Geometric and potential driving formation and evolution of biomolecular surfaces.

This paper presents new geometrical flow equations for the theoretical modeling of biomolecular surfaces in the context of multiscale implicit solvent models. To account for the local variations near the biomolecular surfaces due to interactions between solvent molecules, and between solvent and solute molecules, we propose potential driven geometric flows, which balance the intrinsic geometric forces that would occur for a surface separating two homogeneous materials with the potential forces induced by the atomic interactions. Stochastic geometric flows are introduced to account for the random fluctuation and dissipation in density and pressure near the solvent-solute interface. Physical properties, such as free energy minimization (area decreasing) and incompressibility (volume preserving), are realized by some of our geometric flow equations. The proposed approach for geometric and potential forces driving the formation and evolution of biological surfaces is illustrated by extensive numerical experiments and compared with established minimal molecular surfaces and molecular surfaces. Local modification of biomolecular surfaces is demonstrated with potential driven geometric flows. High order geometric flows are also considered and tested in the present work for surface generation. Biomolecular surfaces generated by these approaches are typically free of geometric singularities. As the speed of surface generation is crucial to implicit solvent model based molecular dynamics, four numerical algorithms, a semi-implicit scheme, a Crank-Nicolson scheme, and two alternating direction implicit (ADI) schemes, are constructed and tested. Being either stable or conditionally stable but admitting a large critical time step size, these schemes overcome the stability constraint of the earlier forward Euler scheme. Aided with the Thomas algorithm, one of the ADI schemes is found to be very efficient as it balances the speed and accuracy.

Minimal molecular surfaces and their applications.

This article presents a novel concept, the minimal molecular surface (MMS), for the theoretical modeling of biomolecules. The MMS can be viewed as a result of the surface free energy minimization when an apolar molecule, such as protein, DNA or RNA is immersed in a polar solvent. Based on the theory of differential geometry, the MMS is created via the mean curvature minimization of molecular hypersurface functions. A detailed numerical algorithm is presented for the practical generation of MMSs. Extensive numerical experiments, including those with internal and open cavities, are carried out to demonstrated the proposed concept and algorithms. The proposed MMS is typically free of geometric singularities. Application of the MMS to the electrostatic analysis is considered for a set of twenty six proteins.

Aerobic conditioning in mild asthma decreases the hyperpnea of exercise and improves exercise and ventilatory capacity.

STUDY OBJECTIVE: To determine the effect of an aerobic conditioning program on fitness, respiratory physiology, and resting lung function in patients with mild asthma. DESIGN: Prospective cohort study. SETTING: Outpatient rehabilitation facility. METHODS: Five patients with mild intermittent asthma and five normal control subjects completed a 10-week aerobic conditioning program. Pulmonary function studies and noninvasive cardiopulmonary exercise tests were performed before and after the conditioning program. RESULTS: After aerobic conditioning, there were significant gains in maximum oxygen consumption (VO(2)max; 22.73 mL/kg/min vs 25.29 mL/kg/min, p = 0.01, asthma; 22.94 mL/kg/min vs 27.85 mL/kg/min, p = 0.03, control) and anaerobic threshold (0.99 L/min vs 1.09 L/min, p = 0.03, asthma; 0.89 L/min vs 1.13 L/min, p = 0.01, control) in both groups. Although FEV(1) was unchanged, the maximum voluntary ventilation (MVV) improved in the asthma group (96.0 L/min vs 108.2 L/min, p = 0.08, asthma; 134.0 L/min vs 131.2 L/min, p = 0.35, control). During exercise, minute ventilation (VE) for each level of work was decreased in the asthma group after conditioning, while little change occurred in the control group (68. 48 L/min vs 51.70 L/min at initial VO(2)max, p = 0. 02, asthma; 65.82 L/min vs 63.12 L/min at initial VO(2)max, p = 0.60, control). A significant decrease in the ventilatory equivalent (VE/oxygen consumption, 40.8 vs 30.4 at VO(2)max, p = 0.02, asthma; 37.2 vs 35.8 4 at VO(2)max, p = 0.02, control) and the dyspnea index (VE/MVV) at submaximal (0.44 vs 0.38, p = 0.05, asthma; 0.32 vs 0.38, p < 0.01, control) and maximal exercise (0.72 vs 0.63, p = 0.03, asthma; 0.49 vs 0.62, p = 0.02, control) occurred in the asthma group. CONCLUSIONS: Exercise rehabilitation improves aerobic fitness in both asthmatic and nonasthmatic participants of a 10-week aerobic fitness program. Additional benefits of improved ventilatory capacity and decreased hyperpnea of exercise occurred in patients with mild asthma.

UPL1 and 2, two 405 kDa ubiquitin-protein ligases from Arabidopsis thaliana related to the HECT-domain protein family.

The ubiquitin/26S proteasome pathway is a major route for degrading abnormal and important short-lived regulatory proteins in eukaryotes. Covalent attachment of ubiquitin, which triggers entry of target proteins into the pathway, is accomplished by an ATP-dependent reaction cascade involving the sequential action of three enzymes, E1s, E2s and E3s. Although much of the substrate specificity of the pathway is determined by E3s (or ubiquitin-protein ligases, UPLs), little is known about these enzymes in plants and how they choose appropriate targets for ubiquitination. Here, we describe two 405 kDa E3s (UPL1 and 2) from Arabidopsis thaliana related to the HECT-E3 family that is essential in yeast and animals. UPL1 and 2 are encoded by 13 kbp genes 26 cM apart on chromosome I, that are over 95% identical within both the introns and exons, suggesting that the two loci arose from a recent gene duplication. The C-terminal HECT domain of UPL1 is necessary and sufficient to conjugate ubiquitin in vitro in a reaction that requires the positionally conserved cysteine within the HECT domain, E1, and an E2 of the UBC8 family. Given that HECT E3s help define target specificity of the ubiquitin conjugation, a continued characterization of UPL1 and 2 should be instrumental in understanding the functions of ubiquitin-dependent protein turnover in plants and for identifying pathway substrates.

"Health law, ethics and policy: challenges and new avenues for the 21st century and new millennium".

The 50th anniversary of the World Health Organization on 7th April 1998 stands at the dawn of a new century and millennium. These symbolic markers encourage reflection on past achievements, scrutiny of current problems, and contemplation of the possibilities and practicalities of coordinated action to promote the global vision of 'Health For All'. Will that global vision remain inspirational, important and inclusive enough to sustain policy commitment, and unite diverse regional, national and local customs and traditions in ethics, human rights and laws so as to overcome inequities in health status, and improve health systems and health services?"

Peripheral blood manifestations of T(H)2 lymphocyte activation in stable atopic asthma and during exercise-induced bronchospasm.

BACKGROUND: Recently, TH2 lymphocyte activation has been shown to play a key role in initiating and propagating the inflammatory response in asthmatic airways. This is manifest through increased numbers of "activated" CD25-(IL-2R)-bearing T-helper cells and can be seen through the IL-5 driven recruitment of eosinophils and IL-4-mediated B-cell expression of CD23 (low affinity IgE receptor) and ultimately IgE production. OBJECTIVE: To gain a better understanding of the role of immune cells in asthma by describing the peripheral blood immune cell phenotypes in mild atopic asthma. METHODS: We enrolled 13 patients with mild atopic asthma and a group of seven nonatopic, nonasthmatic controls. Objective measures of lung function were obtained. The peripheral blood was analyzed by flow cytometry for specific cellular markers at rest and during the development of exercise induced bronchospasm. RESULTS: At rest the number of CD23-bearing B cells (169/mL versus 117/mL; P = .05) and the number of CD25-bearing T cells (355/mL versus 237/mL; P = .03) were increased in the asthma group. There was a linear relationship between these two lymphocyte subsets and the maximum voluntary ventilation at rest (r = 0.56, P = .01 and r = 0.57, P = .01). With the development of exercise-induced bronchospasm there was a significantly greater increase in CD23-positive B cells (96.7/mL versus 59.7/mL; P = .05) and CD25-positive T cells (111.8/mL versus 45.1; P = .01) in the asthma group. CONCLUSIONS: These data indicate that TH2 lymphocyte activation is manifested by increased numbers of CD23-bearing B cells and CD25-bearing T cells in the peripheral blood of patients with stable mild atopic asthma. Further, these immune cell subsets correlate with markers of resting lung function and increase in the peripheral blood early after the development of exercise-induced bronchospasm.

Identification of a family of closely related human ubiquitin conjugating enzymes.

Two very closely related human E2 ubiquitin conjugating enzymes, UbfH5B and UbcH5C, have been identified. These enzymes are products of distinct genes and are 88-89% identical in amino acid sequence to the recently described human E2, UbcH5 (now designated UbcH5A), UbcH5A-C are homologous to a family of five ubiquitin conjugating enzymes from Arabidopsis thaliana, AtUBC8-12. They are also closely related to Saccharomyces cerevisiae ScUBC4 and ScUBC5, which are involved in the stress response, and play a central role in the targeting of short-lived regulatory proteins for degradation. mRNAs encoding UbcH5A-C were co-expressed in all cell lines and tissues evaluated, with UbcH5C transcripts generally expressed at the highest levels. Analysis of Southern blots suggests that there are likely to be other related members of this family. Both UbcH5B and UbcH5C form thiol ester adducts with ubiquitin, and have activities similar to UbcH5A and AtUBC8 in the conjugation of ubiquitin to target proteins in the presence of the human ubiquitin protein ligase E6-AP. These results establish the existence of a highly conserved, and widely expressed, family of human ubiquitin conjugating enzymes.

The role of legislation in health services development (with particular reference to China and Australia).

The World Health Organization has supported initiatives in many countries including China to improve the effectiveness and quality of legislation as a form of technical support to help achieve and consolidate the global strategy of health for all by the year 2000. These initiatives are reviewed. Traditionally China did not rely much on legislation as a technique to underpin and implement the organization and delivery of health services, but it appears that more use will be made of it in the future for a number of reasons, including the implementation of the momentous decision of the National People's Congress in October 1992 to move towards a 'socialist market economy'.

Persistent bronchopleural air leak during mechanical ventilation. A review of 39 cases.

Bronchopleural fistula (BPF), or bronchopleural air leak, is regarded as an ominous complication of ventilator management in acute respiratory failure, but data on its natural course and prognosis are lacking. We reviewed all instances of mechanical ventilation at a major trauma center during a four-year period, and found that 39 of the 1,700 mechanically-ventilated patients developed BPF lasting at least 24 hrs. Overall mortality in these 39 patients was 67 percent, and this was higher when BPF developed late in the illness (16 of 17, or 94 percent, when mean onset was hospital day 13), than when it occurred within 24 hours of admission (ten of 22, or 45 percent, p = 0.002). Survival in patients with chest trauma (12 of 27, 44 percent), most of whom had air leaks on or just after admission, was better than in those with other primary diagnoses (one of 12, 8 percent, p less than 0.005). All eight patients whose maximum air leak exceeded 500 ml per breath died, whereas 13 of 30 with smaller maximum leaks survived (p less than 0.05). Despite leaks as large as 900 ml per breath, however, conventional ventilator adjustments permitted avoidance of severe respiratory acidosis (pH less than 7.30) in all but two patients. We conclude that the occurrence of BPF during mechanical ventilation identifies patients with high mortality, but that unmanageable respiratory acidosis from this complication is rare.

Contract law for the hospital and health administrator.

The author discusses the concept of a legal 'contract' and gives many examples of its application in hospitals and health settings. He describes the main features of a contract and gives special attention to personnel and clinical ramifications and to the role of agents in making contracts on behalf of hospitals.

Effect of acetazolamide on normoxic and hypoxic exercise in humans at sea level.

Acetazolamide (A) is a potent inhibitor of carbonic anhydrase. It has been shown to be efficacious in preventing acute mountain sickness as well as decreasing the O2 desaturation that occurs during sleep in individuals with chronic mountain sickness who live at altitude. Very little data, however, are available about its effect on exercise. We studied six healthy males in a double-blind cross-over design using acetazolamide and placebo (P) during normoxic and hypoxic (fractional inspired O2 = 0.118) progressive work exercise to exhaustion on a bicycle ergometer. A metabolic acidosis was documented in all subjects on A (P less than 0.045). Before exercise, subjects on A had 2.0 and 3.5 l/min increase in minute ventilation (VE) during normoxia (P = not significant) and hypoxia (P less than 0.005), respectively, and a 2.2% increase in arterialized O2 hemoglobin saturation (SaO2) during hypoxia. During normoxic and hypoxic exercise, VE/kpm and SaO2/kpm were significantly higher while the respiratory exchange ratio (R) was significantly lower on A. These effects were greater on hypoxia. During normoxia, maximal O2 consumption (1/min) was lower on A [3.1 +/- 0.4 (A) vs. 3.8 +/- 0.2 (P), P less than 0.025] and higher during hypoxia on A[2.6 +/- 0.7 (A) vs. 2.4 +/- 0.1 (P), P less than 0.05]. The increase in exercise VE on A may result in an increased alveolar and subsequent arterial O2 tension which may be important for exercise at altitude. Carbonic anhydrase inhibition may also affect CO2 transport in the lung, which may explain the lower R.