A model to study intestinal and hepatic metabolism of propranolol in the dog

A model to investigate hepatic drug uptake and metabolism in the dog was developed for this study. Catheters were placed in the portal and hepatic veins during exploratory laparotomy to collect pre- and posthepatic blood samples at defined intervals. Drug concentrations in the portal vein were taken to reflect intestinal uptake and metabolism of an p.o. administered drug (propranolol), while differences in drug and metabolite concentrations between portal and hepatic veins reflected hepatic uptake and metabolism. A significant difference in propranolol concentration between hepatic and portal veins confirmed a high hepatic extraction of this therapeutic agent in the dog. This technically uncomplicated model may be used experimentally or clinically to determine hepatic function and metabolism of drugs that may be administered during anaesthesia and surgery.

Disposition kinetics of propranolol isomers in the perfused rat liver

The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)- propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S(-)- propranolol differs from the R(+)- isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.

Predictive regression equations and clinical uses of peripheral pulse timing characteristics in children

Studies have shown that increased arterial stiffening can be an indication of cardiovascular diseases like hypertension. In clinical practice, this can be detected by measuring the blood pressure (BP) using a sphygmomanometer but it cannot be used for prolonged monitoring. It has been established that pulse wave velocity (PWV) is a direct measure of arterial stiffening but its usefulness is hampered by the absence of non-invasive techniques to estimate it. Pulse transit time (PTT) is a simple and non-invasive method derived from PWV. However, limited knowledge of PTT in children is found in the present literature. The aims of this study are to identify independent variables that confound PTT measure and describe PTT regression equations for healthy children. Therefore, PTT reference values are formulated for future pathological studies. Fifty-five Caucasian children (39 male) aged 8.4 +/- 2.3 yr (range 5-12 yr) were recruited. Predictive equations for PTT were obtained by multiple regressions with age, vascular path length, BP indexes and heart rate. These derived equations were compared in their PWV equivalent against two previously reported equations and significant agreement was obtained (p < 0.05). Findings herein also suggested that PTT can be useful as a continuous surrogate BP monitor in children.

Age-related factors that confound peripheral pulse timing characteristics in Caucasian children

Characteristics obtained from peripheral pulses can be used to assess the status of cardiovascular system of subjects. However, nonintrusive techniques are preferred when prolonged monitoring is required for their comfort. Pulse transit time ( PTT) measurement has showed its potentials to monitor timing changes in peripheral pulse in cardiovascular and respiratory studies. In children, the common peripheries used for these studies are fingers or toes. Presently, there is no known study conducted on children to investigate the possible physiologic parameters that can confound PTT measure at these sites. In this study, PTT values from both peripheral sites were recorded from 55 healthy Caucasian children ( 39 male) with mean age of 8.4 +/- 2.3 years ( range 5 - 12 years). Peripheries' path length, heart rate, systolic blood pressure, diastolic blood pressure ( DBP) and mean arterial pressure ( MAP) were measured to investigate their contributions to PTT measurement. The results reveal that PTT is significantly related to all parameters ( P< 0.05), except for DBP and MAP. Age is observed to be the dominant factor that affects PTT at both peripheries in a child. Regression equations for PTT were derived for measuring from a finger and toe, ( 6.09 age + 189.2) ms and ( 6.70 age + 243.0) ms, respectively.

Testing the reliability of a new ultrasonic cardiac output monitor, the USCOM, by using aortic flowprobes in anesthetized dogs

We have used an animal model to test the reliability of a new portable continuous-wave Doppler ultrasonic cardiac output monitor, the USCOM. In six anesthetized dogs, cardiac output was measured with a high-precision transit time ultrasonic flowprobe placed on the ascending aorta. The dogs' cardiac output was increased with a dopamine infusion (0-15 mug (.) kg(-1) (.) min(-1)). Simultaneous flowprobe and USCOM cardiac output measurements were made. Up to 64 pairs of readings were collected from each dog. Data were compared by using the Bland and Altman plot method and Lin's concordance correlation coefficient. A total of 319 sets of paired readings were collected. The mean (+/-SD) cardiac output was 2.62 +/- 1.04 L/min, and readings ranged from 0.79 to 5.73 L/min. The mean bias between the 2 sets of readings was -0.01 L/min, with limits of agreement (95% confidence intervals) of -0.34 to 0.31 L/min. This represents a 13% error. In five of six dogs, there was a high degree of concordance, or agreement, between the 2 methods, with coefficients >0.9. The USCOM provided reliable measurements of cardiac output over a wide range of values. Clinical trials are needed to validate the device in humans.

Screening of obstructive and central apnoea/hypopnoea in children using variability: A preliminary study

Aim: Polysomnography (PSG) is the current standard protocol for sleep disordered breathing (SDB) investigation in children. Presently, there are limited reliable screening tests for both central (CE) and obstructive (OE) respiratory events. This study compared three indices, derived from pulse oximetry and electrocardiogram ( ECG), with the PSG gold standard. These indices were heart rate (HR) variability, arterial blood oxygen de-saturation (SaO(2)) and pulse transit time (PTT). Methods: 15 children (12 male) from routine PSG studies were recruited (aged 3 - 14 years). The characteristics of the three indices were based on known criteria for respiratory events (RPE). Their estimation singly and in combination was evaluated with simultaneous scored PSG recordings. Results: 215 RPE and 215 tidal breathing events were analysed. For OE, the obtained sensitivity was HR (0.703), SaO(2) (0.047), PTT (0.750), considering all three indices (0) and either of the indices (0.828) while specificity was (0.891), (0.938), (0.922), (0.953) and (0.859) respectively. For CE, the sensitivity was HR (0.715), SaO(2) (0.278), PTT (0.662), considering all indices (0.040) and either of the indices (0.868) while specificity was (0.815), (0.954), (0.901), (0.960) and (0.762) accordingly. Conclusions: Preliminary findings herein suggest that the later combination of these non-invasive indices to be a promising screening method of SDB in children.

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis

Objectives: The antiinflammatory effect of macrolide antibiotics has been well-established, as has their role in the treatment of certain disorders of chronic airway inflammation. Several studies have suggested that long-term, low-dose macrolides may be efficacious in the treatment of chronic rhinosinusitis; however, these studies have lacked a control group. To date, this effect has not been tested in a randomized, placebo-controlled study. Method: The authors conducted a double-blind, randomized, placebo-controlled clinical trial on 64 patients with chronic rhinosinusitis. Subjects received either 150 mg roxithromycin daily for 3 months or placebo. Outcome measures included the Sinonasal Outcome Test-20 (SNOT-20), measurements of peak nasal inspiratory flow, saccharine transit time, olfactory function, nasal endoscopic scoring, and nasal lavage assays for interleukin-8, fucose, and a2-macroglobulin. Results. There were statistically significant improvements in SNOT-20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid (P < .05) in the macrolide group. A correlation was noted between improved outcome measures and low IgE levels. No significant improvements were noted for olfactory function, peak nasal inspiratory flow, or lavage levels for fucose and a2-macroglobulin. No improvement in any outcome was noted in the placebo-treated patients. Conclusion: These findings suggest that macrolides may have a beneficial role in the treatment of chronic rhinosinusitis, particularly in patients with low levels of IgE, and supports the in vitro evidence of their antiinflammatory activity. Additional studies are required to assess their place in clinical practice.

Use of regression equation of peripheral pulse timing characteristics to predict hypertension in children

Studies have shown that an increase in arterial stiffening can indicate the presence of cardiovascular diseases like hypertension. Current gold standard in clinical practice is by measuring the blood pressure of patients using a mercury sphygmomanometer. However, the nature of this technique is not suitable for prolonged monitoring. It has been established that pulse wave velocity is a direct measure of arterial stiffening. However, its usefulness is hampered by the absence of techniques to estimate it non-invasively. Pulse transit time (PTT) is a simple and non-intrusive method derived from pulse wave velocity. It has shown its capability in childhood respiratory sleep studies. Recently, regression equations that can predict PTT values for healthy Caucasian children were formulated. However, its usefulness to identify hypertensive children based on mean PTT values has not been investigated. This was a continual study where 3 more Caucasian male children with known clinical hypertension were recruited. Results indicated that the PTT predictive equations are able to identify hypertensive children from their normal counterparts in a significant manner (p < 0.05). Hence, PTT can be a useful diagnostic tool in identifying hypertension in children and shows potential to be a non-invasive continual monitor for arterial stiffening.

Anemômetro ultrassônico baseado em sensor de distância

In this work we propose the development of an ultrasonic anemometer using distance sensors. The wind is an important tool for studying the dynamics of the atmosphere, changes in climate and agricultural crops meteorological variable. Thus it is necessary advances in studies that provide increasingly characterizing the behavior of the wind. Currently there are several types of anemometers to measure wind speed, among which stands out due to the ultrasonic anemometer accuracy in measurements. But this device has a high cost difficult to use. Therefore, we sought to lower the cost of the ultrasonic anemometer, developing an apparatus capable of measuring wind velocity using distance sensors. In this type of anemometer wind speed is measured based on the transit time of the ultrasonic pulse, in this same distance sensors to space technique measures. Here various assemblies seeking the best configuration which could use the distance sensor to measure wind speed were made. Arrangements bulkhead and separate transducers are examples of worked assemblies that will be detailed in chapter 3. With the measures collected (with and without wind) histograms, which show the distribution of records transit time of the sound wave for each case were generated. Two of the studied configurations show favorable results regarding the use of the distance sensor as the wind speed.

Chlorofluorocarbons, helium, and neon measured on water bottle samples during POLARSTERN cruise ANT-XXII/2 (ISPOL)

During Ice Station POLarstern (ISPOL; R.V. Polarstern cruise ANT XXII/2, November 2004-January 2005), hydrographic and tracer observations were obtained in the western Weddell Sea while drifting closely in front of the Larsen Ice Shelf. These observations indicate recently formed Weddell Sea Bottom Water, which contains significant contributions of glacial melt water in its upper part, and High-Salinity Shelf Water in its lower layer. The formation of this bottom water cannot be related to the known sources in the south, the Filchner-Ronne Ice Shelf. We show that this bottom water is formed in the western Weddell Sea, most likely in interaction with the Larsen C Ice Shelf. By applying an Optimum Multiparameter Analysis (OMP) using temperature, salinity, and noble gas observations (helium isotopes and neon), we obtained mean glacial melt-water fractions of about 0.1% in the bottom water. On sections across the Weddell Gyre farther north, melt-water fractions are still on the order of 0.04%. Using chlorofluorocarbons (CFCs) as age tracers, we deduced a mean transit time between the western source and the bottom water found on the slope toward the north (9±3 years). This transit time is larger and the inferred transport rate is small in comparison to previous findings. But accounting for a loss of the initially formed bottom water volume due to mixing and renewal of Weddell Sea Deep Water, a formation rate of 1.1±0.5 Sv in the western Weddell Sea is plausible. This implies a basal melt rate of 35±19 Gt/year or 0.35±0.19 m/year at the Larsen Ice Shelf. This bottom water is shallow enough that it could leave the Weddell Basin through the gaps in the South Scotia Ridge to supply Antarctic Bottom Water. These findings emphasize the role of the western Weddell Sea in deep- and bottom-water formation, particularly in view of changing environmental conditions due to climate variability, which might induce enhanced melting or even decay of ice shelves.

Development and reliability of a direct access sensor using flip chip on flex technology with anisotropic conductive adhesive

Technological developments in biomedical microsystems are opening up new opportunities to improve healthcare procedures. Swallowable diagnostic sensing capsules are an example of these. In none of the diagnostic sensing capsules, is the sensor’s first level packaging achieved via Flip Chip Over Hole (FCOH) method using Anisotropic Conductive Adhesive (ACA). In a capsule application with direct access sensor (DAS), ACA not only provides the electrical interconnection but simultaneously seals the interconnect area and the underlying electronics. The development showed that the ACA FCOH was a viable option for the DAS interconnection. Adequate adhesive formed a strong joint that withstood a shear stress of 120N/mm2 and a compressive stress of 6N required to secure the final sensor assembly in place before encapsulation. Electrical characterization of the ACA joint in a fluid environment showed that the ACA was saturated with moisture and that the ions in the solution actively contributed to the leakage current, characterized by the varying rate of change of conductance. Long term hygrothermal aging of the ACA joint showed that a thermal strain of 0.004 and a hygroscopic strain of 0.0052 were present and resulted in a fatigue like process. In-vitro tests showed that high temperature and acidity had a deleterious effect of the ACA and its joint. It also showed that the ACA contact joints positioned at around or over 1mm would survive the gastrointestinal (GI) fluids and would be able to provide a reliable contact during the entire 72hr of the GI transit time. A final capsule demonstrator was achieved by successfully integrating the DAS, the battery and the final foldable circuitry into a glycerine capsule. Final capsule soak tests suggested that the silicone encapsulated system could survive the 72hr gut transition.

The effect of metoclopramide in capsule enteroscopy

Clinical utility of prokinetics in capsule endoscopy (CE) is not clearly established. The objective of this prospective, randomized, single-blind, controlled trial was to determine if metoclopramide is useful in CE by increasing the rate of complete enteroscopy. Ninety-five patients referred for CE were randomized to no metoclopramide (group B, n = 48) or 10 mg metoclopramide (group A, n = 47). Complete enteroscopy was possible in 38 patients of group A (80.9%) and 37 of group B (77.1%) (P = 0.422) with two cases of gastric retention in group B (4.2%; P = 0.253). Median gastric transit time was 26 min (1-211) in group A and 28 min (4-200) in group B (P = 0.511). Mean small bowel transit time, calculated after excluding 20 patients with incomplete enteroscopy, was similar in both groups (221.2 +/- 89 min vs. 256 +/- 82.2 min; P = 0.083). There were also no differences in the total number of findings (group A 4.5 +/- 4.7; group B 4.7 +/- 3.7, P = 0.815). Administration of 10 mg metoclopramide orally 15 min before capsule ingestion did not significantly increase the rate of total enteroscopies and had no effect on transit times. It also did not modify CE diagnostic yield.

Effectiveness of inulin intake on indicators of chronic constipation; a meta-analysis of controlled randomized clinical trials

Background: Constipation is an intestinal dysfunction. Prebiotics, such as inulin, can improve bowel function by positively influencing intestinal biota. Aim: To analyze the scientific evidence for the role of inulin in improving bowel function in patients with chronic constipation. Methods: A meta-analysis of randomized controlled clinical trials was conducted, grounded on a literature search for the period 1995-2013 (descriptors: inulin & constipation) on PubMed, ScieLo and Central Trials Register Cochrane databases. A total of 24 articles were found, 5 of them were selected for this meta-analysis, involving 252 subjects (experimental group: n = 144, control group: n = 108). The quality of the studies was assessed using the Jadad scale. Results: We found a significant overall effect of inulin on stool frequency (DEM = 0.69, 95%CI: 0.04, 1.34), stool consistency (Bristol scale) (DEM = 1.07, 95% CI: 0.70, 1.45), transit time (DEM = -0.57, 95% CI: -0.99, -0.15) and hardness of stool (RR = 0.42, 95% CI: 0.26, 0.70). Pain and bloating do not improve with inulin intake. Conclusions: inulin intake has a positive effect on bowel function.

Developing an index of dietary estimation of fermentable carbohydrate to allow dietary analysis for epidemiological studies

It has been proposed that long-term consumption of diets rich in non-digestible carbohydrates (NDCs), such as cereals, fruit and vegetables might protect against several chronic diseases, however, it has been difficult to fully establish their impact on health in epidemiology studies. The wide range properties of the different NDCs may dilution their impact when they are combined in one category for statistical comparisons in correlations or multivariate analysis. Several mechanisms have been suggested to explain the protective effects of NDCs, including increased stool bulk, dilution of carcinogens in the colonic lumen, reduced transit time, lowering pH, and bacterial fermentation to short chain fatty acids (SCFA) in the colon. However, it is very difficult to measure SCFA in humans in vivo with any accuracy, so epidemiological studies on the impact of SCFA are not feasible. Most studies use dietary fibre (DF) or Non-Starch Polysaccharides (NSP) intake to estimate the levels, but not all fibres or NSP are equally fermentable. It has been proposed that long-term consumption of diets rich in non-digestible carbohydrates (NDCs), such as cereals, fruit and vegetables might protect against several chronic diseases, however, it has been difficult to fully establish their impact on health in epidemiology studies. The wide range properties of the different NDCs may dilution their impact when they are combined in one category for statistical comparisons in correlations or multivariate analysis. Several mechanisms have been suggested to explain the protective effects of NDCs, including increased stool bulk, dilution of carcinogens in the colonic lumen, reduced transit time, lowering pH, and bacterial fermentation to short chain fatty acids (SCFA) in the colon. However, it is very difficult to measure SCFA in humans in vivo with any accuracy, so epidemiological studies on the impact of SCFA are not feasible. Most studies use dietary fibre (DF) or Non-Starch Polysaccharides (NSP) intake to estimate the levels, but not all fibres or NSP are equally fermentable. The first aim of this thesis was the development of the equations used to estimate the amount of FC that reaches the human colon and is fermented fully to SCFA by the colonic bacteria. Therefore, several studies were examined for evidence to determine the different percentages of each type of NDCs that should be included in the final model, based on how much NDCs entered the colon intact and also to what extent they were fermented to SCFA in vivo. Our model equations are FC-DF or NSP$ 1: 100 % Soluble + 10 % insoluble + 100 % NDOs¥ + 5 % TS** FC-DF or NSP 2: 100 % Soluble + 50 % insoluble + 100 % NDOs + 5 % TS FC-DF* or NSP 3: 100 % Soluble + 10 % insoluble + 100 % NDOs + 10 % TS FC-DF or NSP 4: 100 % Soluble + 50 % insoluble + 100 % NDOs + 10 % TS *DF: Dietary fibre; **TS: Total starch; $NSP: non-starch polysaccharide; ¥NDOs: non-digestible oligosaccharide The second study of this thesis aimed to examine all four predicted FC-DF and FC-NSP equations developed, to estimate FC from dietary records against urinary colonic NDCs fermentation biomarkers. The main finding of a cross-sectional comparison of habitual diet with urinary excretion of SCFA products, showed weak but significant correlation between the 24 h urinary excretion of SCFA and acetate with the estimated FC-DF 4 and FC-NSP 4 when considering all of the study participants (n = 122). Similar correlations were observed with the data for valid participants (n = 78). It was also observed that FC-DF and FC-NSP had positive correlations with 24 h urinary acetate and SCFA compared with DF and NSP alone. Hence, it could be hypothesised that using the developed index to estimate FC in the diet form dietary records, might predict SCFA production in the colon in vivo in humans. The next study in this thesis aimed to validate the FC equations developed using in vitro models of small intestinal digestion and human colon fermentation. The main findings in these in vitro studies were that there were several strong agreements between the amounts of SCFA produced after actual in vitro fermentation of single fibre and different mixtures of NDCs, and those predicted by the estimated FC from our developed equation FC-DF 4. These results which demonstrated a strong relationship between SCFA production in vitro from a range of fermentations of single fibres and mixtures of NDCs and that from the predicted FC equation, support the use of the FC equation for estimation of FC from dietary records. Therefore, we can conclude that the newly developed predicted equations have been deemed a valid and practical tool to assess SCFA productions for in vitro fermentation.