Gating of cystic fibrosis transmembrane conductance regulator chloride channels by adenosine triphosphate hydrolysis. Quantitative analysis of a cyclic gating scheme.
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Gating of the cystic fibrosis transmembrane conductance regulator (CFTR) involves a coordinated action of ATP on two nucleotide binding domains (NBD1 and NBD2). Previous studies using nonhydrolyzable ATP analogues and NBD mutant CFTR have suggested that nucleotide hydrolysis at NBD1 is required for opening of the channel, while hydrolysis of nucleotides at NBD2 controls channel closing. We studied ATP-dependent gating of CFTR in excised inside-out patches from stably transfected NIH3T3 cells. Single channel kinetics of CFTR gating at different [ATP] were analyzed. The closed time constant (tauc) decreased with increasing [ATP] to a minimum value of approximately 0.43 s at [ATP] >1.00 mM. The open time constant (tauo) increased with increasing [ATP] with a minimal tauo of approximately 260 ms. Kinetic analysis of K1250A-CFTR, a mutant that abolishes ATP hydrolysis at NBD2, reveals the presence of two open states. A short open state with a time constant of approximately 250 ms is dominant at low ATP concentrations (10 microM) and a much longer open state with a time constant of approximately 3 min is present at millimolar ATP. These data suggest that nucleotide binding and hydrolysis at NBD1 is coupled to channel opening and that the channel can close without nucleotide interaction with NBD2. A quantitative cyclic gating scheme with microscopic irreversibility was constructed based on the kinetic parameters derived from single-channel analysis. The estimated values of the kinetic parameters suggest that NBD1 and NBD2 are neither functionally nor biochemically equivalent. (+info)
Human ether-a-go-go-related gene K+ channel gating probed with extracellular ca2+. Evidence for two distinct voltage sensors.
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Human ether-a-go-go-related gene (HERG) encoded K+ channels were expressed in Chinese hamster ovary (CHO-K1) cells and studied by whole-cell voltage clamp in the presence of varied extracellular Ca2+ concentrations and physiological external K+. Elevation of external Ca2+ from 1.8 to 10 mM resulted in a reduction of whole-cell K+ current amplitude, slowed activation kinetics, and an increased rate of deactivation. The midpoint of the voltage dependence of activation was also shifted +22.3 +/- 2.5 mV to more depolarized potentials. In contrast, the kinetics and voltage dependence of channel inactivation were hardly affected by increased extracellular Ca2+. Neither Ca2+ screening of diffuse membrane surface charges nor open channel block could explain these changes. However, selective changes in the voltage-dependent activation, but not inactivation gating, account for the effects of Ca2+ on Human ether-a-go-go-related gene current amplitude and kinetics. The differential effects of extracellular Ca2+ on the activation and inactivation gating indicate that these processes have distinct voltage-sensing mechanisms. Thus, Ca2+ appears to directly interact with externally accessible channel residues to alter the membrane potential detected by the activation voltage sensor, yet Ca2+ binding to this site is ineffective in modifying the inactivation gating machinery. (+info)
The validation of interviews for estimating morbidity.
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Health interview surveys have been widely used to measure morbidity in developing countries, particularly for infectious diseases. Structured questionnaires using algorithms which derive sign/symptom-based diagnoses seem to be the most reliable but there have been few studies to validate them. The purpose of validation is to evaluate the sensitivity and specificity of brief algorithms (combinations of signs/symptoms) which can then be used for the rapid assessment of community health problems. Validation requires a comparison with an external standard such as physician or serological diagnoses. There are several potential pitfalls in assessing validity, such as selection bias, differences in populations and the pattern of diseases in study populations compared to the community. Validation studies conducted in the community may overcome bias caused by case selection. Health centre derived estimates can be adjusted and applied to the community with caution. Further study is needed to validate algorithms for important diseases in different cultural settings. Community-based studies need to be conducted, and the utility of derived algorithms for tracking disease frequency explored further. (+info)
Primary hip and knee replacement surgery: Ontario criteria for case selection and surgical priority.
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OBJECTIVES: To develop, from simple clinical factors, criteria to identify appropriate patients for referral to a surgeon for consideration for arthroplasty, and to rank them in the queue once surgery is agreed. DESIGN: Delphi process, with a panel including orthopaedic surgeons, rheumatologists, general practitioners, epidemiologists, and physiotherapists, who rated 120 case scenarios for appropriateness and 42 for waiting list priority. Scenarios incorporated combinations of relevant clinical factors. It was assumed that queues should be organised not simply by chronology but by clinical and social impact of delayed surgery. The panel focused on information obtained from clinical histories, to ensure the utility of the guidelines in practice. Relevant high quality research evidence was limited. SETTING: Ontario, Canada. MAIN MEASURES: Appropriateness ratings on a 7-point scale, and urgency rankings on a 4-point scale keyed to specific waiting times. RESULTS: Despite incomplete evidence panellists agreed on ratings in 92.5% of appropriateness and 73.8% of urgency scenarios versus 15% and 18% agreement expected by chance, respectively. Statistically validated algorithms in decision tree form, which should permit rapid estimation of urgency or appropriateness in practice, were compiled by recursive partitioning. Rating patterns and algorithms were also used to make brief written guidelines on how clinical factors affect appropriateness and urgency of surgery. A summary score was provided for each case scenario; scenarios could then be matched to chart audit results, with scoring for quality management. CONCLUSIONS: These algorithms and criteria can be used by managers or practitioners to assess appropriateness of referral for hip or knee replacement and relative rankings of patients in the queue for surgery. (+info)
Understanding the basis of treatment choices for varicose veins: a model for decision making with the repertory grid technique.
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OBJECTIVES: To use the repertory grid technique as a method for identifying and rating the criteria that clinicians use to make a choice between the different treatment options for patients with a common condition such as varicose veins. DESIGN: The "expert panel" consensus method for rating the appropriateness of clinical procedures was modified with an existing psychometric method, the repertory grid technique. To identify the criteria used to decide about treatment, the panel members compared and contrasted a range of nine "treatment prototypes". They were then required to rate each criterion for its relevance to each treatment prototype. SETTING: The panel was selected from different geographical locations in the South Western Regional Health Authority. SUBJECTS: The expert panel was composed of six vascular surgeons, three from teaching and three from non-teaching hospitals; two general practitioners who were also clinical assistants in vascular surgery; and one honorary senior lecturer in general practice. MAIN MEASURES: Decision making criteria were categorised according to their content. Their frequency of replication was noted-that is, how many clinicians used the same criterion. Computer analysis of the rating scores for the nine panel members identified the relative importance of each treatment criterion for each treatment option. RESULTS: 161 criteria for the treatment of varicose veins were elicited from the nine participants. These criteria were wide ranging, from clinical indications (48% of those used), to social (32%), and organisational factors (20%). Clinical indications were more likely to be used when deciding about surgery as a high priority, whereas social and organisational criteria were more likely to be applied in decisions about surgery as a low priority, day case surgery, and cosmetic surgery. CONCLUSIONS: The repertory grid technique proved to be effective in modelling decision making for a condition such as varicose veins: its use enabled both the identification of the wide range of criteria underlying the decision to treat and the exploration of the relative importance of these criteria in relation to several treatment options. Its potential as a method for reducing variation in clinical decision making and thus improving distribution of high quality care lies in its ability to pinpoint dilemmas of decision making rather than as the basis for drawing up guidelines to regulate decision making practice. (+info)
Bridging the gap between managed care and academic medicine: an innovative fellowship.
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Numerous challenges face academic medicine in the era of managed care. This environment is stimulating the development of innovative educational programs that can adapt to changes in the healthcare system. The U.S. Quality Algorithms Managed Care Fellowship at Jefferson Medical College is one response to these challenges. Two postresidency physicians are chosen as fellows each year. The 1-year curriculum is organized into four 3-month modules covering such subjects as biostatistics and epidemiology, medical informatics, the theory and practice of managed care, managed care finance, integrated healthcare systems, quality assessment and improvement, clinical parameters and guidelines, utilization management, and risk management. The fellowship may serve as a possible prototype for future post-graduate education. (+info)
Clinical improvement with bottom-line impact: custom care planning for patients with acute and chronic illnesses in a managed care setting.
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A fully capitated, integrated healthcare delivery system endeavored to improve the care of its sickest members. A computer algorithm severity index that encompassed a 1-year history of hospitalization and adjusted for inclusion of a variety of chronic conditions was calculated on the basis of clinical and administrative claims databases for the entire membership of the healthcare system. Monthly updated lists were produced to find patients with acute and chronic illnesses. These patients accounted for one-fourth of hospital admissions and almost half of inpatient days, but they numbered less than 1% of system membership. Each listed person, regardless of age or diagnosis, had a custom care plan formulated by nurses in consultation with the primary care physician and involved specialists. Plan development featured in-home assessments in most instances and incorporated a variety of ancillary services, telephone and home-care follow-up, and strategies to increase continuity and access to care. Patient-reported functional status was obtained at establishment of the care plan and periodically thereafter in expectation of raising the cross-sectional mean values of the population. Three months after initiation of the program, the expected winter hospitalization peak did not occur, and utilization tended to be lower in subsequent months. Inpatient admissions among members with acute and chronic illnesses decreased 20%, and inpatient days decreased 28% from baseline levels. Among the subset of seniors in the population, inpatient days decreased 37%. Net financial impact was a medical expenditure decrease of more than 5% from 1995 levels. On a population basis, functional status was raised, and the acuity of patients' conditions and need for inpatient hospital care were reduced. (+info)
Gastrointestinal illness in managed care: healthcare utilization and costs.
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Identification of inefficiencies is a first step to improving the quality of gastrointestinal (GI) care at the most reasonable cost. This analysis used administrative data to examine the healthcare utilization and associated costs of the management of GI illnesses in a 2.5 million-member private managed care plan containing many benefit designs. An overall incidence of 10% was found for GI conditions, with a preponderance in adults (patients older than 40 years) and women. The most frequently occurring conditions were abdominal pain, nonulcer peptic diseases, lower GI tract diseases, and other GI tract problems. These conditions, along with gallbladder/biliary tract disease, were also the most costly. Claims submitted for care during GI episodes averaged $17 per member per month. Increasing severity of condition was associated with substantial increases in utilization and costs (except for medication use). For most GI conditions, approximately 40% of charges were for professional services (procedures, tests, and visits) and 40% of charges were for facility admissions. The prescription utilization analysis indicated areas where utilization patterns may not match accepted guidelines, such as the low use of anti-Helicobacter pylori therapy, the possible concomitant use of nonsteroidal anti-inflammatory drugs in patients with upper GI diseases, and the use of narcotics in treating patients with lower GI disease and abdominal pain. Also, there was no clear relationship between medication utilization and disease severity. Thus, this analysis indicated that GI disease is a significant economic burden to managed care, and identified usage patterns that potentially could be modified to improve quality of care. (+info)