Knowledge of blood pressure targets among patients with diabetes.

INTRODUCTION: Tight blood pressure (BP) control is the single most important intervention to prevent cardiovascular mortality among patients with diabetes mellitus (DM). However, little is known about how many patients have specific target BP levels or the factors associated with patients' knowledge of these targets. OBJECTIVES: (1) To determine what proportion of patients with diabetes have BP targets; (2) To determine patient characteristics associated with having a BP target. METHODS: Cross-sectional, anonymous survey of 500 randomly selected outpatients with hypertension and DM receiving care in any Veterans Health Administration outpatient clinic in 2003. We examined multivariate associations between patient characteristics and having targets for BP. Covariates included age, race, gender, and education level; and factors specific to diabetes and BP treatment, including medication use, diabetes duration, and number of visits to diabetes healthcare providers in the previous year. RESULTS: Three hundred and seventy-eight (80%) patients responded. Although most (91%) had blood glucose targets, fewer than 60% reported having a BP target. In multivariate analyses, college education was associated with having a BP target (AOR 1.97 [95% CI: 1.16-3.34]). CONCLUSIONS: Less than two-thirds of diabetic, hypertensive patients had BP targets. Encouraging patients to set target BPs may promote hypertension self-management in this high-risk patient population. Less educated patients may especially benefit from interventions to increase awareness of BP targets.

Avoiding pitfalls in chronic disease quality measurement: a case for the next generation of technical quality measures.

The true utility of quality measurement lies in its ability to inspire quality improvement, with resultant enhancements in the processes and outcomes of care. Because quality measurement is expensive, it is difficult to justify using measures that are not likely to lead to important improvements in health. Many current measures of chronic disease technical quality, however, have one or more pitfalls that prevent them from motivating quality improvement reactions. These pitfalls include that: (1) measured processes of care lack strong links to outcomes; (2) actionable processes of care are not measured; (3) measures do not target those at highest risk; (4) measures do not allow for patient exceptions; and (5) intermediate outcome measures are not severity adjusted. To exemplify recent advancements and current pitfalls in chronic disease quality measurement, we examine the evolution of quality measures for diabetes mellitus and discuss the limitations of many currently used diabetes mellitus care measures. We then propose more clinically meaningful "tightly linked" measures that examine clinical processes directly linked to outcomes, target populations with specific diagnoses or intermediate disease outcomes that contribute to risk for poor downstream health outcomes, and explicitly incorporate exceptions. We believe that using more tightly linked measures in quality assessment will identify important quality of care problems and is more likely to produce improved outcomes for those with chronic diseases.

A new approach for measuring quality of care for women with hypertension.

BACKGROUND: Guidelines for care of hypertensive patients have proliferated recently, yet quality assessment remains difficult in the absence of well-defined measurement systems. Existing systems have not always linked process measures to blood pressure outcomes. METHODS: A quality measurement system was developed and tested on hypertensive women in a West Coast health plan. An expert panel selected clinically detailed, evidence-explicit indicators using a modified Delphi method. Thirteen indicators (1 screening, 5 diagnostic, 5 treatment, and 2 follow-up indicators) were selected by this process. Trained nurses used a laptop-based tool to abstract data from medical records for the most recent 2 years of care. RESULTS: Of 15 004 eligible patients with hypertensive and other chronic disease codes, 613 patients were sampled, all eligible for the screening indicator. Of these, 234 women with an average blood pressure of 140/90 mm Hg or more, or a documented diagnosis of hypertension, were studied for the remaining indicators. The average woman received 64% of the recommended care. Most patients did not receive adequate initial history, physical examination, or laboratory tests. Only 37% of hypertensive women with persistent elevations to more than 160/90 mm Hg had changes in therapy or lifestyle recommended. The average adherence proportion to all indicators was lower in patients with uncontrolled blood pressure (>140/90 mm Hg) than in those with controlled blood pressure (54% vs 73%; P<.001). CONCLUSIONS: Quality of hypertensive care falls short of indicators based on randomized controlled trials and national guidelines. Poor performance in essential care processes is associated with poor blood pressure control.

Quantitative and functional characterization of muscarinic receptor subtypes in insulin-secreting cell lines and rat pancreatic islets.

Expression of muscarinic receptors in rat islets, RINm5F cells, and INS-1 cells was established by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantified by RNase protection. Both methods indicated that m3 and m1 receptors were expressed approximately equally in the various cellular preparations and to a much greater extent than the m5 subtype. However, the cell lines, especially RINm5F cells, expressed less of a given receptor subtype than did islets. Immunohistochemistry indicated that m3 receptors were expressed throughout the islet core. Binding studies using the radiolabeled muscarinic receptor antagonist QNB demonstrated a maximal binding capacity of INS-1 cells of 23.0+/-2.9 fmol/mg protein. Functional analyses were undertaken using INS-1 cells stably transfected with either m1 or m3 receptor cDNAs. Overexpression of either receptor did not affect basal responses but markedly enhanced maximal responses to the muscarinic receptor agonist carbachol. Although maximal hydrolysis of phosphatidylinositol 4,5-bisphosphate (Ptd InsP2) was twofold greater in m1-transfectants as compared with m3-transfectants, cell lines overexpressing either receptor gave essentially equivalent secretory responses to a full range of carbachol doses. The results demonstrate that both m1 and m3 muscarinic receptors are well expressed in pancreatic beta-cells, functionally linked to signaling pathways, and capable of initiating insulin secretion with equal potencies.

Associations between primary care physician satisfaction and self-reported aspects of utilization management.

OBJECTIVE: To evaluate the association between physician-reported utilization management (UM) techniques in capitated physician groups and physician satisfaction with capitated care. STUDY SETTING: 1,138 primary care physicians from 89 California capitated physician groups in 1995. STUDY DESIGN: Eighty percent of physicians (N = 910) responded to a mail survey regarding the UM policies in their groups and their satisfaction with the care they deliver. Physician-reported UM strategies measured included group-mandated preauthorization (number of referrals requiring preauthorization, referral denial rate, and referral turnaround time), group-provided explicit practice guidelines, and group-delivered educational programs regarding capitated care. We also measured two key dimensions of satisfaction with capitated care (multi-item scales): (1) satisfaction with capitated care autonomy and quality, and (2) satisfaction with administrative burden for capitated patients. EXTRACTION METHODS: We constructed two multivariate linear regression models to examine associations between physician-reported UM strategies and physician satisfaction, controlling for demographic and practice characteristics and adjusting for clustering. PRINCIPAL FINDINGS: Physician-reported denial rate and turnaround time were significantly negatively associated with capitated care satisfaction. Physicians who reported that their groups provided more guidelines were more satisfied on both dimensions, while physicians who reported that their groups sponsored more educational programs were more satisfied with administrative burden. The number of clinical decisions requiring preauthorization was not significantly associated with either dimension of satisfaction. CONCLUSIONS: Physicians who reported that their groups used UM methods that directly affected their autonomy (high denial rates and long turnaround times) were less satisfied with care for capitated patients. However, a preauthorization policy for referrals or tests was not, in and of itself, associated with satisfaction. Indirect control mechanisms such as guidelines and education were positively associated with satisfaction.

Measuring antidepressant prescribing practice in a health care system using administrative data: implications for quality measurement and improvement.

BACKGROUND: Up to one in eight Americans experiences an episode of depression that requires treatment in his or her lifetime. The direct and indirect costs associated with major depression are high but may be reduced with appropriate treatment. To decrease the probability of relapse, guidelines specify that treatment with antidepressant medications should continue for at least 4 months after symptom remission and that adequate doses of antidepressants be used. A study was conducted in 1997-1999 to examine how different specifications in the construction of quality of care measures for depression treatment influence conclusions about the adequacy of antidepressant prescribing practices. METHODS: Subjects were all adult members of two United Healthcare plans who each had at least one outpatient or inpatient claim with a diagnosis of depression during the years 1993-1995 and were continuously enrolled for 12 months. Pharmacy claims data were used to construct measures of duration of treatment, dose, and type of antidepressant. The effects of two different definitions of a new episode (4-month versus 9-month clean period) and two different ways of identifying an episode of depression (one visit versus two visits with a code for depression) were examined on conclusions about adequacy of antidepressant prescribing practices (dose and duration). Whether antidepressant type was related to the likelihood that antidepressants were prescribed at therapeutic doses was also examined. RESULTS: Patients with two or more visits with depression diagnosis codes were significantly more likely to receive antidepressants than those with only one visit, and were more likely to receive therapeutic doses at each time period (1-5 months). The duration of the clean period was not related to conclusions about therapeutic dosing. Among persons receiving antidepressants, those receiving selective serotonin reuptake inhibitors (SSRIs) were more likely to receive therapeutic doses and to continue treatment for at least 5 months than were those prescribed other classes of antidepressants. In multivariate analysis, being prescribed an SSRI versus another class of antidepressants was significantly associated with receiving both 1 month (OR = 7.3 [5.7-9.3]) and 5 months (OR = 2.0 [1.6-2.5]) of therapeutic treatment. DISCUSSION: Conclusions regarding the appropriateness of antidepressant prescribing can vary markedly, depending on how the quality measure is specified. Given that administrative data are and will continue to be used for both monitoring and quality improvement purposes in the short run, it is critical that we understand how variations in measurement specifications influence the conclusions that are drawn about treatment of depression in health plans.

Evaluating the quality of cancer care: development of cancer quality indicators for a global quality assessment tool.

BACKGROUND: The rise of managed care has increased interest in measuring, reporting, and improving quality of care. To date, quality assessment has relied on a leading indicator approach, which may miss important variations in care. The authors developed cancer specific indicators using a novel case-based approach for a quality measurement tool designed to compare different managed care organizations. METHODS: Based on a review of the literature, quality indicators were developed for 6 types of cancer and the human immunodeficiency virus (HIV) as well as 39 general adult conditions (GAC). The validity and feasibility of these candidate indicators were evaluated using three modified Delphi expert panels. The strength of evidence, type of care (preventive, acute, or chronic), function (screening, diagnosis, treatment, and follow-up), and modality (history, physical examination, laboratory, medication, or other intervention) of the cancer/HIV quality indicators were compared with indicators developed for GAC. RESULTS: The final system included 117 of the 145 proposed cancer/HIV quality indicators (81%) and 569 of the 705 proposed GAC indicators (81%). A greater percentage of the cancer/HIV indicators were based on evidence from clinical trials compared with the GAC indicators (59% vs. 31%; P = 0.001). Cancer/HIV had significantly more indicators pertaining to chronic care than did GAC (74% vs. 56%; P = 0.001) as well as more indicators for treatment (53% vs. 39%; P = 0.004). CONCLUSIONS: Using the case-based approach, it is feasible to develop quality indicators for cancer that cover the continuum of care. Future studies will evaluate the reliability and validity of measurements made using these indicators in three managed care plans.

What is an error?

CONTEXT: Launched by the Institute of Medicine's report, "To Err is Human," the reduction of medical errors has become a top agenda item for virtually every part of the U.S. health care system. OBJECTIVE: To identify existing definitions of error, to determine the major issues in measuring errors, and to present recommendations for how best to proceed. DATA SOURCE: Medical literature on errors as well as the sociology and industrial psychology literature cited therein. RESULTS: We have four principal observations. First, errors have been defined in terms of failed processes without any link to subsequent harm. Second, only a few studies have actually measured errors, and these have not described the reliability of the measurement. Third, no studies directly examine the relationship between errors and adverse events. Fourth, the value of pursuing latent system errors (a concept pertaining to small, often trivial structure and process problems that interact in complex ways to produce catastrophe) using case studies or root cause analysis has not been demonstrated in either the medical or nonmedical literature. CONCLUSION: Medical error should be defined in terms of failed processes that are clearly linked to adverse outcomes. Efforts to reduce errors should be proportional to their impact on outcomes (preventable morbidity, mortality, and patient satisfaction) and the cost of preventing them. The error and the quality movements are analogous and require the same rigorous epidemiologic approach to establish which relationships are causal.

The influence of gatekeeping and utilization review on patient satisfaction.

OBJECTIVE: To examine the influence of utilization review and denial of specialty referrals on patient satisfaction with overall medical care, willingness to recommend one's physician group to a friend, and desire to disenroll from the health plan. DESIGN: Two cross-sectional questionnaires: one of physician groups and one of patient satisfaction. SETTING: Eighty-eight capitated physician groups in California. PARTICIPANTS: Participants were 11,710 patients enrolled in a large California network-model HMO in 1993 who received care in one of the 88 physician groups. MEASUREMENTS AND MAIN RESULTS: Our main measures were how groups conducted utilization review for specialty referrals and tests, patient-reported denial of specialty referrals, and patient satisfaction with overall medical care. Patients in groups that required preauthorization for access to many types of specialists were significantly (p

Development of a quality of care measurement system for children and adolescents. Methodological considerations and comparisons with a system for adult women.

OBJECTIVES: To describe the development of a pediatric quality of care measurement system designed to cover multiple clinical topics that could be applied to enrollees in managed care organizations and to compare the development of this system with the concurrent development of a similar system for adult women. DESIGN: Indicators were developed for 21 pediatric (ages 0-18 years) clinical topics and 20 adult (ages 17-50 years) women's clinical topics. Indicators were classified by the strength of evidence supporting them. A modified Delphi method was used to obtain validity and feasibility ratings from a pediatric expert panel and an adult women's expert panel. Indicators were categorized by type of care (preventive, acute, or chronic), function (screening, diagnosis, treatment, or follow up), and modality (history, physical examination, laboratory/radiology study, medication, other intervention, or other contact). RESULTS: Of 557 pediatric and 391 adult women's proposed indicators, 453 (81%) and 340 (87%), respectively, were retained by the 2 expert panels. A lower percentage of final pediatric indicators than adult indicators were based on randomized, controlled trials and other rigorous studies (18% vs 40%, P < .001). The expert panels were more likely to retain indicators based on rigorous studies (93% retained) than on descriptive studies and expert opinion (81% retained, P < .001). A higher percentage of pediatric indicators than women's indicators were for preventive care (30% vs 11%, P < .001) and a lower percentage were for acute care (36% vs 49%, P < .001) or chronic care (34% vs 41%, P = .06). CONCLUSIONS: This study contributes to the field of pediatric quality of care assessment by providing many more indicators than have been available previously and by documenting the strength of evidence supporting these indicators. Formal consensus methods are essential for the development of pediatric quality measures because the evidence base for pediatric care is more limited than for adult care.

Primary care physicians' satisfaction with quality of care in California capitated medical groups.

CONTEXT: Managed care and capitation have placed new responsibilities on primary care physicians, including formally acting as "gatekeepers" for specialty services and tests. Previous studies have not examined whether primary care physicians who provide services to patients under many coverage arrangements feel differently about caring for patients covered under capitation vs those covered through more traditional forms of insurance. An understanding of whether California primary care physicians feel that they deliver a different level of quality to capitated patients could help signal whether variations in care for patients with different coverage forms are evolving. OBJECTIVE: To evaluate whether primary care physicians in California capitated groups report different satisfaction levels with quality of care for patients in their overall practice than for patients covered by capitated contracts and to examine whether physicians' satisfaction with capitated care quality is influenced by the characteristics of the practice setting. DESIGN: Cross-sectional questionnaire. SETTING: A total of 89 California physician groups with capitated contracts. PARTICIPANTS: A total of 910 primary care physicians (80% response rate). MAIN OUTCOME MEASURE: Satisfaction with 4 aspects of quality of care provided to patients covered by capitated contracts vs patients overall. RESULTS: Physicians reported lower satisfaction with all 4 aspects of care for patients covered by capitated contracts than for patients in their overall practice: 71% were very or somewhat satisfied with relationships with capitated patients (compared with 88% for overall practice), 64% were very or somewhat satisfied with the quality of care they provided to capitated patients (compared with 88% for overall practice), 51% were very or somewhat satisfied with their ability to treat capitated patients according to their own best judgment (compared with 79% for overall practice), and 50% were very or somewhat satisfied with their ability to obtain specialty referrals (compared with 59% for overall practice) (P< or =.001 for all comparisons). Being in a medical group practice (vs an independent practice association) and having a larger percentage of capitated patients were independently associated by multivariate analysis with higher levels of satisfaction with capitated quality of care (P< or =.005). CONCLUSION: These California primary care physicians were less satisfied with the quality of care they deliver to patients covered by capitated contracts than with the quality of care they deliver to patients covered by other payment sources. However, those in medical group practices and with a higher percentage of capitated patients were more satisfied with capitated care. National expansion of capitation should be accompanied by efforts to ensure that the satisfaction of practicing physicians with the care they deliver does not decline.

Quality assurance in capitated physician groups. Where is the emphasis?

OBJECTIVE: To describe quality assurance (QA) programs implemented by capitated physician groups; to measure their relative emphasis on monitoring of overuse compared with underuse and monitoring and improving preventive services compared with chronic disease care; and to examine how group characteristics influence QA activity. DESIGN: Cross-sectional questionnaire. SETTING: A large network-model health maintenance organization in California (133 contracting physician groups). PARTICIPANTS: Ninety-four physician groups (71%) caring for 2.9 million capitated patients. MAIN OUTCOME MEASURES: Self-reported use of quality monitoring and improvement methods. RESULTS: All capitated physician groups conducted some QA. Groups' QA programs monitored areas subject to overuse, such as cesarean delivery and angioplasty rates, more than areas subject to underuse, such as childhood immunization rates and performance of retinal examinations for diabetic patients (64% vs 43%, P<.001). They monitored underuse of preventive services more than follow-up services for chronic diseases (54% vs 31%, P<.001). Groups also used reminders for preventive services more than they monitored follow-up services for chronic diseases (26% vs 15%, P<.01). Physician group characteristics independently associated with higher overall QA activity were greater number of years in existence, higher profitability, and capitated care penetration. CONCLUSION: Capitation places a large share of responsibility for QA in the hands of physician groups, but not all aspects of QA are being equally addressed. The emphasis on overuse may result from financial incentives inherent in capitation, while the focus on preventive services may stem from lack of adequate quality measurement tools for monitoring chronic disease care. Further research efforts should address how capitated physician groups might expand their QA programs to include monitoring of underuse, especially for patients with chronic disease.

Cytokines and immunological control of Eimeria spp.

Protozoan parasites belonging to the genus Eimeria cause considerable losses in livestock production in which stocking densities are high or environments restricted. The ability of hosts to mount immunological responses which limit parasite reproduction vary according to the particular species of Eimeria. Typically though, immune responses restrict parasite reproduction during primary infection and limit, if not prevent, subsequent infections. Although mechanisms of immunity are unknown, host immune responses have been exploited in the development of a method to control coccidiosis-immunisation with attenuated strains of Eimeria. Limitations of this control method, predominantly the cost of producing the attenuated parasites, necessitates identification of protective immune responses to facilitate selection of antigens for use in non-living vaccines. As in immune responses to many other parasitic infections of the gastrointestinal tract, the role of antibodies is at best minor, whereas T-cells are crucial. Numerous studies have shown that the intestinal mucosal T-cell population is dynamic; the number and phenotype of T-cells changes in response to Eimeria-infection. Specific changes in the intestinal T-cell population have not, however, been correlated with limitation of parasite reproduction. Experiments involving adoptive transfer of T-cell sub-populations and in vivo depletion of specific T-cells have shown that CD4+ T-cells and to a lesser extent CD8+ T-cells are important in immune responses which limit primary infection. In contrast, CD8+ T-cells are more important in subsequent infections with CD4+ T-cells having a lesser role. The effects of T-cells on Eimeria are partially mediated by the cytokines they release. Most attention has concentrated on interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) because these cytokines have been shown to limit other protozoan infections. IFN-gamma is produced in Eimeria-infected hosts but evidence that it is present at the site of infection is limited. Intestinal levels of IFN-gamma increase earlier in response to primary Eimeria-infection in mice which are relatively resistant, than in mice which are relatively susceptible. Neutralisation of endogenously produced IFN-gamma has shown that this cytokine limits oocyst production in either primary or secondary infections depending on the species of Eimeria. Production of TNF-alpha is also increased in infected hosts. In comparison with relatively susceptible mice, TNF-alpha is produced earlier and to a greater extent in the intestines of relatively resistant mice. Unexpectedly, injections of TNF-alpha into infected mice increased oocyst production. It remains to be determined whether the effects of endogenous TNF-alpha are the same as those of exogenous TNF-alpha. Mechanisms by which IFN-gamma and TNF-alpha modulate parasite reproduction have not been identified. A number of lines of experimentation have suggested that it is unlikely that IFN-gamma limits parasite reproduction through induction of the synthesis of reactive oxygen or reactive nitrogen intermediates, since both of these reactive intermediates have the capacity to exacerbate Eimeria-infection.

Managed care and capitation in California: how do physicians at financial risk control their own utilization?

OBJECTIVE: To describe the structure and range of utilization management methods initiated by physicians in response to capitation. DESIGN: Cross-sectional questionnaire. SETTING: A large network-model health maintenance organization (133 contracting physician groups) in California. PARTICIPANTS: 94 (71%) physician groups caring for 2.9 million capitated patients. MEASUREMENTS: Self-reported use of five major utilization management methods. RESULTS: All physician groups reported using gate-keeping and preauthorization for certain referrals or tests. Most also used profiling of utilization patterns (79%), guidelines (70%), and managed care education (69%). Most physician groups asked gatekeepers to submit preauthorization requests for specialty referrals and restricted patient self-referral. For example, 60% of groups required preauthorization for an internal medicine subspecialty referral, and 7% allowed patient self-referral. Most groups also asked gatekeepers to obtain preauthorization for many tests (for example, 95% for magnetic resonance imaging and 53% for pulmonary function tests). Preauthorization requests were denied infrequently (less than 10% of the time) by more than 75% of groups. Of the 54 groups reporting utilization profiles to their physicians, 61% never adjusted for case-mix among patients and more than 60% suggested practice changes to their physicians based on utilization. Fewer than 35% of the groups used written guidelines for expensive tests that required preauthorization (such as angiography). CONCLUSIONS: Physicians are responding to capitation by using utilization management techniques, some at early stages of development, that were previously used only by insurers. This physician-initiated management approach represents a fundamental transformation in the practice of medicine.

Follow-up after hospital discharge: does insurance make a difference?

As the length of hospital stays decreases, important medical problems are often deferred for follow-up after discharge. We investigated whether patients without regular physicians actually receive post-discharge care. Patients without regular physicians at the time of admission to a private nonprofit teaching hospital were surveyed by telephone one month after discharge. Forty-six percent were non-Caucasian and 53 percent had Medicaid or no insurance. Although discharge planning was documented for 97 percent of patients, only 54 percent of study participants had completed follow-up one month later and only 46 percent could identify a regular physician. Among all patients with a particular need for follow-up, Medicaid and uninsured patients were less likely to receive follow-up (p = 0.042), to identify a regular physician (p = 0.007), or to complete discharge instructions (p = 0.018). Cost of medical care was found to be a significant deterrent to obtaining follow-up for patients with Medicaid or with no insurance (p = 0.001). Expanded access to care, along with focused discharge planning, may improve completion of follow-up for Medicaid and uninsured patients.

The toxicity of adenosine analogues against Babesia bovis in vitro.

The toxicities of 20 analogues of deoxyadenosine or adenosine were tested in vitro against the intraerythrocytic parasite Babesia bovis. IC37 values (the concentration of compound required to reduce cell survival to 37%) were determined for each compound. Tubercidin (7-deaza-adenosine), 2-bromo-adenosine, 8-bromo-3-ribosyl adenine and 6-phenylamino-deoxyadenosine were shown to be the most toxic towards B. bovis. Comparison of the toxicity results for these compounds in B. bovis with those in human melanoma cell lines indicated a differential toxicity, in that many of the compounds were toxic towards B. bovis but were relatively non-toxic towards human melanoma cell lines and vice versa. These results suggest that the mechanism of toxicity of the deoxyadenosine and adenosine analogues, whose normal metabolism involves transport, metabolism and incorporation into nucleic acids, may vary significantly between B. bovis and mammalian cells, allowing such drugs to be considered for parasite chemotherapy.

Haem-rotational disorder in monomeric allosteric cyano-Met insect haemoglobins monitored by resonance Raman spectroscopy.

The haem-rotational disorder (insertion of haem into globin rotated about the alpha, gamma-meso axis by 180 degrees) has been investigated in the cyano-Met form of the monomeric allosteric insect haemoglobins, CTT III and CTT IV, by resonance Raman spectroscopy. The effect of haem disorder on the resonance Raman spectra has been observed in proto-IX, deutero-IX, and meso-IX CTTs. Most importantly, in the absence of overlapping vinyl vibrations, we have identified two Fe-C-N bending vibrations at 401 cm-1 and 422 cm-1 (pH 9.5) for 57Fe deutero-IX CTT IV ligated with 13C15N-, which are attributed to the two haem-rotational components. One Fe-C-N bending mode at 422 cm-1 shows a pH-induced shift to 424 cm-1 (pH 5.5) indicating the t----r conformational transition, whereas the other bending mode is pH-insensitive, representing a non-allosteric component. By replacing the unsymmetrical porphyrins with the "symmetrical" protoporphyrin-III we eliminate the haem disorder. Then, sharpening of the Fe-N epsilon(His) (at 313 cm-1) and Fe-CN (at 453 cm-1) stretching modes is observed and a single Fe-C-N bending mode (at 412 cm-1) appears. In cyano-Met proto-IX CTT III two vinyl bending vibrations at 412 cm-1 and 591 cm-1 assigned by deuteration of the vinyl groups also reflect the haem disorder. The 412 cm-1 vinyl vibration is intensity-enhanced via through-space coupling with one of the Fe-C-N bending modes (at 412 cm-1). In the cyano-Met form of proto-III CTT III this vinyl vibration is shifted to 430 cm-1 resulting in a dramatic drop in intensity. It is most likely that the specific vinyl-protein interaction at position 4 in one of the haem-rotational components is the origin of the coupling between the Fe-C-N and vinyl bending modes. The Fe-N epsilon(proximal His) and the Fe-CN stretching vibrations as well as the Fe-C-N bending vibration have been identified by 54Fe/57Fe and 13C15N/12C15N/13C14N/12C14N isotope exchange.