Myocardial blood flow in patients with low-flow, low-gradient aortic stenosis: differences between true and pseudo-severe aortic stenosis. Results from the multicentre TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study.

BACKGROUND: Impairment of myocardial flow reserve (MFR) in aortic stenosis (AS) with normal left ventricular function relates to the haemodynamic severity. OBJECTIVES: To investigate whether myocardial blood flow (MBF) and MFR differ in low-flow, low-gradient AS depending on whether there is underlying true-severe AS (TSAS) or pseudo-severe AS (PSAS). METHODS: In 36 patients with low-flow, low-gradient AS, dynamic [13N]ammonia PET perfusion imaging was performed at rest (n = 36) and during dipyridamole stress (n = 20) to quantify MBF and MFR. Dobutamine echocardiography was used to classify patients as TSAS (n = 18) or PSAS (n = 18) based on the indexed projected effective orifice area (EOA) at a normal flow rate of 250 ml/s (EOAI(proj )0.55 cm(2)/m(2)). RESULTS: Compared with healthy controls (n = 14), patients with low-flow, low-gradient AS had higher resting mean (SD) MBF (0.83 (0.21) vs 0.69 (0.09) ml/min/g, p = 0.001), reduced hyperaemic MBF (1.16 (0.31) vs 2.71 (0.50) ml/min/g, p<0.001) and impaired MFR (1.44 (0.44) vs 4.00 (0.91), p<0.001). Resting MBF and MFR correlated with indices of AS severity in low-flow, low-gradient AS with the strongest relationship observed for EOAI(proj) (r(s) = -0.50, p = 0.002 and r(s) = 0.61, p = 0.004, respectively). Compared with PSAS, TSAS had a trend to a higher resting MBF (0.90 (0.19) vs 0.77 (0.21) ml/min/g, p = 0.06), similar hyperaemic MBF (1.16 (0.31) vs 1.17 (0.32) ml/min/g, p = NS), but a significantly smaller MFR (1.19 (0.26) vs 1.76 (0.41), p = 0.003). An MFR <1.8 had an accuracy of 85% for distinguishing TSAS from PSAS. CONCLUSIONS: Low-flow, low-gradient AS is characterised by higher resting MBF and reduced MFR that relates to the AS severity. The degree of MFR impairment differs between TSAS and PSAS and may be of value for distinguishing these entities.

Perception and biomechanics data in a manual handling task: a comparative study.

This paper explores the use of subjective perception tasks and its correlations with biomechanical data in the evaluation of manual material handling. Three main dimensions were considered for perception: physical regroups sensations issued from a specific body area; operative regroups feelings related to the execution of the task; and performance regroups feelings that involve a judgement on the execution or reflect overall sensations. The following questions were then explored. To what extent are perception data related to biomechanics data? Do both approaches lead to similar conclusions or interpretations when effect of practice, format and off-centre were tested? How can they complement one another? The task consisted of transferring 50 series of three 15 kg loads in order to verify the impact of free practice, format (box/cylinder) and load centre of gravity position. Eleven subjects rated perception on a CR-10 scale (Borg 1982) after each series. The session was completed with an interview on perception. The net resulting moment was systematically found to be the best correlated with data perception. While all physical and performance items corresponded in various ways to biomechanics data, perceptions associated with operative dimension appeared to be less related with biomechanical data. As regards the impact of practice, format and off-centre, both approaches would lead to the same conclusions, except for the effect of the off-centre. Verbal data add rational information about how or why perception can or cannot be reflected in biomechanics data. How both approaches can be matched more closely in manual handling is discussed.

Identification of time-varying Hammerstein systems from ensemble data.

In this paper, we describe a new technique to identify rapidly time-varying Hammerstein systems from ensembles of input-output realizations. The technique involves two steps. A correlation approach is first used to obtain initial estimates of the linear subsystem parameters for every sampling time. An iterative optimization algorithm is then employed to produce final estimates of the system parameters. The input does not need to be white. The technique was tested on simulated data and was found to produce excellent results under realistic conditions.

Suppression of inducible nitric oxide generation by agmatine aldehyde: beneficial effects in sepsis.

The induction of inducible nitric oxide synthase (iNOS) serves an important immuno-protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences. Delineation of the mechanisms that can downregulate iNOS-generated NO in inflammation could have therapeutic relevance. Here we show that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations. This effect was not cell type specific. Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AldDH) activities are also representative of inflammatory settings. Increasing the conversion of agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AldDH activity increases the inhibitory effects of agmatine in an additive fashion. Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of agmatine, as did the addition of AldDH or reacting aldehydes with phenylhydrazine. We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of agmatine in vivo. Endotoxic rats administered agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis. Agmatine treatment also increased the survival of LPS treated mice. Our data demonstrate the capacity of agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of agmatine in a model of endotoxic shock. How agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed.

Identification of physiological systems: estimation of linear time-varying dynamics with non-white inputs and noisy outputs.

A new technique to identify linear time-varying systems from ensembles of input-output realisations is presented. First, a correlation-based least-squares method is derived. This method consists of solving, for each sampling time, a matrix equation involving estimates of the input autocorrelation and input-output cross-correlation functions computed from data across the ensemble. Then, the matrix inverse needed to solve this matrix equation is replaced with a pseudo-inverse. The model is thus constrained to describe only those components of the dynamics that can be reliably identified. Ignoring 'unidentifiable' components has virtually no adverse effect on the predicted outputs. Simulation results demonstrate that the pseudoinverse technique yields more reliable estimates of the dynamics than a previously proposed least-squares technique when the inputs are coloured and the output signal-to-noise ratio (SNR) is low. With the input spectrum flat up to approximately 10% of the sampling rate and an output SNR of 5dB, the mean variance accounted for (VAF) between the true instantaneous impulse response functions (IRFs) and the instantaneous IRFs estimated with the least-squares technique was 0.2%. In contrast, the mean VAF between the true instantaneous IRFs and the instantaneous IRFs estimated with the pseudoinverse technique was 89.0%.

Bioactive products of arginine in sepsis: tissue and plasma composition after LPS and iNOS blockade.

Blockade or gene deletion of inducible nitric oxide synthase (iNOS) fails to fully abrogate all the sequelae leading to the high morbidity of septicemia. An increase in substrate uptake may be necessary for the increased production of nitric oxide (NO), but arginine is also a precursor for other bioactive products. Herein, we demonstrate an increase in alternate arginine products via arginine and ornithine decarboxylase in rats given lipopolysaccharide (LPS). The expression of iNOS mRNA in renal tissue was evident 60 but not 30 min post-LPS, yet a rapid decrease in blood pressure was obtained within 30 min that was completely inhibited by selective iNOS blockade. Plasma levels of arginine and ornithine decreased by at least 30% within 60 min of LPS administration, an effect not inhibited by the iNOS blocker L-N(6)(1-iminoethyl)lysine (L-NIL). Significant increases in plasma nitrates and citrulline occurred only 3-4 h post-LPS, an effect blocked by L-NIL pretreatment. The intracellular composition of organs harvested 6 h post-LPS reflected tissue-specific profiles of arginine and related metabolites. Tissue arginine concentration, normally an order of magnitude higher than in plasma, did not decrease after LPS. Pretreatment with L-NIL had a significant impact on the disposition of tissue arginine that was organ specific. These data demonstrate changes in arginine metabolism before and after de novo iNOS activity. Selective blockade of iNOS did not prevent uptake and can deregulate the production of other bioactive arginine metabolites.

Observation procedures characterizing occupational physical activities: critical review.

The first objective of this paper is to compare the observation procedures proposed to characterize physical work. The second objective is to examine the following 3 methodological issues: reliability, observer training, and internal validity. Seventy-two papers were reviewed, 38 of which proposed a new or modified observation grid. The observation variables identified were broken down into 7 categories as follows: posture, exertion, load handled, work environment, use of feet, use of hands, and activities or tasks performed. The review revealed the variability of existing procedures. The examination of methodological issues showed that observation data can be reliable and can present an adequate internal validity. However, little information about the conditions necessary to achieve good reliability was available.

Modulation of stretch reflexes during imposed walking movements of the human ankle.

Our overall objectives were to examine the role of peripheral afferents from the ankle in modulating stretch reflexes during imposed walking movements and to assess the mechanical consequences of this reflex activity. Specifically we sought to define the changes in the electromyographic (EMG) and mechanical responses to a stretch as a function of the phase of the step cycle. We recorded the ankle position of a normal subject walking on a treadmill at 3 km/h and used a hydraulic actuator to impose the same movements on supine subjects generating a constant level of ankle torque. Small pulse displacements, superimposed on the simulated walking movement, evoked stretch reflexes at different phases of the cycle. Three major findings resulted: 1) soleus reflex EMG responses were influenced strongly by imposed walking movements. The response amplitude was substantially smaller than that observed during steady-state conditions and was modulated throughout the step cycle. This modulation was qualitatively similar to that observed during active walking. Because central factors were held constant during the imposed walking experiments, we conclude that peripheral mechanisms were capable of both reducing the amplitude of the reflex EMG and producing its modulation throughout the movement. 2) Pulse disturbances applied from early to midstance of the imposed walking cycle generated large reflex torques, suggesting that the stretch reflex could help to resist unexpected perturbations during this phase of walking. In contrast, pulses applied during late stance and swing phase generated little reflex torque. 3) Reflex EMG and reflex torque were modulated differently throughout the imposed walking cycle. In fact, at the time when the reflex EMG response was largest, the corresponding reflex torque was negligible. Thus movement not only changes the reflex EMG but greatly modifies the mechanical output that results.

Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels.

Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a full-length protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.

Box Handling in the Loading and Unloading of Vans.

The handling of 2,306 boxes being loaded or unloaded from vans onto or from 4-wheeled trolleys by 31 handlers in a warehouse were characterized. Handling was videotaped and characterized through an analysis grid completed by three trained observers. The following execution parameters were observed: nature of the exertion applied by the upper limbs, plane and direction of the exertion, resulting displacement of the box, grip, use of the lower limbs and the back. Results show that execution parameters used by handlers vary considerably from those usually recommended or studied. For example, symmetric grips were rarely used (4%). The grip was modified during the handling of half the boxes. Significant knee flexion was rarely observed (3% of exertions). Each box was moved by applying an average of 3.5 different exertions. Exertions were mostly applied in a plane parallel to the shoulders; they were rarely executed in a strict sagittal plane (11%). The implication of these observations are discussed.

Effect of chronic salt loading on kidney function in early and established diabetes mellitus in rats.

Glomerular hyperfiltration and renal hypertrophy are among the events that characterize the early course of diabetes mellitus in rats and human patients. Previous studies from this laboratory demonstrated that salt restriction paradoxically reduces total renal vascular resistance (RVR) and increases glomerular filtration rate (GFR) in diabetic rats (J Am Soc Nephrol 1995;5:1761-7). In the present study we examined the converse condition by testing the effects of chronic salt loading on kidney function in moderately hyperglycemic insulin-treated rats with early and established streptozotocin diabetes. Salt loading was accomplished by adding 1% NaCl to the drinking water 1 day or 35 days after diabetes was induced. The high-salt diet appropriately increased salt excretion in diabetic rats and nondiabetic controls. GFR and renal plasma flow were determined by inulin and para-amino hippuric acid (PAH) clearance 7 days after salt loading was started. Diabetic rats receiving tap water exhibited hyperfiltration with no change in renal blood flow (RBF). In nondiabetic rats, salt loading caused a reduction in total RVR and proportional increases in RBF, GFR, and kidney weight (KW). Salt loading in early diabetes did not affect RVR, RBF, or KW and caused a paradoxical reduction in GFR. In established diabetes, salt loading reduced RVR and increased RBF, similar to results in nondiabetic rats, but as in rats with early diabetes, it did not increase GFR or KW. In summary, although the response in RVR and RBF to chronic salt loading depends on the duration of diabetes, the increase in GFR and KW as seen in nondiabetic rats is blunted in the early and established state of insulin-treated diabetes in rats. These findings further support the notion that the renal response to variation in salt intake is altered in insulin-treated diabetes in rats.

Relapse and short sickness absence for back pain in the six months after return to work.

OBJECTIVES: To measure the incidence of back pain relapse (causing three consecutive days off work on medical advice) and of short sickness absence (less than three consecutive days), and to determine whether the incidence of such events was affected by overall pain and specific pain related to simple daily movements (functional capacity) assessed at discharge. METHODS: A cohort of workers with a first compensated episode of back pain was prospectively followed up from return to work after rehabilitative treatment. Follow up among 230 workers was carried out monthly by phone for a maximum of six months. Crude and adjusted rate ratios (RRs) along with 95% confidence intervals (95% CIs) were estimated with the Cox's proportional hazards model. RESULTS: Within six months of return to work, 29 workers (12.6%) had relapsed, and another 15 workers (6.5%) had a short sickness absence. 50% of relapses had occurred within 42 days of return to work whereas this figure was 28 days for short sickness absence. In a multivariate model that considered pain and clinical variables at discharge only a scale combining all pain variables (specific daily movements as well as the visual analog overall pain scale) contributed to relapse and short sickness absence as the outcome (RR (95% CI)) (1.53 (0.96-2.43)); the same was true in a model considering pain and workers' views on desired changes to work conditions (1.60; 1.08 to 2.36). CONCLUSIONS: Incidence of relapse or short sickness absence in the first six months after return to work was 19.1%. Of all measured prognostic variables (sociodemographic, clinical, workers' views, and pain), only overall pain and pain associated with carrying out simple daily movements were helpful in predicting relapse or short sickness absence.

Agmatine affects glomerular filtration via a nitric oxide synthase-dependent mechanism.

Arginine decarboxylase is present in the kidney and metabolizes the amino acid, arginine, to agmatine. Agmatine increases filtration rate in single nephrons (J. J. Lortie, W. F. Novotny, O. W. Peterson, V. Vallon, K. Malvey, M. Mendonca, J. Satriano, P. Insel, S. C. Thomson, and R. C. Blantz. J. Clin. Invest. 97:413-420, 1996). Experiments were conducted to determine whether exogenously administered agmatine exerts these effects via interaction with nitric oxide synthase (NOS) and whether this interaction depends upon alpha 2-adrenergic receptors. Agmatine microperfused (1 microM) into the urinary space of surface glomeruli of the rat increased nephron filtration rate from 33 +/- 4 to 40 +/- 5 nl/min with complete recovery within 10 min. When NG-monomethyl-L-arginine (L-NMMA), a nonselective NOS inhibitor, was systemically infused, agmatine no longer increased single-nephron glomerular filtration rate (SNGFR). BHT-933, an alpha 2-adrenergic agonist, did not increase SNGFR and was unaffected by concurrent L-NMMA. In vitro incubation of freshly harvested glomeruli with agmatine resulted in significant increases in the generation of cGMP, effects similar to carbachol, and blocked by nitro-L-arginine methyl ester (L-NAME) but not yohimbine, an alpha 2-adrenergic antagonist. Agmatine exerts effects on glomerular ultrafiltration via a constitutive NOS-dependent mechanism, and this does not require the participation of alpha 2-adrenoreceptors.

Perception of difficulties for the back related to assembly work: general findings and impact of back health.

The study objective was to describe the perceptions of airplane assemblers on job demand for the back and how back pain modulated these perceptions. One hundred and seventy-six workers answered two questionnaires concerning back pain and the perception of work related difficulties (work activities, work contexts, tools, work positions, efforts). Results show that positions and work contexts are perceived as greater sources of difficulty than efforts or dynamic activities. The duration of a given position is more important than its frequency. Back pain has a significant but complex impact on the perception of difficulty. Assemblers appear to integrate several factors when evaluating their difficulties as opposed to individual aspects, as it is often measured in ergonomic studies. The results have important implications for the measurement of ergonomic factors in the genesis of back pain and illustrates the potential for misclassification and biases in current epidemiologic studies.

Knee movement strategies differentiate expert from novice workers in asymmetrical manual materials handling.

One way to generate hypotheses on appropriate handling principles is to compare the strategies of highly skilled workers (experts) with those of novice workers (novices). This study was conducted to determine whether experts differ from novices in their handling strategies and to determine the effects of these differences in joint motions and net reaction moments at the trunk (L5/S1) and knees. Six experts and five novices were compared transferring two loads (12 and 22 kg) from four different initial low positions to a standardized low position on a trolley. The external forces were obtained from two AMTI force platforms, and two 16 mm Locam cameras coupled with two mirrors were used to obtain the three-dimensional kinematic data. An inverse dynamic analysis was performed on each segment and the net reaction moments were evaluated at L5/S1 and the knees; trunk posture, knee flexion angles and feet spacings were also calculated. Results showed that both groups minimized trunk asymmetries of posture and efforts; however, the experts were characterized by reduced knee flexion (31 degrees vs 53 degrees) and total knee excursion (20 degrees vs 38 degrees), increased flexion moments (72 vs 58 Nm) but reduced extension moments (4 vs 26 Nm) and valgus moments (30 vs 54 Nm). The experts' strategies appear safer overall because they reduce trunk asymmetry, asymmetrical efforts on the knee and stress on the femoropatellar joint. Moreover, these strategies present a potential for reduced mechanical energy expenditure due to lower knee excursions and increased knee stability due to reduced knee flexion.

Prognostic factors for return to work after a first compensated episode of back pain.

OBJECTIVES: To determine which factors measured at baseline and during the course of treatment influence time to return to work after a first compensated episode of back pain. METHODS: The design is a treatment inception cohort including 305 compensated workers out of 402 eligible ones presenting at two rehabilitation centres for conventional treatment. Crude and adjusted rate ratios (RRs) along with 95% confidence intervals (95% CIs) were estimated with the Cox's proportional hazards regression. RESULTS: 50% of workers had not returned to work after 112 days of follow up, and 11.3% still had not after 270 days. At the end of the study period (maximum follow up time was 1228 days), 230 workers (75.4%) had returned to work, 6.5% had not, and a similar percentage had retired, gone into vocational training, or returned to school. In the final model stratified for radiating pain during treatment, which was an important prognostic variable, workers between 21 to 30 years of age had a greater chance of returning to work (RR (95% CI) 1.43 (1.04 to 1.98) than those > or = 30. The other factors associated with a greater chance of returning to work were: a diagnosis of sprain or pain upsilon a diagnosis of intervertebral disc disorder (2.20 (1.23-3.91)), < 30 days of waiting between the accident and the beginning of treatment (1.30 (0.96 to 1.77)), a good flexion at baseline (1.52 (1.04 to 2.23)), absence of neurological symptoms during treatment (1.40 (0.98-2.00)), > 24 months of employment in the industry (1.49 (1.10 to 2.03)), working for a public industry upsilon a private one (1.63 (1.21 to 2.19)), and the ability to take unscheduled breaks (1.45 (1.06 to 1.97)). CONCLUSIONS: Even with a first episode of back pain, time to return to work is long and the proportion not returning is high. Return to work as expected is influenced by disease and host characteristics but also by social and work factors. Reinstatement programmes should account for all these factors.

Activities of nitric oxide in normal physiology and uremia.

Nitric oxide (NO) generated from arginine exerts a variety of renal and extrarenal physiological and pathophysiological effects. NO is generated by two types of nitric oxide synthases: acutely responsive, constitutive NOS and slower, more persistent inducible NOS (iNOS). The latter is transcriptionally dependent, often stimulated by cytokines. NO regulates glomerular ultrafiltration, tubular reabsorption, and intrarenal renin secretion; many of these renal effects are mediated by interactions with angiotensin II and adrenergic (alpha 2) activity. Decreased NO activity also enhances tubuloglomerular feedback activity, which could contribute to renal vasoconstriction, NaCl retention, and elevated blood pressure. Loss of renal function could influence NO activity via: (1) endothelial dysfunction; (2) decreased arginine synthesis by kidney; (3) responses to arginine analogs that act as NOS inhibitors; (4) increased cytokine activity; and (5) altered oxidation:reduction status of cells, etc. For example, platelet dysfunction in uremia may be caused by cytokine-induced iNOS activation. Moreover, acutely responsive, constitutive NOS activity may be depressed in progressive loss of renal function. Decreased NO activity might contribute to baroreceptor dysfunction observed in hypertension and progressive renal disease. Studies of the impact of uremia suggest that iNOS may be chronically stimulated by cytokines, whereas acutely responsive, constitutive NOS activity may be concurrently depressed.

Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat.

Until recently, conversion of arginine to agmatine by arginine decarboxylase (ADC) was considered important only in plants and bacteria. In the following, we demonstrate ADC activity in the membrane-enriched fraction of brain, liver, and kidney cortex and medulla by radiochemical assay. Diamine oxidase, an enzyme shown here to metabolize agmatine, was localized by immunohistochemistry in kidney glomeruli and other nonrenal cells. Production of labeled agmatine, citrulline, and ornithine from [3H]arginine was demonstrated and endogenous agmatine levels (10(-6)M) in plasma ultrafiltrate and kidney were measured by HPLC. Microperfusion of agmatine into renal interstitium and into the urinary space of surface glomeruli of Wistar-Frömter rats produced reversible increases in nephron filtration rate (SNGFR) and absolute proximal reabsorption (APR). Renal denervation did not alter SNGFR effects but prevented APR changes. Yohimbine (an alpha 2 antagonist) microperfusion into the urinary space produced opposite effects to that of agmatine. Microperfusion of urinary space with BU-224 (microM), a synthetic imidazoline2 (I2) agonist, duplicated agmatine effects on SNGFR but not APR whereas an I1 agonist had no effect. Agmatine effects on SNGFR and APR are not only dissociable but appear to be mediated by different mechanisms. The production and degradation of this biologically active substance derived from arginine constitutes a novel endogenous regulatory system in the kidney.

Reuse of disposable laparoscopic instruments: a study of related surgical complications.

OBJECTIVE: To determine the rate of surgical complications related to reuse of disposable laparoscopic instruments. DESIGN: A review of all laparoscopic and thoracoscopic procedures done between August 1990 and January 1994 in which disposable laparoscopic instruments were reused. SETTING: Department of general surgery in a 461-bed teaching hospital. PATIENTS: Patients who underwent 874 laparoscopic and thoracoscopic procedures in which disposable laparoscopic instruments were reused according to validated reprocessing protocols. MAIN OUTCOME MEASURES: The incidence of superficial and deep wound infections and complications related to instrument malfunction. RESULTS: The combined rate for deep and superficial infections was 1.8%. No complications related to a disposable instrument malfunction were found. CONCLUSION: Disposable laparoscopic instruments may be safely reused under carefully monitored conditions and with strict guidelines.

Disorders of body fluid balance: a new look into the mechanisms of disease.

OBJECTIVE: To review the mechanisms of disease on the basis of dysfunction in body fluid distribution secondary to abnormalities in capillary permeability and plasma membrane transport disorders, leading to quantitative and qualitative alterations of the interstitial space, a mainly strategic compartment positioned between the microcirculation and cell mass. DATA SOURCES: The recent literature on the mechanisms involved in the control of body fluid balance, with special reference to microcirculation and interstitial compartment physiology, as well as published and unpublished original data from the authors laboratory. DATA EXTRACTION AND SYNTHESIS: To illustrate the importance of capillary permeability dysfunction in the development of disease, animal (rat and dog) models of chronic renal failure, acute diuretic-induced fluid depletion, diabetes mellitus, arterial hypertension and ischemia-reperfusion of the kidney were used in an attempt to show that in all these experimental models, basic capillary permeability dysfunction (measured by the extravasation of Evans blue, a marker of albumin leakage) develops in specific microcirculation beds. As a consequence, tissue edema (interstitial and/or cellular) develops and likely impairs the traffic of nutrients and waste products to and from the cellular mass, and/or challenges the microcirculation, leading to organ damage. Kidney dysfunction is measured by conventional clearance methods (renal hemodynamics and tubular function). In some models, the eventual mediators of vascular abnormality are examined by use of pharmacological tools. CONCLUSIONS: The critical role of microcirculation dysfunctions, in particular capillary permeability, resulting in interstitial compositional changes is presented as the basis of disease. The apparent specificity of target organ damage may represent the nonspecific result of physicochemical alteration in the strategic interstitial fluid compartment.