Comparative NMR analysis of an 80-residue G protein-coupled receptor fragment in two membrane mimetic environments.

Fragments of integral membrane proteins have been used to study the physical chemical properties of regions of transporters and receptors. Ste2p(G31-T110) is an 80-residue polypeptide which contains a portion of the N-terminal domain, transmembrane domain 1 (TM1), intracellular loop 1, TM2 and part of extracellular loop 1 of the α-factor receptor (Ste2p) from Saccharomyces cerevisiae. The structure of this peptide was previously determined to form a helical hairpin in lyso-palmitoylphosphatidyl-glycerol micelles (LPPG) [1]. Herein, we perform a systematic comparison of the structure of this protein fragment in micelles and trifluoroethanol (TFE):water in order to understand whether spectra recorded in organic:aqueous medium can facilitate the structure determination in a micellar environment. Using uniformly labeled peptide and peptide selectively protonated on Ile, Val and Leu methyl groups in a perdeuterated background and a broad set of 3D NMR experiments we assigned 89% of the observable atoms. NOEs and chemical shift analysis were used to define the helical regions of the fragment. Together with constraints from paramagnetic spin labeling, NOEs were used to calculate a transiently folded helical hairpin structure for this peptide in TFE:water. Correlation of chemical shifts was insufficient to transfer assignments from TFE:water to LPPG spectra in the absence of further information.

Antipili antibody affords protection against experimental ascending pyelonephritis.

The ability of antipili antibody to prevent ascending urinary tract infection was investigated in rats. One group of rats was immunized passively with rabbit antisera to purified pili and challenged by intravesicular inoculation of 5 x 10(7) heavily piliated Escherichia coli. Only 2 of 14 immunized animals developed cortical abscesses as compared to 13 of 15 control rats given normal rabbit serum (P equals 0.0001). The mean log titer of bacteria in the kidneys of the immunized rats was 0.85 vs. 6.08 in the controls (P less than 0.005). A second group was actively immunized with pili. 3 of 16 immunized animals became infected as compared to 10 of 15 controls (P equals 0.01). The mean log titers were 2.13 and 4.54, respectively (P less than 0.01). A third group was passively immunized and challenged with a strain that had different O, K, and H antigens but shared pili antigens. Abscesses occurred in 4 of 15 immunized animals as compared to 13 of 15 controls (P equals 0.001). The mean log titers were 2.37 and 5.63, respectively (P less than 0.005). These results indicate that antipili antibody protects rats against ascending urinary tract infections.

Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss.

The hyperphosphorylated microtubule-associated protein tau is present in several neurodegenerative diseases, although the causal relationship remains elusive. Few mouse models used to study Alzheimer-like dementia target tau phosphorylation. We created an inducible pseudophosphorylated tau (Pathological Human Tau, PH-Tau) mouse model to study the effect of conformationally modified tau in vivo. Leaky expression resulted in two levels of PH-Tau: low basal level and higher upon induction (4% and 14% of the endogenous tau, respectively). Unexpectedly, low PH-Tau resulted in significant cognitive deficits, decrease in the number of synapses (seen by EM in the CA1 region), reduction of synaptic proteins, and localization to the nucleus. Induction of PH-Tau triggered neuronal death (60% in CA3), astrocytosis, and loss of the processes in CA1. These findings suggest, that phosphorylated tau is sufficient to induce neurodegeneration and that two different mechanisms can induce cognitive impairment depending on the levels of PH-Tau expression.

Prognostic significance of nonfatal reinfarction during 3-year follow-up: results of the Thrombolysis in Myocardial Infarction (TIMI) phase II clinical trial. The TIMI Investigators.

OBJECTIVES: This study sought to assess the independent contribution of nonfatal reinfarction to the risk of subsequent death in patients with acute myocardial infarction undergoing thrombolytic therapy. BACKGROUND: A composite of "unsatisfactory outcomes" as an end point has increased statistical power and facilitated evaluation of evolving treatment regimens in acute myocardial infarction. The significance of nonfatal reinfarction as a component of a composite end point has not been evaluated in the thrombolytic era. METHODS: Event rate of nonfatal reinfarction over 3-year follow-up was evaluated in patients with acute myocardial infarction entered into the Thrombolysis in Myocardial Infarction Phase II trial. The independent risk of nonfatal reinfarction for subsequent death within various time intervals of follow-up was determined. The mortality rate after nonfatal reinfarction was compared with that of a matched control group. RESULTS: During 3-year follow-up, 349 of 3,339 patients had a nonfatal reinfarction. Univariate predictors were history (antedating the index event) of angina (p = 0.01), hypertension (p = 0.01), multivessel disease (p = 0.007) and not a current smoker (p = 0.003); the latter was an independent predictor (relative risk [RR] 1.3, 99% confidence interval [CI] 1.0 to 1.8). Forty-three of the 349 patients with a nonfatal reinfarction died: RR for death (vs. patients without a nonfatal reinfarction) was 1.9 (99% CI 1.1 to 3.2) if reinfarction occurred within 42 days of study entry, 6.2 (99% CI 3.0 to 12.9) if reinfarction occurred between 43 and 365 days and 2.9 (99% CI 0.6 to 13.4) if reinfarction occurred between 366 days and 3 years. The cumulative 3-year death rate was 14.1% in patients with a nonfatal reinfarction compared with 7.9% (p < 0.01) in a matched control group. Univariate predictors of death after nonfatal reinfarction were age > or = 65 years (p < 0.001), not low risk category (p = 0.015) and history of heart failure before the index event (p < 0.001). Age > or = 65 years was the only independent predictor (RR 5.4, 99% CI 2.3 to 12.4). CONCLUSIONS: Nonfatal reinfarction is a strong and independent predictor for subsequent death. It represents a powerful component for a composite end point in patients who received thrombolytic therapy after acute myocardial infarction.

High dose intravenous streptokinase for acute myocardial infarction: preliminary results of a multicenter trial.

To assess the efficacy of intravenous streptokinase in patients with acute myocardial infarction, 40 patients (30 men and 10 women, mean age 54 years) with acute myocardial infarction were given 1.5 million U of streptokinase intravenously in 1 hour, and coronary arteriography was performed repeatedly to assess reperfusion. Streptokinase treatment was begun 270 +/- 86 (mean +/- SD) minutes after the onset of chest pain. Of the 40 patients, 34 had total or near total coronary occlusion before streptokinase administration. In 14 (41%) of these 34 patients, some reperfusion occurred during the 90 minutes after the administration of streptokinase, but in only 11 of the 14 was reperfusion present at 90 minutes. After streptokinase administration, all patients received heparin for 8 to 10 days; they were subsequently administered aspirin and dipyridamole. Clinical evidence of reocclusion during the first 24 hours of heparin therapy occurred in one patient. Thus, when given to patients with acute myocardial infarction and total coronary occlusion an average of 4 1/2 hours after the onset of chest pain, high dose intravenous streptokinase achieves reperfusion in only about 40% and results in sustained reperfusion in only about 30%.

Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women. METHODS: Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 microgram) or placebo in a 12-week, double-blind, placebo-controlled study. A 4-week washout period followed the 12-week treatment phase. Outcome measures were the Montgomery-Asberg Depression Rating Scale and Blatt-Kupperman Menopausal Index scores. RESULTS: Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder. Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P =.001). Subjects responded similarly to estradiol treatment, regardless of DSM-IV diagnosis. Patients treated with estradiol sustained antidepressant benefit of treatment after the 4-week washout period, although somatic complaints increased in frequency and intensity. Treatment was well tolerated and adverse events were rare in both groups. CONCLUSION: Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women.

Prevalence and predictors of depressive symptoms in older premenopausal women: the Harvard Study of Moods and Cycles.

BACKGROUND: The Harvard Study of Moods and Cycles is a community-based cohort study designed to evaluate the relationship between major depression and changes in menstrual and ovarian function. METHODS: All women aged 36 to 44 years with a verifiable address from 7 Boston, Mass, metropolitan communities were selected from the Massachusetts Town Books. A self-administered questionnaire assessed demographic characteristics and menstrual history, depression history, and current depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D]) in 4161 women. RESULTS: We observed a score of 16 or more on the CES-D in 22.4% of women surveyed, and 8.6% scored 25 or more. Widowed, divorced, or separated women were twice as likely as married women to have depression scores greater than 16 (95% confidence interval, 1.6-2.8), and smokers in the upper tertile of pack-years were 1.9 times more likely to have CES-D scores of 16 or more (95% confidence interval, 1.5-2.3). Relative to nulliparous women, those with 1 or 2 children had a 30% lower risk of historic mood disorder, and those with 3 or more children had an even greater reduction in risk (odds ratio, 0.4; 95% confidence interval, 0.3-0.6). Menstrual cycle irregularities were largely unassociated with current or past depression. However, 5 of 8 premenstrual symptoms were significantly associated with CES-D scores of 16 or more. CONCLUSIONS: These findings corroborate the prevalence of depression reported by other community-based studies, and also support a relationship between depressive symptoms and marital status, cigarette smoking, nulliparity, and premenstrual symptoms.

Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge?

A growing body of literature describes the effects of estrogen and other gonadal steroids on the central nervous system. The ability of estrogen to modulate serotonergic function, in particular, raises the possibility that sex steroids may play a role in the mechanisms associated with depression and its treatment. This review will focus on those aspects of the estrogen-serotonin interaction that relate to possible increased vulnerability to affective disorders and on hormonal treatments that may be clinically applicable to women. After a discussion of the potential relationship between estrogen and mood disorders across the female life cycle, a model is proposed in which differential sensitivity to mood disorders explains the differential response by some women to periods of normal hormonal changes. Possible serotonin receptor-mediated and intracellular mechanisms by which estrogen may exert its effects on mood are also reviewed. These are compared to putative mechanisms of standard antidepressant effect. Lastly, treatment studies in which estrogen has been used as 1) monotherapy for depression, 2) an augmentation strategy, or 3) a prophylactic intervention against recurrence of depression are reviewed.

Prophylactic estrogen in recurrent postpartum affective disorder.

Seven women with histories of puerperal psychosis and four with histories of puerperal major depression were consecutively treated with high-dose oral estrogen immediately following delivery. None of the women had histories of nonpuerperal affective disorder, and all women were affectively well throughout the current pregnancy and at delivery. Despite the high risk for recurrent illness in this population, only one woman developed relapse of postpartum affective disorder. All others remained entirely well and required no treatment with psychotropic medications during the 1 year follow-up period. This low rate of relapse, 9% compared to an expected 35-60% without prophylaxis, suggests that oral estrogen may stem the rapid rate of change in estrogen following delivery, thereby preventing the potential impact on dopaminergic and serotonergic neuroreceptors. It is hypothesized that the rapid rate of change of estrogen after delivery creates an "estrogen withdrawal state." This may be a critical factor in driving acute puerperal affective psychosis and early-onset puerperal major depression.

Course of panic disorder during pregnancy and the puerperium: a preliminary study.

Pregnancy has been referred to as a time of well-being for patients with psychiatric disorder. However, this impression is derived primarily from anecdotal reports and retrospective studies, rather than systematic prospective evaluation. In this study, 10 pregnant women with previous histories of panic disorder were evaluated prospectively across pregnancy and the postpartum period using the Structured Clinical Interview for DSM-III-R and the Clinical Global Impression. Information regarding pharmacotherapy received was also recorded. Seven of 10 subjects continued to meet DSM-III-R criteria for panic disorder at all trimester visits. Symptoms persisted for some patients even in the context of treatment with antipanic medications. Most subjects (n = 9) met DSM-III-R criteria at 1-3 months postpartum despite nearly uniform intensification of antipanic treatment. Although some women may experience diminished symptoms of panic during pregnancy, in this sample most continued to experience panic attacks and to require antipanic treatment to control symptoms.

Birth outcomes following prenatal exposure to fluoxetine.

BACKGROUND: Although pregnancy has frequently been described as a time of emotional well-being, some women experience significant antenatal depression that may require treatment with antidepressants. The purpose of this investigation was to examine the relative effects of early and late trimester exposure to fluoxetine and perinatal outcome. METHODS: Obstetric and neonatal records were reviewed for 64 mother-infant pairs where there was documented use of fluoxetine at some point during pregnancy. Differences in several measures of obstetrical outcome and neonatal well-being were examined in early trimester- and late trimester-exposed infants. RESULTS: No differences in birth weight and acute neonatal outcome were evident across the two groups, though there was a higher frequency of special care nursery admissions for infants with exposure to fluoxetine late in pregnancy. Special care nursery admissions could not be attributed to any specific factor. CONCLUSIONS: Given the growing numbers of women who are treated with antidepressants, including fluoxetine, during pregnancy, and the strong association between depression during pregnancy and risk for postpartum depression, patients may be best advised to continue treatment with antidepressants through labor and delivery versus making any change in intensity of treatment during the acute peripartum period.

Prevalence of body dysmorphic disorder in a community sample of women.

OBJECTIVE: In a large population-based study, the authors examined the prevalence and correlates of body dysmorphic disorder, a debilitating and chronic condition characterized by an imagined defect in appearance. METHOD: Rates and diagnostic correlates of body dysmorphic disorder were examined by using data from the Harvard Study of Moods and Cycles. This study used in-person structured clinical interviews to characterize the diagnostic status of a population-based, cross-sectional sample of 318 depressed and 658 nondepressed women between the ages of 36 and 44 who were selected from seven Boston metropolitan area communities. RESULTS: The presence of body dysmorphic disorder was significantly associated with the presence of major depression and anxiety disorders. The authors estimated the overall point prevalence of body dysmorphic disorder as 0.7% in women in this age range in the community. CONCLUSIONS: The authors found that the presence of body dysmorphic disorder was linked to the presence of major depression and anxiety disorders, which is similar to findings in clinical studies. Their estimate of the point prevalence of body dysmorphic disorder is consistent with data from a community-based sample of Italian women and suggests a prevalence similar to that of other serious psychiatric disorders in women (e.g., schizophrenia and drug abuse and dependence). These prevalence data encourage the further development of treatment options for this debilitating condition.

Postpartum prophylaxis for women with bipolar disorder.

OBJECTIVE: The postpartum period has typically been considered a time of heightened vulnerability for development of affective disorders, and women with bipolar disorder have consistently demonstrated vulnerability to puerperal worsening of mood. This retrospective study examined the extent to which mood-stabilizing agents provide prophylactic benefit to bipolar women during the postpartum period. METHOD: The clinical course of 27 women meeting the DSM-III-R criteria for bipolar disorder was followed during pregnancy and the postpartum period. Information regarding severity of illness (as measured by number of episodes of mania, depression, or both) was obtained, in addition to data on pharmacotherapy (if any) received before, during, and after pregnancy. The extent to which the prophylactic use of antimanic agents minimized the risk of relapse was explored. RESULTS: Only one of the 14 patients taking prophylactic agents during the acute puerperium relapsed within the first 3 months postpartum, while eight of the 13 who did not receive antimanic drugs showed evidence of recurrent affective instability during those 3 months. A survival analysis indicated that the women receiving prophylactic treatment with mood stabilizers maintained well-being significantly longer than the women who did not receive such treatment. CONCLUSIONS: Women with bipolar disorder appear to benefit from puerperal prophylaxis with mood stabilizers. Consistent with results of earlier studies, postpartum prophylaxis was associated with lower rates of relapse into affective disorders. The findings have implications for the early identification and treatment of subgroups of women at particular risk for puerperal illness.

Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance.

OBJECTIVE: Pregnancy poses major challenges for the treatment of bipolar disorder, and information to guide clinical care remains very sparse. The authors sought to determine the illness recurrence risk for women with bipolar disorder who discontinue lithium maintenance during pregnancy. METHOD: The authors retrospectively compared recurrence rates and survival functions for 101 women with DSM-IV bipolar disorder (68 type I, 33 type II) during pregnancy and postpartum (N=42) or during equivalent periods (weeks 1-40 and 41-64) for age-matched nonpregnant subjects (N=59) after either rapid (1-14 days) or gradual (15-30 days) discontinuation of lithium. Recurrence rates also were obtained for the year before discontinuing lithium. RESULTS: Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant (52%) and nonpregnant women (58%) but had been much lower for both in the year before treatment was discontinued (21%). Among subjects who remained stable over the first 40 weeks after lithium discontinuation, postpartum recurrences were 2.9 times more frequent than recurrences in nonpregnant women during weeks 41-64 (70% versus 24%). Depressive or dysphoric-mixed episodes were more prevalent in pregnant than nonpregnant women (63% versus 38% of recurrences). Recurrence risk was greater after rapid than after gradual discontinuation, and for patients with more prior affective episodes, but was similar for diagnostic types I and II. CONCLUSIONS: Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant and nonpregnant women but then sharply increased postpartum. Risk was much lower during preceding treatment and less with gradual discontinuation. Treatment planning for potentially pregnant women with bipolar disorder should consider the relative risks of fetal exposure to mood stabilizers versus the high recurrence risks after discontinuing lithium.

Paroxetine in human breast milk and nursing infants.

OBJECTIVE: The purpose of this study was to determine the extent of infant medication exposure through breast-feeding during maternal treatment with paroxetine. METHOD: Breast milk and paired maternal and infant sera were collected after 10 days of maternal treatment with paroxetine at a stable daily dose (10-50 mg/day). All samples were analyzed by means of high-performance liquid chromatography with ultraviolet detection and a limit of detection of 2 ng/ml. RESULTS: Breast milk paroxetine concentrations were highly variable (2-101 ng/ml) and were present in all breast milk samples (N=108). A significant gradient effect was observed, with greater paroxetine concentrations found in later portions of breast milk (hind milk) than in early portions (fore milk). No clear time course of paroxetine excretion into breast milk was demonstrated, although maternal paroxetine daily dose reliably predicted both trough and peak breast milk concentrations over a 24-hour period. In 16 mother and infant serum pairs, no detectable concentrations of paroxetine were found in the serum of the nursing infants. CONCLUSIONS: This study extends previous data by demonstrating the presence of paroxetine in the breast milk of nursing women treated with this medication. The low concentrations of paroxetine in infant serum and lack of any observable adverse effects after maternal use of this medication while breast-feeding parallels the available data on other selective serotonin reuptake inhibitors.

The short- and long-term prognosis of patients with transmural and nontransmural myocardial infarction.

To compare the long-term prognosis in patients surviving transmural with patients surviving nontransmural myocardial infarctions, the records of 188 consecutive patients with clinical histories and enzyme elevations consistent with acute infarction were reviewed. According to standard electrocardiographic criteria the patients were divided into two groups: 148 with transmural myocardial infarction (group 1) and 40 with nontransmural myocardial infarction (group 2). Of the patients who survived hospitalization, follow-up data were obtained on 119 of 124 patients in group 1 and 36 of 37 patients in group 2 at a mean follow-up period of 36 months. In group 2, the patients had a high incidence of sudden death after discharge (33 per cent in group 2 versus 15 per cent in group 1, p less than 0.02) as well as a significantly higher incidence of death from all cardiac causes (41.6 per cent in group 2 versus 24.3 per cent in group 1, p less than 0.05). Furthermore, the patients in group 2 still alive at the end of the follow-up period had an increased incidence of angina pectoris and of recurrent infarction. The data suggest that patients with nontransmural myocardial infarction carry a particularly guarded prognosis.

Left ventricular peak power during exercise: a noninvasive approach for assessment of contractile reserve.

Cardiac peak power, a contractility index based upon instantaneous changes in intracavitary pressure and systolic peak flow, was measured at rest and during supine exercise in 26 patients with coronary artery disease and 8 healthy subjects. The pathophysiological significance of this index was compared with left ventricular ejection fraction (LVEF) during exercise. Cardiac peak power, ejection fraction, end-diastolic volume, stroke volume, cardiac output and systemic vascular resistance were measured at rest, during three stages of supine bicycle ergometry and two stages of recovery. Cardiac peak power increased continuously in healthy subjects, from 5.4 +/- 0.8 W/ml at rest to 11.4 +/- 3.1 W/ml at peak exercise, p < 0.001. In patients, peak power increased initially, reached a plateau in stage 2, and subsequently remained unchanged in stage 3 (5.6 +/- 2 versus 5.6 +/- 1.6 W/ml, p = ns). Ejection fraction demonstrated a flat response during exercise in patients, contrasting with a 42% increase in cardiac peak power. The lack of increase in ejection fraction was attributed to its dependence on afterload. Peak power showed no correlation with systemic vascular resistance (r = 0.01, p = ns). In a subgroup of patients with low resting LVEF (LVEF = 26% +/- 7%), peak power increased 70% during exercise, from 2.0 +/- 0.7 to 3.5 +/- 1.7 W/ml, p < 0.05, in contrast to a flat ejection fraction response. Thus, cardiac peak power, a relatively afterload-independent index of left ventricular performance and contractility can be obtained noninvasively during exercise.

Radionuclides and the patient with coronary artery disease.

The emergence in the past 20 years of nuclear medicine as a distinct diagnostic discipline has been a major clinical advance. The relatively rapid evolution from the small laboratory limited primarily to the study of thyroid disease to the large unit in which radioactive tracers (radionuclides) are utilized to evaluate structure and function of most organ systems has been accelerated by major advances in instrumentation, new radioactive tracers and application of computer techniques. Application of these radionuclide techniques to the study of coronary artery disease has been quite recent, and has in part been limited by the need for a coordinated effort between the cardiologist and the specialist in nuclear medicine. However, realization of the potential usefulness of these techniques has fostered an increasingly productive liaison between the two specialties. The potential advantages of these radionuclides in evaluating patients with cardiovascular disease is twofold: first, they may permit the noninvasive or atraumatic acquisition of data that might otherwise be obtained only at the time of cardiac catheterization; second, and perhaps more important, they may permit the acquisition of physiologic measurements or observations not attainable by more conventional modes of study. Functionally, these techniques can be divided into those that evaluate cardiac performance and those that evaluate coronary blood flow, regional myocardial perfusion and myocardial viability.

Retrograde catheterization of the left atrium in idiopathic hypertrophic subaortic stenosis.

Retrograde catheterization of the left atrium utilizing the Shirley technique was successfully performed in four patients with idiopathic hypertrophic subaortic stenosis. By traversing the inflow tract of the left ventricle on pullback from the left atrium to the aorta, this method served to separate definitively true hypertrophic subaortic stenosis from cavity obliteration. It was accomplished with relative ease and no complications. In patients with suspected idiopathic hypertrophic subaortic stenosis who are to have retrograde left heart catheterization, this approach to the left atrium is recommended as an alternative to the transseptal technique.