Pneumatic interactive gait rehabilitation orthosis: design and preliminary testing.

Motor rehabilitation techniques based on passive movement of the lower limbs have been developed over the past 15 years. Gait training automation is the latest innovation in these techniques. This paper describes the design and development of a pneumatic interactive gait rehabilitation orthosis (PIGRO), as well as the first experimental results obtained with healthy subjects. PIGRO consists of a modular and size-adaptable exoskeleton, pneumatic actuation systems for the six actuated degrees of freedom (DoF), and a control unit. The foot orthosis and ankle actuation can be removed and/or replaced with orthopaedic shoes so as to permit gait rehabilitation while advancing between parallel bars with ground contact and partial body weight support (i.e. not walking in place). Control logic provides closed-loop position control independently on each joint, with position feedback for each joint in real time. Imposed curves are physiological joint angles: it is also possible to choose between activating one or both legs and to modify curves to obtain different gait patterns if required. The paper concludes with a presentation of experimental results for the device's performance.

Assessment of the hepatic circulation in humans: new concepts based on evidence derived from a D-sorbitol clearance method.

D-Sorbitol (SOR) is safe, is easy to measure, and has an exceptionally high extraction ratio in the normal liver of 0.93+/-0.05 (mean+/-SD). Together with the general interest in hepatic hemodynamics, these facts motivated us to review the usefulness of this compound for the assessment of liver plasma flow in humans. We concluded that in subjects without liver disease the nonrenal clearance of SOR-measured noninvasively-very closely approximates hepatic plasma flow. Because of its lower and more variable extraction ratio, indocyanine green should no longer be used without hepatic vein catheterization. Even in patients with cirrhosis, SOR exhibits higher hepatic extraction ratios than indocyanine green. To fully explore the potential of SOR in the evaluation of such patients attention needs to be paid to the complex changes in architecture and function occurring in this disease. In cirrhotics the noninvasively measured nonrenal clearance of SOR presumably approximates the flow through intact and capillarized sinusoids (functional flow) and reflects the amount of blood having functional contact with hepatocytes. The theoretic background of the method, its accuracy, further research needs, and potentials of various approaches are discussed in detail.

Dynamic behavior of the Provox and Staffieri prostheses for voice rehabilitation following total laryngectomy.

The present study evaluated the differences in aerodynamic behavior between the 1990 Provox and 1986 Staffieri voice prostheses for total laryngectomy patients. Both prostheses were submitted to in vitro laboratory testing to assess their aerodynamic behavior under different conditions of air flow through the valve and tracheal side pressure. In addition, six patients using the Provox and another six using the Staffieri prostheses were submitted to a dynamic study of phonation. This latter study evaluated the intratracheal pressure corresponding to the different intensities at which the vowel sound /a/ was pronounced. In vitro measurements revealed significant differences between the two prostheses, with the best results achieved with Provox. In contrast, the in vivo measurements did not reveal any significant differences between the two groups of patients in the 50-79 dBSPL range, although there was some difference at intensities equal to or greater than 80 dBSPL. Again, in this latter case the best results were achieved with the Provox. However, the ideal prosthesis has yet to be found. In some patients, the so-called low-resistance prostheses fail to maintain their aerodynamic performances, most likely because anatomic resistors interfere with the effort (i.e., pressure) required to produce a voice. At present the choice of prosthesis is best determined on an individual patient-to-patient basis.

Staffieri tracheo-oesophageal prosthesis for voice rehabilitation after laryngectomy: an evaluation of characteristics.

Experimental results on voice prostheses used for the rehabilitation of patients that have lost their vocal function after total laryngectomy are presented. The purpose is to evaluate the difference in aerodynamic behaviour between Staffieri voice prosthesis and other commercial valves (Groningen standard, Groningen low pressure, Panje, Provox). Two different equipments for flow-rate measurement were designed and built to compare the performance of the valves. The valves have been experimentally tested under different conditions of airflow through the valve and tracheal side pressure. The data allow calculation of the airflow resistance, the parameter usually used to compare the performance of valves. The valves have also been experimentally tested under different conditions of fluid flow through the valve and oesophageal side pressure (reverse flow). Comparing the airflow resistance of Staffieri valves of different length L and different angular extension of the razor-thin silt alpha, it has been observed that the parameter alpha has a significant influence on the characteristics, while the effect of the length L is negligible. The airflow resistance of the Provox, Groningen low pressure and Staffieri alpha = 270 degrees valves are comparable; the Panje and Staffieri alpha = 180 degrees have similar behaviour; while the Groningen Standard is comparable to the Staffieri alpha = 90 degrees. Regarding reverse flow, it is pointed out that for most of the valves (Staffieri and commercial valves), at different oesophageal pressures the fluid flow is smaller than the flow that can be tolerated by patients without giving problems.

[General anesthesia without nitrogen monoxide. Its use in abdominal surgery]. / Anestesia generale senza protossido d'azoto. Impiego in chirurgia addominale.

In view of the problems relating to the routine use of nitrogen monoxide in general anesthesia, the authors drew up an anesthesiological protocol excluding the use of N2O and replacing its analgesic effect with higher doses of fentanyl and a higher inspired percentage of isoflurane. Twenty-three patients due to undergo abdominal surgery were included in the study. The established anesthetic protocol was evaluated by the constant measurement of PAOS/D and heart rate, as well as lacrimation and sweating. Satisfactory results were achieved using this protocol in almost all patients, although further modifications to the protocol are planned to make the technique more stable and manageable.

[Subarachnoid anesthesia and peridural anesthesia: which are the causes of total failure? A clinical case]. / Anestesia sub-aracnoidea e anestesia peridurale: quali le cause di un completo insuccesso? Caso clinico.

The paper reports the case of patient undergoing cystoscopy and subsequently radical cystectomy suffering from BPCO and pulmonary emphysema who received sub-arachnoid anesthesia during the first operation and peridural anesthesia during the second, with total failure both times. The techniques were correctly performed and on both occasions it was necessary to resort to general anesthesia in order to perform the operation.

SEQUAL: an interactive computer program for sequential classification of biomedical data.

A computer program for sequential bayesian classification of patterns defined by integer and real-valued data is described. Classified patterns from a training sample are used to estimate the non-parametric (kernel) probability density functions and the a-priori class probabilities necessary to implement the bayesian classification. For each pattern and at each step in the sequential program, the 'best' feature to be measured at the next step is computed on the basis of the estimated misallocation error rate. The user can actually use the proposed feature or any other one; once the chosen feature has been measured, its value is used to allocate the pattern into the class with the highest conditional a-posteriori probability, according to the Bayes formula. The main feature of the program consists in the computation of the 'probability of reversal' at each step of the sequential procedure. The probability of reversal represents the probability that at the next step the pattern will be classified into a class different from the present one. The probability of reversal can be used as a stopping criterion, which is more efficient than other commonly used stopping rules, such as the a-posteriori Bayes probability or the estimated misallocation error rate. The program, available in FORTRAN 77 for a VAX/VMS machine, has been tested both on simulated and real data collected from patients suffering from various forms of hepatic disease.

Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model.

The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.

Simulation of the metabolism and enterohepatic circulation of endogenous deoxycholic acid in humans using a physiologic pharmacokinetic model for bile acid metabolism.

The metabolism and enterohepatic circulation of deoxycholic acid (DCA), a major secondary bile acid in humans, was simulated using a linear multicompartmental physiologic pharmacokinetic model. The model was similar to that previously reported and used to simulate the metabolism of cholic acid and chenodeoxycholic acid, but differed in two respects: (a) the input of newly formed DCA molecules originated from colonic absorption rather than from de novo hepatic biosynthesis and (b) a new type of transfer coefficient was proposed to describe the movement of DCA molecules from an insoluble, bound compartment to a soluble compartment. Simulations were performed to define the effect of varying fractional colonic absorption (from 0.1 to 0.6) as well as varying fractional formation of DCA from cholic acid (from 0.3 to 1). The simulations indicated that the exchangeable total DCA pool expanded up to 12-fold as fractional colonic absorption was increased from 0.1 to 0.6. The fractional turnover rate of the DCA pool showed a corresponding decrease. Increased conversion of cholic acid to DCA had an effect on DCA pool size that was similar to that resulting from increased colonic fractional absorption. So long as ileal absorption was efficient, the "soluble" colonic pool of DCA remained small relative to other organ pools, and the absorption of unconjugated DCA from the colon was less than 10% of the total DCA absorption from the ileum. It is proposed that the relatively large proportion of DCA in the biliary bile acids of white adults in the Western world as compared with that of most other mammals is attributable to (a) a high fractional absorption of DCA because of a diet relatively low in fiber, (b) the absence of hepatic 7-hydroxylation of DCA, and (c) effective competition by DCA conjugates for active transport by the terminal ileum.

Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model.

The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine 'spaces' based on anatomical and physiological considerations (liver, gall-bladder, bile ducts, duodeno-jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartment's contents exiting per unit time, are categorized according to function: flow, for example gall-bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time-dependent by incorporating meals which trigger gall-bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno-jejunum and the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24-h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.

Sorbitol clearance: a parameter reflecting liver plasma flow in the rat.

According to the clearance concepts, the functional liver plasma flow may be directly measured from the plasma kinetics of any substance whose hepatic intrinsic clearance largely exceeds liver perfusion. The present study was designed to ascertain the requirements for the reliability of D-sorbitol plasma clearance in evaluating changes of liver perfusion in the male Wistar rat. The plasma disappearance curve of D-sorbitol (3 mg/100 g b.w. by bolus i.v. injection) followed a first order kinetics and fitted a two-compartment model. Very similar estimates of D-sorbitol plasma clearance were obtained by applying the area under the curve method to data obtained by the trapezoidal rule and by compartmental analysis. D-sorbitol hepatic extraction was almost complete in controls and in rats submitted to porta-caval shunt and hepatic artery ligation, while significantly decreased after partial hepatectomy. Renal output never exceeded 10% of the administered amount. No in-vivo diffusion into red cells was observed. In controls, the functional liver plasma flow, as measured by D-sorbitol clearance was 2.83 +/- 0.68 ml/min/100 g (mean +/- SD). Significantly lower values were found in rats submitted to porta-caval shunt (1.19 +/- 0.38), hepatic artery ligation (2.06 +/- 0.53), and partial hepatectomy (1.03 +/- 0.44).

Should blood transport kinetics be modeled in metabolic processes?

We analyze the interaction between blood transport phenomena and uptake processes when drug kinetics are studied with compartmental models. Relevant advantages in the physiological interpretation of the model parameters are obtained when blood transport is explicitly included in the model. This is done by aggregating into a single compartment all the blood spaces where no exchange with extravascular spaces takes place and separating into different blood compartments those spaces where some uptake and/or return occurs. The proposed strategy extensively uses all available a priori information about the physiological system, instead of considering only the information available in the measurements. This modeling approach has three main advantages: it provides greater insight into the identified quantities; it allows the introduction of quantitative a priori information; and it facilitates the experiment design task.

Advanced modeling and identification techniques for metabolic processes.

This paper will be devoted to demonstrating that a better understanding of complex metabolic processes requires a deep and reliable interpretation of much experimental data. Indeed this aim cannot be satisfied without the use of advanced modeling and identification techniques and their deep critical analysis. In fact, complete procedures should consider all the following steps: (1) definition of scopes, (2) prior information and hypotheses, (3) choice of experimental conditions, (4) derivation of possible classes of models, (5) parameter estimation, (6) errors evaluation, (7) validation and ordering of the identified models. This paper will mainly consider steps 4, 6, and 7 which are certainly the less assessed ones. However some real advances have been obtained in recent years which deserve to be more widely known and applied in practical problems. This paper will review such important contributions and will show, by means of applied examples, how they can be useful in avoiding ambiguities and incorrect interpretation of data and in evaluating the credibility of the inferred results.

Qualitative and quantitative evaluation of liver diseases: functional classifications.

The problem of the best use of experimental data for qualitative and quantitative evaluation of liver disfunction is analysed. Only statistical procedures for classification are considered. Emphasis is placed on a complete description of the most important steps that must be performed (degree of clustering of the data, validity of the hypotheses underlying the statistical methods used, meaning and adequate use of the reference classification, reliability of the different statistical methods used, information content of the laboratory tests studied) since the omission of any of them may contribute to a misleading interpretation of the overall results or may prevent significant practical utilization. An application to BSP tests is carried out: results obtained from 350 subjects are presented and discussed. A classification related to the main functional aspects of liver impairment was chosen. Different combinations of the parameters obtained from BSP blood disappearance curve--initial disappearance rate (K1), 45 min-retention of total (RT45) and conjugated (RC45) BSP- and different mathematical algorithms are compared. Five classes (N, normal subjects; PN, paranormal subjects; H, prevalent hepatocellular damage; C, prevalent cholestatic damage; HC, heavy combined damages) can be satisfactorily discriminated with all three parameters (K1 + RT45 + RC45); however K1 + RC45 give almost the same results and represent an interesting compromise between data information content and laboratory complexity.

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered by drugs or disease. The model can be extended to describe completely the metabolism and enterohepatic circulation of any bile acids in man in health and digestive disease. The model should also be broadly applicable to the description of the pharmacokinetics of all other drugs whose metabolism is similar to that of bile acids, i.e., drugs for which there are tissue and bacterial biotransformations, enterohepatic cycling, and appreciable first-pass clearance.