii) We identify new, naturally occurring cleavage sites in FXII that have so far not been functionally linked to contact system activation. As examples, we show that non-activating truncation of FXII by neutrophil elastase and cathepsin K primes it for activation by PKa in solution. Conclusions FXII truncation, mediated by either pathogenic mutations or naturally occurring cleavage sites, primes FXII for activation in solution. We propose that the surface-binding domains of FXII shield its activating cleavage site, R353. This may help to explain how the contact system contributes to inflammatory pathology.

Hereditary angioedema: the plasma contact system out of control.

The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.

Gastrointestinal tolerance and plasma status of carotenoids, EPA and DHA with a fiber-enriched tube feed in hospitalized patients initiated on tube nutrition: Randomized controlled trial.

BACKGROUND & AIMS: During the first days of tube feeding (TF) gastrointestinal (GI) complications are common and administration of sufficient nutrition is a challenge. Not all standard nutritionally complete formulas contain dietary fiber, fish oil or carotenoids, key dietary nutrients for health and wellbeing. The aim of this study was to investigate the effects of a fiber, fish oil and carotenoid enriched TF formula on diarrhea, constipation and nutrient bioavailability. METHODS: A multi-center randomized, double-blind, controlled, parallel trial compared the effects of a dietary fiber, fish oil and carotenoid-enriched TF formula (test) with an isocaloric non-enriched formula (control) in 51 patients requiring initiation of TF. Incidence of diarrhea and constipation (based on stool frequency and consistency) was recorded daily. Plasma status of EPA, DHA and carotenoids was measured after 7 days. RESULTS: The incidence of diarrhea was lower in patients receiving the test formula compared with the control group (19% vs. 48%, p = 0.034). EPA and DHA status (% of total plasma phospholipids) was higher after 7 days in test compared with control group (EPA: p = 0.002, DHA: p = 0.082). Plasma carotenoid levels were higher after 7 days in the test group compared with control group (lutein: p = 0.024, α-carotene: p = 0.005, lycopene: p = 0.020, ß-carotene: p = 0.054). CONCLUSIONS: This study suggests that the nutrient-enriched TF formula tested might have a positive effect on GI tolerance with less diarrhea incidence and significantly improved EPA, DHA and carotenoid plasma levels during the initiation of TF in hospitalized patients who are at risk of diarrhea and low nutrient status. CLINICAL TRIAL REGISTRATION: This trial was registered at trialregister.nl; registration number 2924.

C-reactive protein levels in hereditary angioedema.

Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P = 0·049) and during the next 24 h CRP rose significantly (P = 0·002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P = 0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset.

Root resorption during orthodontic tooth movements.

The aim of the study was to compare the extent of maxillary incisor root resorption during different orthodontic tooth movements using three different techniques, namely the basal intrusion arch, the three component arch, and levelling of the upper dental arch with the straightwire appliance. The radiographs of 49 subjects (20 males and 29 females) with a mean age of 14.5 years were taken at two time points: in groups 1 and 2 after the levelling phase and in group 3 immediately after placement of the archwire (T1) and in all groups after a period of 6 months (T2). The amount of root resorption of the central incisors was determined at T2. The average incisor resorption was different in the three groups, with group 2 (three component arch) showing greater resorption (0.46 mm) than groups 1 (basal arch) and 3 (straightwire) of 0.26 and 0.25 mm, respectively. Analysis of variance (ANOVA) demonstrated that differences in root resorption in the three groups were not significant. Wilcoxon paired test showed that the root resorption occurring between T1 and T2 in the three groups was not significant. There was also no significant difference among the rates of resorption in the three groups. Grouping the subjects on the basis of the extent of root resorption and the biomechanics used showed differences in the percentage of subjects with the least (<0.5 mm) and greatest (0.5-0.9 mm) amounts of root resorption between the three groups. This again showed that the technique of three component intrusion arch resulted in the greatest increase in root resorption.

Preoperative fasting: an outdated concept?

Recent studies have shown that fasting during the preoperative period for elective surgery induces a metabolic state that seems unfavorable for patients. Results from animal studies indicate that rapid depletion of liver glycogen before surgery leads to mobilization of muscle glycogen after surgery, in turn leading to reduced muscle strength. Depletion of liver glycogen also influences the function of the mononuclear phagocytic system (MPS), which is located predominantly in the liver. The MPS is essential in restricting endotoxin, which may translocate from the gut. In addition, surgery per se puts a substantial physical strain on the patient, and fasting may adversely affect the metabolic response to surgery. This paper presents experimental and clinical data that, when combined together, prove that fasting before surgery has adverse consequences for the patient.

The effect of different nutritional feeds on the postprandial glucose response in healthy volunteers and patients with type II diabetes.

OBJECTIVE: Assessment of postprandial glycaemic response to four nutritional feeds with different macronutrient and fibre composition. DESIGN: A randomized, double-blind, crossover study. SETTING: University of Maastricht, the Netherlands. SUBJECTS: A total of 10 healthy volunteers and 10 patients with type II diabetes. INTERVENTIONS: Subjects received 200 kcal of four enteral nutrition products (two standard products and two diabetes-specific products). Fasting and postprandial plasma glucose were measured for 2 h. Peak glucose level and area under the curve were calculated. RESULTS: In healthy volunteers and diabetic patients, the feed with a low carbohydrate (CHO), high monounsaturated fatty acid (MUFA) and high fibre content significantly decreased peak glucose concentration and area under the curve compared to the feeds with standard composition. CONCLUSIONS: Special feeds with a low CHO, high MUFA and high fibre content improve glycaemic balance and therefore should be considered in diabetic patients who are in need of nutritional support.

Acute effects of different nutritional supplements on symptoms and functional capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Use of nutritional supplements in depleted patients with chronic obstructive pulmonary disease (COPD) requires optimization between positive effects on outcome and potential acute adverse effects on metabolism and exercise performance. OBJECTIVE: The aim of this study was to investigate the acute effects of nutritional supplements on metabolism and exercise capacity in stable COPD patients. DESIGN: In part 1, the effects of 3 different energy loads (placebo, 1046 kJ, and 2092 kJ) with a normal distribution of macronutrients were investigated in 14 COPD patients. In part 2, the effects of a fat-rich compared with a carbohydrate-rich supplement (both 1046 kJ) were studied in 11 COPD patients. The study was performed in a randomized, double-blind, crossover fashion. Metabolic and ventilatory variables were measured postprandially and during a submaximal cycle endurance exercise test. RESULTS: Overall, no immediate negative effects of the supplements were found in part 1. A slight but significant postprandial increase in respiratory quotient was found after the 1046-kJ and 2092-kJ supplements compared with placebo. There was no significant difference in metabolism or exercise capacity after a fat-rich or carbohydrate-rich supplement. Surprisingly, the change in shortness of breath (postprandial compared with preprandial) was significantly greater after the fat-rich supplement. CONCLUSIONS: An energy load up to 2092 kJ had no adverse immediate effect in COPD patients compared with placebo. The subjects who consumed the fat-rich supplement experienced more shortness of breath than did the subjects who consumed the carbohydrate-rich supplement.

Nasogastric tube feeding in children with cancer: the effect of two different formulas on weight, body composition, and serum protein concentrations.

BACKGROUND: Treatment of cancer cachexia partly involves the administration of adequate amounts of energy. The aim of this study was to assess the tolerance and efficacy of two equal volumes of tube feeding, one with a standard (1 kcal/mL) and one with a high energy density (1.5 kcal/mL), during the intensive phase of treatment. METHODS: Nutritional status was assessed weekly, in 27 children with a solid tumor, by measuring weight, height, midupper arm circumference, biceps and triceps skinfold, and serum proteins. Tolerance was assessed by recording the occurrence of vomiting and by expressing the administered volume as a percentage of the required volume. RESULTS: Both formulas were equally well tolerated, leading to a significantly higher energy intake in the energy-enriched formula group. In both formula groups, all anthropometric variables increased significantly (range of mean increase, 5.2% to 25.5%; p < .05) during the first 4 weeks of intervention. Between 4 and 10 weeks, variables continued to increase significantly in the energy-enriched group, resulting in adequate repletion, in contrast to the standard formula group. The concentration of serum proteins, low at initiation of tube feeding, returned to the normal range within 2 to 4 weeks with no significant differences between the two groups. CONCLUSIONS: The energy-enriched formula was more effective in improving the nutritional status of children with cancer during the intensive phase of treatment than the standard formula. Intensive, protocolized administration of an energy-enriched formula should therefore be initiated as soon as one of the criteria for initiation of tube feeding is met.

Effects of naso-gastric tube feeding on the nutritional status of children with cancer.

OBJECTIVE: To study the effect of sufficient energy intake, by means of the protocolized administration of naso-gastric tube feeding, on the nutritional status of a child with cancer. DESIGN: A comparative experimental study. SETTING: Tertiary care at the Centre for Pediatric Oncology, South East Netherlands, University Hospital, Nijmegen. SUBJECTS: Seven children, newly diagnosed with cancer, were included in the experimental study and all completed the trial period. Fourteen patients were included in the retrospective study. They were randomly chosen from a group of patients previously treated for a malignancy at our department and who had received naso-gastric tube feeding for at least 16 weeks. INTERVENTION: Protocolized (experimental group) vs non-protocolized (retrospective group) administration of naso-gastric tube feeding over a period of 16 weeks. The main difference was the amount of tube feeding administered. In addition to energy from other foods, children in the experimental group received 106+/-13% of their total daily energy requirements (TDER) by means of tube feeding, whereas children in the retrospective group had received 75+/-24%. MAIN OUTCOME MEASURES: Weight as a percentage of weight for height according to the 50th percentile of a healthy reference population=ideal weight. RESULTS: Weight, expressed as a percentage of the ideal weight, increased significantly in the experimental group (18.2 8.4; P=0.01) and the retrospective study group (5.2 7.3; P=0.001). However, the increase was statistically significant in favour of the experimental group (P=0.003), in which all the children reached their ideal weight, compared to 21% in the retrospective group. CONCLUSION: Aggressive protocolized nutritional intervention during the intensive phase of anti-cancer treatment, in the form of naso-gastric tube feeding that provides the child's total daily energy requirements, results in considerable improvement in the nutritional status.

Glucose and insulin responses after commonly used sport feedings before and after a 1-hr training session.

This investigation examined the plasma glucose and insulin response in 6 trained athletes after consumption of four commercially available sport feedings 2 hr before as well as immediately after 1 hr of running under common training conditions. Four feedings were compared: Feeding 1, 160 g CHO/400 ml; Feeding 2, 69 g CHO/400 ml; Feeding 3, 69 g CHO + 6 g protein/400 ml; and Feeding 4, solid 69 g CHO + 5 g protein + 4 g fat. Before the training session, there were no differences between the four sport feedings in the area under the glucose and insulin curves and the insulin/glucose ratio. However, after exercise, Feeding 2 resulted in a significantly greater area under the glucose curve compared with Feedings 1, 3, and 4 (respectively, 352 vs. 241, 251, and 182) and a significantly lower insulin/glucose ratio compared with Feeding 1 (respectively, 6.2 vs. 15.8). Therefore, it is concluded that the kind of sport feeding may influence postexercise glucose and insulin responses.

Effects of propranolol and pindolol on cardiac output during extended periods of low-intensity physical activity.

The effects of a nonselective beta-adrenergic blocking agent with (pindolol) and without (propranolol) intrinsic sympathomimetic activity properties, compared with placebo-controlled conditions, on metabolic and cardiorespiratory function during long-duration (2 hours) physical activity were examined. After initial cardiorespiratory testing, subjects performed 2-hour walks at 25 and 45% of maximal oxygen consumption (VO2max) under each of the following 3 treatments: pindolol, propranolol and placebo. Medication distribution was randomized and double-blinded. A supine resting blood pressure and electrocardiogram were obtained before each exercise trial. Oxygen consumption, heart rate, stroke volume, cardiac output and blood pressure were determined after 5 minutes of quiet sitting and every 30 minutes during each 2-hour exercise trial. Cardiac output was not significantly different at rest or during exercise, comparing pindolol and propranolol with placebo conditions. Cardiac output tended to decrease over time earlier during propranolol treatment for the 25% VO2max trials in trained normotensive subjects than for the other treatments. Cardiac output decreased at approximately the same time across treatments during the 45% VO2max trials in trained normotensive and untrained hypertensive groups. Finally, owing to the observation that a reduction in cardiac output was delayed or prevented in trained normotensive subjects when compared with that in untrained hypertensives while exercising at 25% VO2max, developing a subject's cardiovascular fitness level may be important in the maintenance of cardiac output during extended periods of low-to-moderate physical activities while under the influence of beta-adrenergic blockade.

Nutrition and blood pressure among elderly men and women (Dutch Nutrition Surveillance System).

Associations between blood pressure and nutrition-related variables (body mass index, dietary intake, and 24-hr excretion of sodium, potassium, magnesium, and calcium in the urine) were investigated in men (n = 138) and women (n = 117) 65-79 years old not using drugs known to affect blood pressure and not on a diet. Among men, body mass index was positively and creatinine clearance was inversely associated with systolic blood pressure, whereas body mass index and urinary sodium:potassium ratio were positively associated with diastolic blood pressure. Among women, both age and urinary calcium:creatinine ratio were positively associated with systolic as well as diastolic blood pressure. Coffee consumption was positively correlated with blood pressure and urinary calcium:creatinine ratio among the women. From the results it appears that, besides "normal" weight, increased potassium intake and urinary excretion may exert a protective effect among elderly men against hypertension when sodium exposure is relatively high. The positive association between urinary calcium:creatinine ratio and blood pressure among the women may be partly due to coffee consumption.

The metabolic consequences of low and moderate intensity exercise with or without feeding in lean and borderline obese males.

The purpose of this study was to investigate the role of exercise intensity on the post-exercise thermogenic effect (PETE), with or without feeding, in five lean (less than 15 percent body fat) and five borderline obese (between 20 and 25 percent body fat) individuals when the total caloric expenditure during exercise was equated to 720 kcal by adjusting exercise duration. Each subject participated in six testing sessions, including the measurement of resting metabolic rate (RMR), dietary induced thermogenesis (DIT) following a 720 kcal liquid meal, and four exercise trials including: (1) exercising on a treadmill at both 30 percent and 60 percent of VO2 max followed by a 720 kcal liquid meal (30F and 60F); and (2) exercising on a treadmill at both 30 percent and 60 percent of VO2 max followed by a non-caloric liquid meal substitute (water) matched by volume to the caloric liquid meal (30NF and 60NF). Indirect calorimetry was used to determine metabolic rate prior to each treatment (0-30 min RMR) and at 0-30, 50-60, 80-90, 110-120, 140-150, and 170-180 min following the feeding, exercise only, or exercise and feeding treatments. A significant difference in the post-exercise oxygen consumption was found between the two calorically equated exercise bouts (720 kcal) at 30 percent and 60 percent of each subject's VO2 max without feeding when all measurement periods following exercise were averaged together (60NF = 13.5 percent increase and 30NF = 5.5 percent). This difference was observed in both the lean and borderline obese subjects, with no significant difference between the two groups. In addition, when walking at either 30 percent or 60 percent of VO2 max preceded feeding, a significant attenuation in the rise of post-feeding RER values was observed in both groups with the higher exercise intensity showing the greatest RER attenuation when compared to the DIT trial. These results suggest that exercise intensity may play a significant role independent of the total energy expenditure in potentiating a person's post-exercise oxygen consumption rate and post-exercise substrate utilization for periods of up to 180 mins.

Stroke volume during submaximal exercise in endurance-trained normotensive subjects and in untrained hypertensive subjects with beta blockade (propranolol and pindolol).

The effect of beta-adrenergic blockade on stroke volume (SV) at increasing submaximal exercise intensities was studied in 12 endurance-trained normotensive and 12 untrained hypertensive (diastolic blood pressure greater than 95 mm Hg) men, aged 18 to 34 years. Subjects were assigned to each of 3 treatments in a double-blind, randomized order: placebo, propranolol (80 mg twice daily) and pindolol (10 mg twice daily) for 10 days, with a period of 48 to 60 hours from the initial dose to the first treadmill test and a 4-day washout period between drugs. Cardiac output was measured using the carbon dioxide rebreathing method and SV was calculated from cardiac output and heart rate as follows: SV = cardiac output/heart rate. Cardiac outputs were estimated at rest and while walking on a treadmill at 25, 45, 60 and 75% of the subject's previously determined maximal oxygen uptake (VO2max). No significant differences were found in cardiac output between either of the drugs and placebo at rest, or at any of the 4 rates of work. Propranolol significantly increased SV above placebo values (p less than 0.05) for both trained and untrained groups at the intensities of 45, 60 and 75%. Significant differences in SV were found between pindolol and placebo only at the intensities of 60 and 75% in the trained group. Contrary to expectations, SV showed no indication of a plateau with propranolol in the trained subjects throughout the 4 different exercise intensities, whereas a plateau was established under placebo conditions by 45% of VO2max in both trained and untrained subjects. These results suggest that both trained and untrained hypertensive persons can exercise with beta-adrenergic blockade at submaximal levels without compromised cardiac function.

Changes in plasma free fatty acids and glycerols during prolonged exercise in trained and hypertensive persons taking propranolol and pindolol.

The extent to which lipolysis is attenuated during prolonged submaximal exercise during beta blockade was determined in 12 normotensive endurance-trained and 12 hypertensive sedentary men using nonselective drugs with and without intrinsic sympathomimetic activity (ISA). Initially, subjects performed a graded treadmill test to determine maximal oxygen uptake (VO2max). This was followed by 2-hour walks at 25 and 45% of the subject's VO2max under each of 3 treatments: pindolol (ISA), propranolol (non-ISA) and placebo. The distribution of medication was randomized and double blinded. Blood samples taken at rest and every 30 minutes during the 2-hour walks were analyzed to determine the concentrations of free fatty acids (FFA) and glycerol. On the basis of the respective changes in FFA, glycerols and the respiratory exchange ratio, beta-adrenergic blockade did not attenuate lipolysis in the untrained hypertensive subjects when compared with the placebo administration. However, beta blockade did demonstrate a tendency to attenuate lipolysis in the trained, normotensive subjects when compared with results after placebo administration. This was particularly evident at 30 minutes of exercise, when both glycerol and FFA concentrations were not increased above resting values under both conditions of beta blockade. No differences between pindolol and propranolol were observed. Therefore, a beta-blocking agent with ISA properties appears to have no clear benefit with respect to lipid metabolism during low and moderate intensity exercise. Furthermore, these data demonstrate that beta blockade does not inhibit exercise-induced lipolysis at low and moderate intensities of exercise as formerly believed, and is unlikely to be the cause of fatigue normally observed during work in patient populations taking beta-blocking medication.

[A study of the relationship between blood pressure and mineral intake in elderly Dutch subjects]. / Onderzoek naar de samenhang tussen bloeddruk en mineralenvoorziening bij Nederlandse ouderen.

In a nationwide survey among 530 apparently healthy elderly people, aged 65-79 years, the prevalence of hypertension was 58% in males and 68% in females. About 40% of them had no medical antihypertensive treatment. After exclusion of subjects on antihypertensive medication or on a prescribed diet, the energy, fat, alcohol, potassium and calcium intake, the sodium, potassium, magnesium and calcium excretion in the 24-hour urine and the Quetelet Index of normotensive elderly were compared with those of hypertensive elderly. Hypertensive males had a higher sodium:potassium ratio and a lower potassium:creatinine ratio in the 24-hour urine. Hypertensive females had a higher calcium excretion. No differences were observed between normotensive and hypertensive elderly in the mineral intake, whereas there were some differences in mineral excretions with the urine. The correlations of the mineral excretions with the creatinine clearance proved to be stronger among hypertensives. This might indicate a lower bioavailability and (or) aberrant metabolism of minerals (especially calcium in hypertensive women and potassium in hypertensive men).

Comparison of the effects of pindolol and propranolol on exercise performance in young men with systemic hypertension.

To determine the effect of intrinsic sympathomimetic activity (ISA) on exercise performance during beta blockade, 12 hypertensive men were studied. The subjects underwent graded treadmill testing while taking pindolol (a beta blocker with ISA), propranolol (a beta blocker without ISA) and placebo, in a double-blind, crossover fashion. Blood pressure, heart rate, oxygen consumption (VO2), cardiac output and stroke volume were determined at 25, 45, 60 and 75% of each subject's VO2 max. Heart rate was significantly lower with pindolol compared with placebo at all stages of exercise, but significantly higher compared with propranolol at all stages of exercise except at 75% of VO2 max and at VO2 max (no significant differences between the 2 beta blockers were recorded at these stages). Mean arterial pressure was statistically equivalent with pindolol and propranolol at all stages of exercise and significantly lower while beta-blocked compared with placebo conditions at 45, 60 and 75% of VO2 max. Cardiac output and VO2 were statistically equivalent across all 3 treatments at all submaximal levels of exercise. It was concluded that, although heart rate was significantly higher with pindolol compared with propranolol at the 3 lower rates of work, cardiac output and VO2 were not different between the drugs, thus making little impact on exercise performance.