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Biomedical subjects

C Manzoni

Publications and source records attributed to C Manzoni.

At least 19 recordsLinked to original sources
PubMed2001

Piperazine-like compounds: a new group of designer drugs-of-abuse on the European market.

1-Aryl-piperazine compounds are, depending on their substituents, selective for certain serotonin receptors and together with their easy availability and their so-called legal status, this group of psychoactive compounds are potential designer drugs-of-abuse. Internet in that respect is an important source of information and distribution facilities. Because this development may have consequences for the interpretation of future clinical and forensic toxicological case studies, some analytical aspects of 1-benzyl-piperazine (BZP), 1-[4-methoxyphenyl]-piperazine (pMeOPP) and 1-[3-trifluoromethylphenyl]-piperazine (TFMPP) were studied. BZP was not detected by the AxSYM FPIA technology designed to determine amphetamine-like compounds, but had showed some cross reactivity with EMIT d.a.u.. The cross reactivities at 300 and 12,000ng/ml (RS)-amphetamine equivalents were 0.4 and 1.3%, respectively. Although BZP was not identified directly by the REMEDi HS Drug Profiling System, it can be detected by this HPLC/UV scanning system. Using GC/NPD without derivatisation, BZP, pMeOPP and TFMPP can be analysed for and applying GC/MS without or with acetylation or trifluoroacetylation, these compounds can be identified unambiguously. The usefulness of GC/NPD and GC/MS in this respect was demonstrated by the quantitative and qualitative analysis of the content of a capsule with the synthetic stimulant A2, which proved to contain 86.4mg of BZP.

Chromatography, High Pressure Liquid↗
PubMed2001

Mapping and fitting the peripheral benzodiazepine receptor binding site by carboxamide derivatives. Comparison of different approaches to quantitative ligand-receptor interaction modeling.

The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910-2921) has been extended. A series of carboxamide derivatives endowed with differently substituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the carbonyl and aromatic moieties for interaction with the PBR binding site. The synthesis of most of these compounds involves Weinreb amidation of the appropriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PBR affinity similar to that shown by 1 and the presence of a basic N-ethyl-N-benzylaminomethyl group in 3-position of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational methods were used to furnish descriptors of the isolated ligands (indirect approaches) able to rationalize the variation in the binding affinity of the enlarged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributions to ligand-receptor interactions. Molecular descriptors which explicitly account for the electrostatic contribution to the interaction (CoMFA, CoMSIA, and surface approaches) perform well, but they do not improve the quantitative models. Moreover, useful hints for the identification of the antagonist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmacophoric approach. The ligand-receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestions for further experiments.

Amino Acid Sequence↗
PubMed2001

Contrast-enhanced gray-scale and color Doppler voiding urosonography versus voiding cystourethrography in the diagnosis and grading of vesicoureteral reflux.

PURPOSE: The purpose of this study was to compare contrast-enhanced gray-scale voiding urosonography (CE-VUS) and contrast-enhanced color Doppler voiding urosonography (CE-CDVUS) with voiding cystourethrography (VCUG) to verify whether the use of color Doppler imaging improves the diagnosis and grading of vesicoureteral reflux (VUR). METHODS: In 74 patients, CE-VUS and CE-CDVUS were compared with VCUG, which was used as the gold standard. SHU 508 A (Levovist) was used as the echo-enhancing contrast agent. VUR was diagnosed if hyperechoic dots or color signals were visualized in the ureter on sonograms. VUR grading was based on morphologic and dynamic findings on CE-VUS and morphologic and color findings on CE-CDVUS. VCUG was performed conventionally, and grading by VCUG was in accordance with the international system of radiographic VUR grading. Patients who voided during 1 examination only (either CE-VUS and CE-CDVUS or VCUG) were excluded from the study. Agreement between the results of CE-VUS and VCUG and between those of CE-CDVUS and VCUG in diagnosing VUR was calculated by kappa statistics. CE-VUS and CE-CDVUS were compared for diagnostic accuracy by the McNemar test. RESULTS: The agreement between CE-VUS and VCUG in predicting VUR was 90% (kappa score, 0.77; p < 0.001). The agreement between CE-CDVUS and VCUG was 96% (kappa score, 0.91; p < 0.001). CE-CDVUS showed a significantly higher diagnostic accuracy than did CE-VUS (96% versus 90% of cases correctly classified; McNemar chi2 = 4; p < 0.05). This was mainly related to the lower number of false-negative results for grade I and grade II VUR when CE-CDVUS was used. CONCLUSIONS: The use of color Doppler imaging significantly improves the accuracy of contrast voiding urosonography in the detection and grading of VUR.

Adolescent↗
PubMed2001

An original technique for bladder autoaugmentation with protective abdominal rectus muscle flaps: an experimental study in rats.

BACKGROUND: Bladder autoaugmentation uses partial detrusorectomy to create a diverticular bulge in the bladder mucosa. This technique has eliminated certain serious complications of cystoplasty with gastrointestinal tissues (e.g., fluid/electrolyte/acid-base imbalances, mucous hypersecretion), but the exposed mucosa is subject to fibrosis and, sometimes, to perforation, which can annul the benefits of surgery. METHODS: We have developed an original technique based on traditional autoaugmentation with protection of the herniated mucosa by split-thickness pedunculated rectus abdominis muscle flaps that are sutured to the incised margins of the detrusor. Preliminary testing was done on 30 adult Wistar rats. A control group of 15 rats underwent laparotomy alone. Bladder capacity was measured via suprapubic cystography before and after (4 weeks, 8 weeks, 1 year) surgery, just before sacrifice. Sections of the reconstructed bladder were examined histologically. RESULTS: Twenty-three bladder-augmented rats and 13 controls survived. In the experimental group, bladder capacity increased by 38% (mean). None of the rats experienced urinary retention, although one developed bladder stones. Histology revealed no pathologic changes (other than chronic inflammatory infiltrates at suture sites) in the mucosa, detrusor, or muscle flaps, which were all viable and well integrated by the fourth postoperative week. There were no signs of mucosal or muscle fibrosis. CONCLUSIONS: Preliminary results in a rat model suggest that this new technique can produce an enlarged bladder that is fully functional and less vulnerable to fibrotic retraction and rupture. Residual contractility in the muscle flaps might theoretically be exploited to facilitate paraphysiologic micturition.

Abdominal Muscles↗
PubMed2001

Varicocele in pediatric patients: comparative assessment of different therapeutic approaches.

OBJECTIVES: The best therapeutic approach for varicocele correction in pediatric patients is still an object of some debate. We analyzed a series of 99 patients to identify the most effective approach in terms of low recurrence rates and preservation of testicular growth. METHODS: One hundred four operations were performed on 99 patients between 9 and 16 years of age (mean 13.3). The first 18 patients underwent sclerotherapy of the internal spermatic vein. Twenty others underwent inguinal varicocelectomy. In 12 patients, a modified Palomo procedure (ie, sparing of the internal spermatic artery) was performed (four laparoscopically), and 54 were treated with the original Palomo procedure (ie, sectioning of the entire spermatic cord), using laparoscopy in 20. RESULTS: Three recurrences (16.6%) occurred among the patients treated with sclerotherapy. Similar rates of recurrence were observed in those who underwent inguinal varicocelectomy (3 [15%] of 20) and modified Palomo procedures (2 [16.6%] of 12). Only one recurrence occurred in the 54 patients treated with the original Palomo procedure (1.85%). CONCLUSIONS: Our experience, together with a review of published reports, leads us to believe that the open Palomo procedure as originally described is the most effective approach to the correction of varicoceles in adolescents.

Adolescent↗
PubMed2001

How to determine ionic dialysance for the online assessment of delivered dialysis dose.

BACKGROUND: Ionic dialysance may be equivalent to blood-water urea clearance corrected for recirculation (effective urea clearance); however, this is controversial. The aims of our study were (1) to verify in vivo whether the value of ionic dialysance is affected by the method of determination, given the effect of cardiopulmonary recirculation on inlet plasma water conductivity when the inlet dialysate conductivity is changed; and (2) to define the operative modalities for determining ionic dialysance to obtain an adequate estimate of effective urea clearance. METHODS: Thirty-three hemodialysis patients were studied during 186 dialysis sessions with low-flux polysulfone dialyzers using a modified Fresenius Medical Care 4008 B machine equipped with meters to measure inlet and outlet dialysate conductivities. This machine varied inlet dialysate conductivity (Cdi) according to the following pattern: starting from baseline (step 0), Cdi was increased by 8% (step 1). After Cdi had reached the target value, which took 8 to 10 minutes, it was lowered to 8% below the baseline value (step 2). After 8 to 10 minutes, when Cdi had reached the new target, it was returned to its starting value (step 3). Four values of conventional ionic dialysance (using the standard formula) and actual ionic dialysance (taking into account cardiopulmonary recirculation) were obtained for each cycle and were compared among them and with effective urea clearance (Kde). RESULTS: Mean conventional dialysance values at steps 0 to 2 and 2 to 3 (190 and 189 mL/min) were similar and higher than those at steps 0 to 1 and 1 to 2 (171 and 181 mL/min). Mean conventional ionic dialysance values underestimated Kde, particularly at steps 0 to 1 (-22.2 mL/min, P < 0.001) and 1 to 2 (-12.6 mL/min, P < 0.001). The actual dialysance values underestimated Kde by no more than 4.3 mL/min (P < 0.001). In steps 0 to 1 and 1 to 2, the underestimate of Kde by conventional dialysance increased at higher values of Kde, but this relationship did not exist when considering actual dialysance. CONCLUSIONS: The value of ionic dialysance is affected by the method of determination, given the effect of cardiopulmonary recirculation on inlet plasma water conductivity when inlet dialysate conductivity is changed. As a consequence, to provide a correct and direct estimate of effective urea clearance, ionic dialysance must be determined by changing inlet dialysate conductivity in such a way as to keep inlet plasma water conductivity constant by means of two symmetrical high and low dialysate conductivity steps.

Dialysis Solutions↗
PubMed2001

Dry weight and sodium balance.

To achieve good blood pressure control and minimal intradialytic patient discomfort, it is very important to define the correct dry weight and individualize the "adequate" dialysate sodium concentration. Given the highly variable amounts of sodium introduced during interdialytic periods, the use of the sodium and conductivity kinetic models guarantees adequate sodium removal in each patient with each treatment. According to our data, the imprecision of the sodium kinetic model was less than 0.84 mEq/L; that of the conductivity kinetic model, which has the advantage not requiring blood or dialysate samples, was less than 0.14 mS/cm. In paired filtration dialysis (PFD), the corresponding figures were less than 1.1 mEq/L and less than 0.1 mS/cm. A multicenter prospective, controlled and randomized trial has demonstrated that the application of the conductivity kinetic model in PFD makes it possible to improve cardiovascular stability in patients prone to dialysis hypotension. The sodium kinetic model is difficult to apply in routine clinical practice because of the need for blood and dialysate samples, but this may be overcome by the conductivity kinetic model, which is a very promising tool for achieving a zero intradialytic sodium balance and improving cardiovascular stability.

Blood Pressure↗
PubMed2000

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.

BACKGROUND: Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. METHODS: We studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. RESULTS: All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. CONCLUSIONS: Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Adolescent↗
PubMed2000

Relevance of the conductivity kinetic model in the control of sodium pool.

Changes in the body sodium pool caused by dialytic treatment have very important clinical implications, mainly in terms of intradialytic cardiovascular instability and interdialytic hyperhydration and hypertension with long-term cardiac hypertrophy and dilation. A kinetic model could be helpful in order to define the dialysate sodium concentration needed to match intradialytic hydrosodium removal with interdialytic sodium and water intake, but unfortunately, none of the sodium kinetic models are suitable for routine clinical application. Two conductivity kinetic models (one for hemodialysis and one for paired filtration dialysis) have been developed on the basis of the linear relationship between the sodium content and conductivity of every saline solution and plasma water and according to basic theory for ionic dialysance determination. These models make it possible to know at the start of each session the dialysate conductivity needed to obtain the desired final plasma water conductivity or to know the latter when the former is known. Clinical evaluations showed that conductivity kinetic models are very precise and accurate and may be used instead of sodium kinetic models. Furthermore, they are suitable for routine use because they do not require blood sampling or laboratory determinations. Clinical application of the conductivity kinetic model has shown that the reduced variability of end-dialysis plasma water conductivity obtained when using the model to identify dialysate conductivity significantly reduces cardiovascular instability, even without any changes in average sodium removal. Given that ionic dialysance can be easily, inexpensively, and repeatedly measured at each dialysis session, it seems realistic to expect that conductivity kinetic modeling will soon become a part of everyday clinical practice.

Blood Pressure↗
PubMed2000

Soy protein peptides regulate cholesterol homeostasis in Hep G2 cells.

The activation of LDL receptors was described recently in a human hepatoma cell line (Hep G2) exposed both to alpha + alpha' subunits from 7S soy globulin and to Croksoy(R)70, a commercial isoflavone-poor soy concentrate. To assess the final identity of the peptide(s) putatively responsible for the biochemical effect, experiments were performed in Hep G2 cells, exposed either to synthetic peptides corresponding to specific sequences of 7S soy globulin or to peptides from the in vitro digestion of Croksoy(R)70. Moreover, the ability of the whole 7S globulin, its subunits and whole Croksoy(R)70 to interfere in the apolipoprotein B (apo B) secretion in the medium as well as in sterol biosynthesis was evaluated in the same model. Increased (125)I-LDL uptake and degradation vs. controls were shown after Hep G2 incubation with a synthetic peptide (10(-)(4) mol/L, MW 2271 Da) corresponding to positions 127-150 of the 7S globulin. Cells exposed to Croksoy(R)70 enzyme digestion products showed a more marked up-regulation of LDL receptors vs. controls, compared with vs. Hep G2 cells incubated with undigested Croksoy(R)70. Among soy-derived products, only the 7S globulin inhibited apo B secretion and (14)C-acetate incorporation when tested in Hep G2 cells at a concentration of 1.0 g/L. These findings support the hypothesis that if one or more peptides can reach the liver after intestinal digestion, they may elicit a cholesterol-lowering effect. Moreover, the protein moiety, devoid of isoflavone components, is likely to be responsible for this major biochemical effect of soy protein.

Amino Acid Sequence↗
PubMed2000

Removal of small and middle molecules by convective techniques.

The current renewed interest in haemofiltration (HF) is due mainly to its potential advantages in reducing morbidity and mortality. We analysed the data obtained from eight patients treated with pre-dilution HF and compared them with the calculated post-dilution HF and haemodialysis (HD) data in order to quantify the depurative performance of HF and to assess whether its claimed ability to improve cardiovascular stability is at least partially related to less sodium removal. The urea clearance (as a marker of small molecules) of pre-dilution HF was equivalent to that of standard low-flux HD and approximately 20% higher than that of postdilution HF. For a calculated increase of 117% in the dialytic clearance of beta2-microglobulin using high-flux HD, the increase in beta2-microglobulin removal with HF was only 30%. The intradialytic decrease in plasma water beta2-microglobulin concentrations was 73% (vs 53% in HD) followed by a post-dialytic rebound of 85% (vs 42% in HD). The interdialytic concentrations of beta2-microglobulin were always lower. At the start of the subsequent session, the beta2-microglobulin concentrations observed in HF-treated patients were 92% of those in the patients treated with HD. Sodium removal was similar using both HF modalities at the same total dialysate and reinfusate sodium concentrations, and lower than in the case of HD. HF makes it possible to obtain constantly lower plasma water beta2-microglobulin concentrations whose long-term clinical relevance has to be verified. Under usual operational conditions, sodium removal is less with pre-dilution HF than with HD, thus raising some doubts about the intrinsic capacity of HF to improve cardiovascular stability by a mechanism other than less sodium removal.

Hemofiltration↗
PubMed2000

Treatment modalities in comparison: when do clinical differences emerge?

BACKGROUND: Despite technological advances in dialysis equipment and modalities, the survival, morbidity and quality of life of uraemic patients undergoing regular haemodialysis treatment are still severely affected by acute intradialysis and long-term complications, possibly related to the treatment itself. Convective treatment modalities, such as haemodiafiltration and haemofiltration, are thought to be further improvements over standard diffusive haemodialysis. Moreover, several of the pathways activated in patients during dialysis have the potential to produce many side-effects. These occur three times a week, and are particularly intense in patients dialysed with so-called 'bio-incompatible' membranes. Thus the biocompatibility of dialysis membranes is increasingly recognized as one of the main factors in the improvement of dialysis treatment. METHODS: The main clinical studies to date are reviewed to highlight the clinical effects of different treatment modalities and membranes on the most important acute and long-term haemodialysis-related complications. RESULTS: Epidemiological studies suggest that semisynthetic and synthetic membranes may reduce morbidity and mortality in dialysis patients. Despite the proven biological superiority of biocompatible membranes, we lack definitive evidence that thrice-weekly complement and cell activation over a period of years is detrimental to patients, because the results of prospective randomized studies are conflicting. However, it is important to remember that factors other than the dialysis membrane could influence the 'biocompatibility' of dialysis, including the dialysate, dialyser geometry, the distribution of blood in the dialyser, reuse, the sterilizant and materials used in reprocessing. CONCLUSIONS: Further large-scale prospective and randomized trials with a long follow-up are needed in order to better clarify the clinical effect of different treatment modalities on the morbidity and mortality of patients on chronic renal replacement therapy. In particular, it must be clarified whether the possible clinical differences in treatment modalities are based on differences in the clearance of middle molecules or on biocompatibility, or, more generally, on the increasingly recognized clinical importance of high-flux treatments, and the possible interaction between membrane flux and biocompatibility.

Anemia↗
PubMed2000

Blood flow distribution in sorbent beds: analysis of a new sorbent device for hemoperfusion.

A new polymer-based sorbent cartridge has been recently developed for enhancing middle molecule removal during hemodialysis. The cartridge (Betasorb, Renaltech, New York, USA) has been designed to be placed in series with the dialyzer in the blood circuit. It is therefore important to evaluate the distribution of flow into the blood compartment of the device in order to assess if the surface of the sorbent is utilized to the best. For this purpose, a special imaging technique was utilized. Cartridges were analyzed during a simulated in vitro circulation at 250 and 350 ml/min of blood flow and 25% and 40% hematocrit. Cartridges were placed in vertical position and a cross longitudinal section 1 cm thick was analyzed in sequence by a helical scanner. Dye was injected into the arterial inlet and the progressive distribution was evaluated by sequential densitometrical measures carried out automatically by the machine. The sequential images analyzed by the scanner demonstrated excellent distribution of the flow in the blood compartment with minimal difference between the central and the peripheral regions of the compartment. In particular the following flow velocity pattern could be observed under the different experimental conditions tested. We may conclude that the cartridge design is adequate and no channelling effects could be detected in the blood compartment. The flow distribution is slightly affected by changes in flow rate and hematocrit showing an optimal utilization of the available surface for molecule adsorption.

Adsorption↗
PubMed1999

Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice.

We studied ionotropic glutamate receptor subtypes and the effect of chronic treatment with NBQX [6-nitro-7-sulphamoyl-benzo(F)quinoxaline-2,3-dione], a selective (rs)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, in the spinal cord of mnd mice. NBQX (8 mg/kg daily i.p. for 3 weeks starting from 24 weeks old) significantly improved the behavioural scores (hind leg extension reflex, cage rung grasping and gait) in mnd mice, measured after the last drug injection, and increased the number of mice with 'normal' gait (from 50% to 90%, P < 0.05). Receptor binding autoradiography of the competitive N-methyl-D-aspartate (NMDA) antagonist, [3H]CGP 39653, of [3H]AMPA and [3H]kainic acid in spinal cord sections, measured after 1 week of drug washout, were not significantly different in control and mnd mice, and were not modified by NBQX. GluR2/3 immunoreactivity, assessed using Western blotting, was significantly enhanced (by 59%, P < 0.01) in the spinal cord but not in the brain of 28-week-old mnd mice compared to age-matched control mice. NBQX treatment increased GluR2/3 immunoreactivity in the spinal cord of control mice and mnd mice by 327 +/- 74% (P < 0.01) and 212 +/- 52% (P < 0.01), respectively. The changes in GluR2/3 subunits may involve adaptive mechanisms of the receptor and play some role in the protective effect of NBQX. These findings suggest that selective antagonism of ionotropic non-NMDA receptors may be of value in the treatment of motor neuron disease.

2-Amino-5-phosphonovalerate↗
PubMed1999

On-line monitoring and convective treatment modalities: short-term advantages.

BACKGROUND: Despite technological advances in dialysis equipment, the morbidity and quality of life of uraemic patients undergoing regular haemodialytic treatment are still severely affected by acute intradialytic complications possibly related to the treatment itself. Cardiovascular instability still affects >30% of dialytic sessions and, although its pathogenesis is multifactorial, dialysate sodium concentration (and, consequently, intradialytic sodium removal) is one of the main factors affecting intradialytic hypotension. Convective treatment modalities and so-called biocompatible membranes increasingly are recognized as improving acute and particularly chronic dialytic complications because a number of the pathways activated in patients during dialysis with 'bioincompatible' membranes have the potential to produce many side effects. METHODS: The main clinical studies are reviewed to highlight the advantages of on-line monitoring and convective modalities on acute intradialytic symptoms. RESULTS: The conductivity kinetic model has been shown to be a reliable and inexpensive method of matching intradialytic sodium removal and interdialytic load. By applying this model to patients prone to dialysis hypotension, a smaller reduction in intradialytic systolic blood pressure has been observed, without any change in dialysate and reinfusate sodium concentrations or dry body weight. Furthermore, a new model of haemodialysis potassium removal based on a decreasing intradialytic potassium concentration and a constant plasma-dialysate potassium gradient is capable of reducing the arrhythmogenic effect of standard haemodialysis. Despite the proven biological superiority of biocompatible membranes, there is no definitive evidence that membrane biocompatibility and/or flux lead to a decrease in acute intradialytic clinical symptoms. CONCLUSIONS: On-line monitoring of intradialytic sodium removal and the potassium gradient is capable of reducing intradialytic hypotension and the arrhythmogenic effect of haemodialysis, and thus having a considerable clinical impact on acute intradialysis complications. As far as the effects of biocompatibility and/or flux on the incidence of acute intradialytic clinical symptoms are concerned, further trials involving a sicker patient population with higher prevalence of intradialytic hypotension are needed in order to achieve statistical power.

Cardiovascular System↗