Reference values for lung function tests: II. Maximal respiratory pressures and voluntary ventilation

The strength of the respiratory muscles can be evaluated from static measurements (maximal inspiratory and expiratory pressures, MIP and MEP) or inferred from dynamic maneuvers (maximal voluntary ventilation, MVV). Although these data could be suitable for a number of clinical and research applications, no previous studies have provided reference values for such tests using a healthy, randomly selected sample of the adult Brazilian population. With this main purpose, we prospectively evaluated 100 non-smoking subjects (50 males and 50 females), 20 to 80 years old, selected from more than 8,000 individuals. Gender-specific linear prediction equations for MIP, MEP and MVV were developed by multiple regression analysis: age and, secondarily, anthropometric measurements explained up to 56% of the variability of the dependent variables. The most cited previous studies using either Caucasian or non-Caucasian samples systematically underestimated the observed values of MIP (P<0.05). Interestingly, the self-reported level of regular physical activity and maximum aerobic power correlates strongly with both respiratory and peripheral muscular strength (knee extensor peak torque) (P<0.01). Our results, therefore, provide a new frame of reference to evaluate the normalcy of some useful indexes of respiratory muscle strength in Brazilian males and females aged 20 to 80.

Reference values for lung function tests: III. Carbon monoxide diffusing capacity (transfer factor)

Carbon monoxide diffusing capacity (DLCO) or transfer factor (TLCO) is a particularly useful test of the appropriateness of gas exchange across the lung alveolocapillary membrane. With the purpose of establishing predictive equations for DLCO using a non-smoking sample of the adult Brazilian population, we prospectively evaluated 100 subjects (50 males and 50 females aged 20 to 80 years), randomly selected from more than 8,000 individuals. Gender-specific linear prediction equations were developed by multiple regression analysis with single breath (SB) absolute and volume-corrected (VA) DLCO values as dependent variables. In the prediction equations, age (years) and height (cm) had opposite effects on DLCOSB (ml min-1 mmHg-1), independent of gender (-0.13 (age) + 0.32 (height) - 13.07 in males and -0.075 (age) + 0.18 (height) + 0.20 in females). On the other hand, height had a positive effect on DLCOSB but a negative one on DLCOSB/VA (P<0.01). We found that the predictive values from the most cited studies using predominantly Caucasian samples were significantly different from the actually measured values (P<0.05). Furthermore, oxygen uptake at maximal exercise (VO2max) correlated highly to DLCOSB (R = 0.71, P<0.001); this variable, however, did not maintain an independent role to explain the VO2max variability in the multiple regression analysis (P>0.05). Our results therefore provide an original frame of reference for either DLCOSB or DLCOSB/VA in Brazilian males and females aged 20 to 80 years, obtained from the standardized single-breath technique.

Developed pressure data may provide misinformation when used alone to evaluate systolic function in isovolumetric left ventricle preparations

We report data showing that developed pressure (DPmax) may lead to opposite conclusion with respect to maximal developed circumferential wall stress (smax) when used to assess contractile function in left ventricle isovolumic preparations. Isovolumetric left ventricle preparations of rats with cardiac hypertrophy (H; N = 10) induced by isoproterenol administration showed higher DPmax (174 ± 14 mmHg) than control (C; N = 8) animals (155 ± 12 mmHg) or rats with regression (R; N = 8) of hypertrophy (144 ± 11 mmHg). In contrast, the estimated smax for C (145 ± 26 kdynes/cm2) and R (133 ± 17 kdynes/cm2) was higher than for H (110 ± 13 kdynes/cm2). According to Laplace's law, the opposite results of DPmax and smax may depend on the increased mass/volume left ventricle ratio of the hypertrophied hearts, which favored pressure generation. These results clearly show that DPmax should be used with caution to analyze systolic function.

P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships

Resistance to chemotherapy in cancer cells is mainly mediated by overexpression of P-glycoprotein (Pgp), a plasma membrane ATP-binding cassette (ABC) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. Pgp consists of two homologous halves each containing a transmembrane domain and a cytosolic nucleotide-binding domain (NBD) which contains two consensus Walker motifs, A and B, involved in ATP binding and hydrolysis. The protein also contains an S signature characteristic of ABC transporters. The molecular mechanism of Pgp-mediated drug transport is not known. Since the transporter has an extraordinarily broad substrate specificity, its cellular function has been described as a "hydrophobic vacuum cleaner". The limited knowledge about the mechanism of Pgp, partly due to the lack of a high-resolution structure, is well reflected in the failure to efficiently inhibit its activity in cancer cells and thus to reverse multidrug resistance (MDR). In contrast to the difficulties encountered when studying the full-length Pgp, the recombinant NBDs can be obtained in large amounts as soluble proteins. The biochemical and biophysical characterization of recombinant NBDs is shown here to provide a suitable alternative route to establish structure-function relationships. NBDs were shown to bind ATP and analogues as well as potent modulators of MDR, such as hydrophobic steroids, at a region close to the ATP site. Interestingly, flavonoids also bind to NBDs with high affinity. Their binding site partly overlaps both the ATP-binding site and the steroid-interacting region. Therefore flavonoids constitute a new promising class of bifunctional modulators of Pgp.

Structure and function of the cystic fibrosis transmembrane conductance regulator

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat Cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseudomonas aeruginosa and Staphylococcus aureus lung infection, responsible for 90% of the mortality of CF patients. The gene responsible for the cellular defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (NBDs), and a cytoplasmic domain. In this review we discuss the studies that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- channels (ORCCs).