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RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The U.S. prison population has increased substantially in recent years, and violent injury is common among prisoners. We sought to describe injury patterns and other characteristics of prisoners who presented to a trauma center after injury. Because penetrating trauma from an improvised weapon (e.g., shank) is frequent, we also sought to compare characteristics and outcomes of prisoners and non-prisoners who sustained an anterior abdominal stab or shank wound (AASW)., Methods: We analyzed injured adult prisoners who presented to a Level 1 trauma center between February, 2011, and April, 2017. We described characteristics of the injured prisoners and their hospitalizations. We compared prisoners who sustained an AASW to a random sample of non-prisoners with the same mechanism of injury using the chi-square test, Student's t-test, and logistic and Poisson regression., Results: Of 14,461 hospitalized injured adults, 299 (2.0%) were injured while incarcerated. 185 (62%) encounters involved interpersonal violence and 36 prisoners (12%) presented with self-inflicted injuries. 98 (33%) had a psychiatric disorder. Among 33 prisoners and 66 non-prisoners who sustained an AASW, prisoners were less likely to have undergone a laparotomy [14/33 (42%) vs 44/66 (67%); RR 0.64 (95% CI 0.41-0.98)] or sustained an injury requiring operative intervention [2/33 (6%) vs 23/66 (35%); RR 0.17 (95% CI 0.04-0.69)]., Conclusions: Many injured prisoners have psychiatric illness, are involved in interpersonal violence, or harm themselves. Among hospitalized patients, abdominal stab/shank wounds sustained in prison are less likely to result in significant injuries or operative intervention than similar wounds in non-prisoners., (Copyright © 2021. Published by Elsevier Inc.)

Treatment of psychiatric patients is frequently complicated by medical comorbidities, complex pharmacologic regimens, and side effects occurring secondarily to those regimens. Acute urinary retention is an infrequently discussed side effect of such regimens. This report describes the development of acute urinary retention (AUR) in a 60-year-old man with a history of benign prostatic hyperplasia. The patient developed AUR during treatment with combination buprenorphine/naloxone, trazodone, and lurasidone. We discuss the potential relationship of these agents to the development of this patient's AUR, the complicated neurochemical dynamic of the voiding process, and the pathologic consequences that psychotropic agents can have on that process., (Copyright © 2018 by the American Psychiatric Association.)

Purpose: A probable case of severe drug-induced hyponatremia associated with boceprevir use is reported., Summary: A 55-year-old woman was started on boceprevir (800 mg orally thrice daily) during week 5 of triple therapy for chronic hepatitis C. Her serum sodium concentration the morning before starting boceprevir use was 140 mmol/L. After the fourth dose of boceprevir, the patient developed progressive dizziness leading to eventual loss of consciousness. She was taken to the emergency department (ED), where her serum sodium concentration was measured as 126 mmol/L; boceprevir use was temporarily discontinued. The patient's symptoms improved with infusion of 0.9% sodium chloride injection, and she was discharged home the same day. After resuming boceprevir use that evening, the woman developed extreme dizziness and headache upon awakening the next morning. On her return to the ED later that day, she had a serum sodium value of 134 mmol/L and was admitted to the hospital for monitoring and evaluation. Over the next three days, her symptoms improved with additional infusion therapy and discontinuation of boceprevir. The patient continued to receive dual therapy (peginterferon alfa-2a and ribavirin) without further documented serum sodium instability. Using the adverse drug reaction probability scale of Naranjo et al., the case was assigned a score of 5, indicating a probable reaction to boceprevir., Conclusion: Soon after initiating boceprevir use as part of hepatitis C triple therapy, a woman required hospitalization for probable drug-induced hyponatremia, which resolved with discontinuation of the medication., (Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Purpose: The purpose of the study was to examine the impact of incorporating certified diabetes educator trainees into medical practices on patient diabetes outcomes., Methods: This was a mixed methods practice-based evaluation study undertaken in 2 primary care practices in high-poverty neighborhoods in Buffalo, New York. The evaluation entailed a physician-referred patient cohort with pre- and postanalysis of chart review data corresponding to the American Diabetes Association's diabetes indicators. Patient charts were reviewed at baseline and 12 months. A brief survey was administered to the providers and staff to ascertain the extent to which the certified diabetes educator trainees were perceived as useful as part of the medical practice team., Results: Among 74 patients enrolled in diabetes classes, A1C levels decreased from a mean of 8.8% to 8.3%. Among a subset of patients (35%) with poorly controlled diabetes at baseline (A1C ≥ 9), there was a 15% decrease in A1C levels. Overall improvement in A1C was observed among 219 patients seen by a diabetes educator, in either a diabetes education class or a one-on-one visit., Conclusions: Results suggest that having a certified diabetes educator trainee as part of the primary care practice team may advance diabetes care, as evidenced by improvements in glucose control. Responses from providers and staff suggest that the certified diabetes educator trainees were well integrated into the practices and were perceived as instrumental in educating patients to better manage their diabetes.

Alcohol withdrawal continues to present significant morbidity and mortality in hospitalized medical/surgical patients. The authors present a case of a patient with delirium tremens requiring up to 1,600 mg/day of lorazepam and discuss alternative treatments for alcohol withdrawal.

Objective: The main goals, of this observational study were to clarify and categorize decisional capacity assessments performed by a psychosomatic medicine (PSM) consult service at an academic medical center. Areas of investigation included types of decisional capacity requests, the relationship between Folstein Mini-Mental State Exam (MMSE) and PSM decisional capacity determination, psychiatric diagnoses of patients, and the agreement between primary clinician capacity assessment and that of the PSM clinician., Method: This was a prospective study of 100 consecutive decisional capacity consultations. Twelve requests were for second consultations for patients previously seen, for a net of 88 patients., Results: In 77 cases, patients lacked decisional capacity. Assessments for capacity to leave against medical advice (AMA), capacity to accept medical/surgical procedures, capacity to refuse medical/surgical procedures, and capacity to participate in discharge planning were nearly equally frequent. An MMSE cutoff score of < 21 was found to be 100% specific and 69% sensitive for identifying the patients without capacity, while a cutoff of < 24 was found to be 83% sensitive and 90% specific for identifying patients without capacity. The primary psychiatric diagnosis was a cognitive disorder in 52 cases. In 38 of the 39 cases where the primary team believed the patient lacked capacity, the PSM service agreed. In only two of the seven cases where primary teams believed patients had capacity did the PSM team agree., Conclusions: The MMSE was a useful predictor of capacity determination by PSM personnel, but using MMSE alone results in a number of erroneous determinations. Cognitive disorders were the most common primary psychiatric diagnoses in decisional capacity cases. Primary teams tended to be more accurate when they found patients to lack capacity.

Background: Postbypass refractory right ventricle (RRV) may develop due to right ventricular (RV) ischemia or infarction. In cases with RV infarction, recovery is often prolonged and salvage rate is extremely poor. In this retrospective study, we have examined the role of right ventricular exclusion (RVE), as a possible option to conventional weaning or bridging to heart transplant (B-HTX), in patients who were unsuitable for heart transplant., Methods: During last 5 years, cumulative incidence of postbypass refractory circulatory failure (RCF) in our adult patients was 0.39% (26/6542). This problem was caused by a RRV in 17 (65%) patients. After CABG, these patients developed a grossly distended and poorly contracting RV (RVEDV: 330-400 ml, RVEF: 0-10%), high central venous pressure (> or =18 mmHg) and an inadequate aortic pressure for weaning off cardiopulmonary bypass. Three patients, who were unacceptable for HTX under UNOS program (age >65 years), were weaned off bypass after RVE, and remaining patients with RVAD (n=3) or BiVAD support, depending upon their concomitant moderate or poor left ventricular performance., Results: The significant predictors of RRV by univariate analysis were; 2nd or 3rd redo CABG for a recent myocardial infarction, and failed graft angioplasty. Hospital mortality (14-60 days) was 0/3, 3/3 and 3/11 for the patients weaned off with RVE, RVAD and BiVAD respectively. At 3 years, overall salvage rate was 9/17 (RVE: 3/3, BiVAD B-HTX 4/6 + 2 weaned with BiVAD support)., Conclusion: Right ventricular exclusion is a possible option to conventional B-HTX with mechanical support, in patients who develop postinfarct RRV and are unsuitable for transplant.

In this retrospective series overall results after reoperative coronary artery bypass surgery and the subsequent management of recurrent ischemic heart disease in these patients were reviewed. Between September 1980 and September 1993, 17% (n = 1300) of our patients (Pts) undergoing myocardial revascularization (CABG) were reoperative. Of these, 75% were male and 17% were > or = 70 years. One or both internal thoracic arteries (ITA) were used in 25% Pts; a saphenous vein graft (SVG) was used sequentially in 67% or as a separate conduit in 8%. Hospital mortality was higher after redo CABG than after primary CABG (6.9% vs 2.1%, p < 0.0001) and also in Pts receiving SVG rather than IMA as a conduit (7% vs 3.8%, p < 0.001), and in Pts receiving retrograde coronary sinus cardioplegia (RCSC) (n = 504) as compared to those who received antigrade cardioplegia since 1989 (n = 334) (2.5 vs 5.4%, p < 0.05). Throughout the series, independent predictors of hospital mortality by multivariate analysis were: female gender, postoperative myocardial infarction, congestive cardiac failure and stroke. Actuarial survival at 10 years for the patients receiving ITA as a conduit was 86% and for the patients receiving SVG only 76% (p < 0.02); for patients > 70 years was 66% and for patients < 70 years 80% (p < 0.005). Pts with a LVEF < 20% had a poor survival after 2 years. At 10 years cardiac related event free survival after 1st reoperation was 53%. During 13 years 94 Pts underwent subsequent reoperations and 125 Pts underwent saphenous vein graft angioplasty (PTCA), for recurrent ischemic heart disease. Cardiac event free survival at 6 years was clearly superior after multiple reoperative surgery than after graft angioplasty (45% vs 35% p < 0.05). In conclusion, in this series, use of the ITA as a conduit and RCSC has significantly improved Pts survival after redo CABG. Survival and quality of life were further improved in patients requiring multiple reop CABG or graft PTCA.

Between January 1980 and December 1992, 3% (210/6,862) of our patients undergoing myocardial revascularization (CABG) had high grade (> 80%) internal carotid stenosis (CS). One hundred seventy-five of these patients with complete follow up for a minimum of 18 months were studied. Bilateral internal CS was present in 60%, and 75% had other vascular lesions, mainly as peripheral vascular disease (PVD) of the lower limb (50.8%). All patients underwent CAE (carotid endarterectomy) followed by CABG under the same anesthesia. Peripheral vascular lesions, contralateral internal CS and recurrent (n = 43) and progressive vascular lesions (n = 50), were subsequently treated as staged procedures. Hospital mortality was 3.42%. By univariate analysis significant predictors of late mortality were congestive heart failure, COPD, PVD, postoperative myocardial infarction, postoperative stroke, and ischemic cardiomyopathy. Only the latter two were also significant by multivariate analysis. At 12 years, actuarial survival in the presence of these risk factors were 46%, 49%, 22%, 37%, 53%, and 27% respectively. All are significantly lower as compared with the corresponding subsets of patients with the risk factor absent. At 12 years, actuarial survival for the entire series was 65%. Cumulative incidence of postoperative strokes was higher in patients with bilateral internal CS than in patients with unilateral internal CS (p < 0.07) and in patients with neurologic symptoms than asymptomatic patients. At 12 years, actuarial freedom from all cardiac related events, postoperative stroke, and symptomatic PVD were 49%, 82%, and 76% respectively. After successful revascularization these patients should be carefully followed for recurrent and progressive vascular lesions.

We retrospectively analyzed early and late results for two treatment strategies of significant coronary artery disease in 310 octogenarians seen in the last 10 years. One hundred five patients 80 or more years of age had percutaneous transluminal coronary angioplasty (PTCA) and 205 had coronary artery bypass grafting (CABG). The PTCA group differed from the CABG group in having a greater proportion of women (71.4% versus 45.8%; p < 0.001); fewer patients with unstable angina (24.7% versus 33.6%; p < 0.04), acute myocardial infarction (11% versus 23%; p < 0.04), three-vessel coronary artery disease (20% versus 56%; p < 0.0001), and a left ventricular ejection fraction less than or equal to 0.30 (10% versus 21%; p < 0.008); and fewer vessels revascularized (1.2 +/- 0.6 versus 3.5 +/- 0.9; p < 0.0001). Hospital mortality was 8.57% after PTCA (9/14 failed PTCA) and 5.8% after CABG (4/14 emergent, 6/101 urgent, and 2/90 elective). Hospital stay was 7 +/- 0.9 days after PTCA and 14 +/- 1.5 days after CABG (p < 0.01). Independent predictors of hospital mortality obtained by multivariate analysis included failed PTCA and acute myocardial infarction (PTCA group), a left ventricular ejection fraction equal to or less than 0.30, and acute myocardial infarction and emergency CABG (CABG group). Survivors after both CABG and PTCA showed a significant improvement in their New York Heart Association class. Actuarial survival at 5 years after PTCA was 55% and after CABG it was 66% (p < 0.01). Cardiac event-free survival (deaths, myocardial infarction, PTCA, CABG) at 3 years was 61% after PTCA and 81% after CABG (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Primary malignant pericardial mesothelioma is a rare tumor of unknown etiology. The prognosis is extremely poor due to generally late presentation, inability to completely eradicate it surgically and its poor response to radiotherapy or chemotherapy. An unusual case of pericardial mesothelioma which presented as constrictive pericarditis is described. A comprehensive review of the 140 cases reported in the literature so far is presented to assist the readers in the management and prognosis of this rare, pathological tumor.

Factors influencing the survival of 35 consecutive patients in end-stage renal disease who required 40 open heart surgical procedures over the past 8 years were studied. The mean age in these patients was 57.7 +/- 3 years (range, 32 to 77 years); 74.3% of the patients were male; and the average duration of hemodialysis was 3.6 +/- 0.6 years. Twenty-nine myocardial procedures (20 of 29 for unstable angina), six valve replacements, and five combined procedures were performed. The actuarial survivals at 1 and 3 months, and at 1, 5, and 8 years were 90%, 85%, 76%, 55%, and 43%, respectively. Based on the results of univariate analysis, the most significant predictor of both early and late mortality was New York Heart Association (NYHA) class IV congestive heart failure. The 5-year survival in the patients 60 years and older was less favorable than that in patients younger than 60 years (45% versus 63%) (p < 0.05). The 5-year survival in the patients in NYHA class IV was only 27%, as compared to 63% in the patients in class II or III (p < 0.001). All survivors have remained free of angina and 19 of the 21 survivors showed an improvement in their NYHA class. Four patients under 40 years of age have subsequently been able to undergo renal transplantation. Overall, these results justify proceeding with an open heart surgical procedure in dialysis patients, when needed, but before the onset of congestive heart failure.

Simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CE) were done on 133 patients over an 8-year period. Twenty-seven patients (20%) had previous transient ischemic attacks (TIAs), 12 (9%) had previous strokes, and the remainder (71%) were asymptomatic. All asymptomatic patients had greater than 85% stenosis of the internal carotid artery demonstrated by noninvasive ultrasonography and four-vessel angiography. CE was performed prior to the sternotomy for coronary artery bypass, under the same anesthesia. Nineteen patients had bilateral carotid artery disease. Postoperatively, three patients (2.3%) suffered strokes, an additional three patients (2.3%) suffered transient upper extremity weakness, and one patient from each of these groups died. There were no postoperative strokes or TIAs in patients with bilateral carotid artery disease. Average length of hospital stay was 10 days. Our experience leads us to conclude that the morbidity and mortality of the simultaneous procedure are not affected by bilateral carotid artery disease. In patients with symptomatic coronary artery disease and symptomatic carotid artery disease or asymptomatic carotid artery disease with a high-grade stenosis, we think that simultaneous repair of both lesions should be done.

Using an intraabdominal heterotopic cardiac transplant procedure, we determined that the Fischer 344 rat (donor)/Long Evans rat (recipient) combination provides a suitable model for studying acute rejection of cardiac allografts. Rejection time was 9.7 +/- 0.2 days. With this model we investigated the effect of donor pretreatment with methotrexate on allograft survival. Methotrexate injection at a single optimum dose of 100-200 mg/kg, i.p., resulted in a 55-60% increase in allograft survival with indefinite survival of some allografts. The optimum time for methotrexate administration was found to be 3-24 hr before transplant, indicating the clinical feasibility of this approach. Combining methotrexate with different recipient treatments (cyclosporine, methylprednisolone, or methylprednisolone plus azathioprine) resulted in significantly longer allograft survival than with any treatment alone. We have demonstrated a novel and clinically feasible approach to the treatment or prevention of acute allograft rejection. Such a treatment could allow reduction in the dose of immunosuppressant drugs to the recipient and thus lessen the toxicity of immunosuppressant therapy.

A heterotopic cardiac transplant model, with male Fischer 344 rats as donors and Long Evans rats as recipients, was utilized to investigate the effect of dietary n-3 polyunsaturated fatty acids on acute rejection. Both donor and recipient rats were fed purified diets high in either n-3 polyunsaturated fatty acids (from concentrated n-3 ethyl esters [EE] or fish oil [FO]) or n-6 polyunsaturated fatty acids (from corn oil [CO]) for either 2-3 or 3-4 weeks before transplant. The recipient rats continued on their diets until rejection. The AIN-76A-based diets (with 30% of calories as fat) had adequate essential fatty acids and were balanced for sterols and antioxidants. Allograft survival was significantly increased by 45% when recipient rats were fed EE as compared to the control (CO diet fed to both donor and recipient), regardless of the diet fed to the donor. There was a slight but significant increase in allograft survival when only donor rats were fed the EE diet 2-3 weeks before transplant. With the FO diet (containing one third of the n-3 fatty acids in the EE diet), only the group fed FO to both donor and recipient (starting 2-3 weeks before transplant) showed a significant increase in allograft survival over the control. However, if the FO diets were fed for 3-4 weeks before transplant, increased survival was seen in groups fed FO to either the donor or recipient alone. In this case, allograft survival with FO feeding to both donor and recipient was not different from recipient treatment alone. In all the studies there was a significant and direct correlation between allograft survival and the donor heart phospholipid n-3/n-6 fatty acid ratio and the n-3 fatty acid content (at rejection). There was an indirect relationship with the n-6 fatty acid content. There was no detectable 20:3 (n-9) in the cardiac phospholipids, indicating the absence of essential fatty acid deficiency. Recipient diets were the strongest determinant of the fatty acid composition in the transplanted donor heart. The data indicate that providing dietary n-3 polyunsaturated fatty acids before and after cardiac transplant to recipient animals provides a significant protection against acute rejection.

A patient with total occlusion of the distal right pulmonary artery secondary to the performance of a Waterston shunt is reported. A nearly fatal intrapulmonary steal occurred at the time of corrective operation when an attempt was made to revascularize both pulmonary arteries.

Prolonged extracorporeal membrane oxygenation (PEMO) was performed in 6 adult ponies with the membrane oxygenator in vein-to-artery bypass circuit. A flow rate equal to 46 per cent of control cardiac output was diverted through the PEMO circuit of 10 to 24 hours. Three of the 6 ponies were perfused for at least 20 hours and developed no complications. Immediately following initiation of PEMO, left ventricular output decreased; however, in the interval between 6 and 24 hours, left ventricular output was increased above control levels. Aortic pressure and left ventricular work were markedly elevated during PEMO. Pulmonary ventilation and oxygen uptake also decreased initially but were elevated during later stages of bypass. Pulmonary compliance did not change, except in those studies in which problems were encountered with perfusion techniques. Hepatic glycolysis and hyperglycemia occurred and were more severe in ponies with catheter-produced thrombi. Marked diuresis, which could be attributed only partially to the hyperglycemia, was present throughout PEMO. Based on the minimal morphologic changes observed in the ponies, extracorporeal circulation diverting one half of the cardiac output through a membrane oxygenator can be safely performed for up to 24 hours.

We tested the ability of various cardiac preservation techniques to preserve left ventricular function of isolated canine hearts using preservation temperatures of 4 degrees or 15 degrees C. The four techniques tested were: (1) topical hypothermia, and hypothermic arrest induced by (2) perfusion of 1 liter of a modified Collins solution, (3) perfusion of 1 liter of a modified extracellular solution (DKS), or (4) perfusion of 500 ml of blood cardioplegia. Following the cold ischemia period, the hearts were reperfused with blood in the working heart preparation and tested for their ability to recover left ventricular function. Hearts preserved 2 hours at 15 degrees C using hypothermia, modified Collins solution, or DKS solution achieved an average of 60, 73, and 95%, respectively, of baseline function. Hearts preserved 3 hours at 4 degrees C using topical hypothermia attained 70% of baseline function, while hearts stored 5 hours at 4 degrees C using modified Collins solution or DKS solution recovered 83 and 92%, respectively, of baseline function. Hearts preserved at 4 degrees C functioned at levels equal to or greater than that of hearts stored at 15 degrees C, even though the hearts preserved at 4 degrees C were stored for longer periods than those preserved at 15 degrees C. Hearts preserved with blood cardioplegia for 2 hours at either 4 degrees or 15 degrees C achieved functions statistically the same as baseline levels during the reperfusion period. These data show no advantage for preservation temperatures of 15 degrees C compared with 4 degrees C. Our data provide a firm experimental basis for the clinical use of myocardial preservation temperatures of 4 degrees C, especially when combined with cardioplegia.

Tissue levels of creatine phosphate (CP), creatine, adenosine-triphosphate(ATP), inorganic phosphate (Pi), glycogen, glucose and lactate were determined in heterotopically transplanted and recipient hearts as well as in the myocardium of sham-operated rabbitsmthe ATPase activity in these tissues was also estimatedmthe results revealed no biochemical indication of ischemic conditions in the transplanted organs relative to the other investigated tissue. The tissue levels of CP in the donor heart were even higher then in both the recipient and sham-operated organs. The concentrations of the other above listed compounds in all the studied tissue were similar throughout the first 5 post-operative days. The effect of surgery was manifested in decreased levels of CP, still prevailing 3 days post-operative in all of the investigated tissue. However, on the fifth day after surgery, the tissue concentration of CP showed a trend toward recovery. The activity of Na,K-ATPase in both donor and recipient hearts was similar. One day after surgery, the activity of the Mg-ATPase was 27% lower relative to its value on days 3 and 5 post-operatively. However no correlation was obtained between the change in Mg-ATPase and tissue concentrations of ATP.

Patients receiving heterotopic ("piggyback") cardiac transplants, when the patient's own and transplanted donor hearts are connected in parallel, present special problems in determining their relative contributions to total cardiac function. Three patients who had transplants because of intractable heart failure were studied using first pass and gated equilibrium technetium-99m-labeled blood pool scintigraphy. In one patient, thallium-201 myocardial perfusion scans were obtained. These nuclear cardiology techniques provided anatomic and functional information noninvasively that proved helpful in patient management.

Phasic blood flow recorded in five unobstructed dog aortocoronary bypass grafts to the left coronary artery was similar to that of normal coronary arteries, with a high diastolic-to-systolic flow ratio which averaged 2.7 +/- 0.4. With an average of 52 +/- 7% and 72 +/- 6% stenosis in the coronary artery distal to the graft, the phasic graft-flow pattern was altered, with a decrease in the diastolic-to-systolic flow ratio to 1.9 +/- 0.4 and 1.2 +/- 0.4, respectively. Phasic patterns recorded in 42 human saphenous vein grafts to branches of the left coronary artery subsequently shown to be patent by postoperative coronary arteriography were similar to those of a normal coronary artery, with an average diastolic-to-systolic flow ratio of 2.3 +/- 0.83 and an average flow of 76 +/- 48 ml/min. Phasic flow measured in 20 grafts shown to be occulded at restudy had an average diastolic-to-systolic flow of 1.3 +/- 0.45, with an average flow of 72 +/- 33 ml/min and a phasic graft flow which was similar to that obtained from partially obstructed coronary arteries. We conclude that partial obstruction of the graft or the distal coronary artery alters the flow pattern, and this partial obstruction may lead to closure of the graft.

From 1971 to 1975, 17 consecutive patients aged 1 day to 4 years underwent Blalock-Taussig shunts for severe tetralogy of Fallot. Three infants were under 6 weeks of age and 7 (41%) under 1 year. There were no hospital deaths. Modification of the shunt technique adapts it to any size infant. The subclavian artery is divided at its major branches and the end spatulated to enlarge it. The artery is occluded while the shunt is constructed. No intraoperative complications were encountered; all patients have a shunt murmur with no early or late closure. No child has had heart failure or hypoxic spells. Flows measured at operation equaled one-quarter to one-half of the child's normal cardiac output. Ligation of the shunt at subsequent repair is uncomplicated. One child died three years later at correction from causes unrelated to the shunt. With appropriate modifications in technique, the Blalock-Taussig shunt is the operation of choice, at any age, for palliation of severe tetralogy of Fallot.

Tweleve patients with the complete form of persistent atrioventricular (AV) canal were operated upon at the University of Wisconsin between May, 1972, and November, 1975. The technique originally described by Rastelli and his associates was used. All 12 patients are asymptomatic and well, with no hospital or late deaths. Postoperative cardiac catheterization in 8 patients showed a return to near normal dynamics, with minimal residual mitral insufficiency. Half of these children had type A and half type C malformations; both types could be repaired without the need for valve replacement. Since 3 of these patients were less than 2 years of age, we now feel that complete repair of the AV canal can be undertaken in children between 12 and 18 months of age for optimal management.

We have shown previously that acute aortic insufficiency in chronically instrumented dogs reverses the normally high ratio of diastolic to systolic coronary blood flow. Phasic blood flow in the dominant right coronary artery was measured directly with an electromagnetic flow meter during surgery in eight patients with severe aortic insufficiency before and after relacement of the aortic valve. Before the insufficiency was eliminated, right coronary flow average 116 +/- 37 ml./minute and the diastolic to systolic flow ratio was 0.88 +/- 17. Mean arterial blood pressure averaged 106 +/- 17 mm. Hg, heart rate 84 +/- 19 beats/minute, and mean diastolic pressure averaged 67 +/- 10 mm. Hg. After the aortic valve was replaced with an average heart rate of 90 +/- 15 and mean blood pressure of 103 +/- 13 mm. Hg, the average right coronary blood flow increased to 180 +/- 40 ml./minute with a D/S ratio of 2.18 +/- 0.8. In all cases the right coronary blood flow increased after the aortic insufficiency was eliminated surgically. Right coronary flow probably increased because of the improved diastolic perfusion pressure and the change from predominantly systolic to diastolic coronary flow.

A 63 year old woman with a large true posterior ventricular aneurysm and mitral regurgitation is presented. Simple aneurysmectomy without replacement or repair of the mitral valve completely alleviated the mitral insufficiency.

Heart and kideny allografts showed markedly prolonged survival in unrelated mongrel dogs following total lymphoid irradiation (TLI) and donor bone marrow without any other immunosuppression. In every animal the heart survived longer than the kidney; genetic disparity was ruled out, since the heart and kidney from the same donor were placed into one recipient. Placing the kidney allograft in the abdomen with the bone marrow given intraperitoneally doubled kidney survival over placement in the neck, but heart survival was equally prolonged in the abdomen or neck. Splenectomy before TLI or after TLI, but just before transplantation, almost completely eliminated the prolonged survival of both heart and kidney allografts. Thus there is suggestive evidence from the work of Slavin and his colleagues and from our study that TLI plus bone marrow from the donor may be valuable for transplantation in man, particularly heart transplantation.

Actin from human blood platelets or rabbit skeletal muscle can serve as substrate for factor XIIIa. The latter catalyzes the incorporation of 1.5-2 mol monodansylcadaverine/mol rabbit actin and 0.5 mol/mol platelet actin. Highly cross-linked platelet and muscle actin polymers form in the absence of added amines, indicating the presence of both acceptor and donor sites. As expected, the cross-link was found to be a gamma-glutamyl-epsilon-lysine bone, with an average of 0.3-0.4 mol dipeptide/mol platelet actin. Both cross-linking and amine incorporation are prevented by ATP, ADP, GTP, CTP, but not by AMP and cyclic AMP. These nucleotides may have important regulatory role in muscle and non-muscle systems.

The histochemical and ultrastructural effects of extracorporeal circulation and aortic cross-clamping during coronary heart surgery have been examined in drill biopsy samples of the left ventricle in 22 patients. The biopsies were obtained before and after bypass with a DeSoutter drill. Histochemical studies indicated definite differences between control and experimental biopsies, with increased succinic dehydrogenase, cytochrome oxidase, and LDH activity, while phosphorylase A and myosin ATPase activities declined. Furthermore, free phospholipid levels increased, as determined by the acid hematein reaction. Ultrastructural examination demonstrated loss of glycogen, intracellular swelling, and mitochondrial damage, which included loss of matrix density, loss of cristae, and eventual disruption in the postbypass biopsy. These results, which closely resemble the effects of ischemia and reperfusion observed in animal experiments, suggest that the initial insult is a change in membrane permeability regulation.

A technique is presented to eliminate the residual gradient more completely after removing the main pulmonary band at the time of primary repair of ventricular septal defect. The band and underlying pulmonary artery are circumferentially excised, except for a small posterior part, and pulmonary artery is reanastomosed.

A 48-year-old woman with known Ebstein's anomaly had bilateral, lower-extremity arterial emboli after a total abdominal hysterectomy. She underwent embolectomy, placement of a Greenfield caval filter, subsequent tricuspid valve replacement, and closure of an atrial septal defect. Antemortem diagnosis of a paradoxical embolus is rare. To our knowledge, this is the first case associated with this congenital cardiac anomaly in a survivor.

Hearts preserved for 2 hours at 15 degrees C were evaluated for maximum function with the use of an isolated working dog heart subjected to stress. We determined left ventricular function by controlling aortic flow resistance and flow into the left atrium. Groups studied were hypothermia alone (H), hypothermia with a modified extracellular solution (H + DKS), hypothermia with a modified Collins solution (H + C), six periods of 20 minutes of hypoxic hypothermia followed by 10 minutes of blood reperfusion (H20 + R10) and blood cardiplegia (BC). Hypothermia alone for 1 hour was also evaluated. Functions were studied for 2 1/2 hours following reperfusion by determining Starling's curves for each heart. Our data show that H alone gave adequate myocardial protection for only 1 hour but not for 2 hours. H20 + R10 was better than H, but function was depressed. Use of H + C provided protection equal to H20 + R10, but the hearts recovered function slowly. Only hearts preserved by H + DKS and BC for 2 hours had normal function. Hearts from all groups except H + DKS and BC became edematous. Excellent function was obtained with DKS or BC following 2 hours of ischemia at 15 degrees C. Initial clinical use of BC supported these laboratory findings.

A routine chest X-ray taken four months after blunt chest trauma revealed a left ventricular aneurysm in a totally asymptomatic patient. At surgery a thin-walled, clot-filled aneurysm was successfully removed. This case demonstrates the need for careful follow-up of all patients sustaining blunt chest trauma even though the initial cardiac evaluation may be negative. Our feeling that all such aneurysms should be treated surgically is further reinforced by our operative findings.

Eighty-six patients admitted with evolving myocardial infarction within 6 hours of symptom onset were treated with streptokinase. Thirty-nine received intracoronary streptokinase, and 47 received intravenous streptokinase. There were no streptokinase-related complications. Twenty-three patients treated with intracoronary streptokinase and 28 patients receiving intravenous streptokinase underwent coronary artery bypass grafting. On admission, 16 patients receiving intracoronary streptokinase had electrocardiographic evidence of anterolateral evolving myocardial infarction and seven had evidence of inferior evolving myocardial infarction. Time from first symptom to intracoronary streptokinase was 4.4 +/- 1.6 hours. In seven patients, intracoronary streptokinase failed to open the obstructed coronary. All developed severe left ventricular hypokinesia in the area supplied by that coronary artery. In spite of recanalization, nine of 14 patients developed severe hypokinesia in the supplied area, and one an apical aneurysm. Four patients developed mild to moderate hypokinesia, and one had no left ventricular damage. On admission, 14 patients receiving intravenous streptokinase had electrocardiographic evidence of anterolateral evolving myocardial infarction and four had evidence of inferior evolving myocardial infarction. Time from first symptom to intravenous streptokinase was 3.2 +/- 1.5 hours. In seven patients, intravenous streptokinase failed to open the coronary, and all developed severe hypokinesia of the supplied area, with formation of apical left ventricular aneurysm in three. In 21 patients, intravenous streptokinase opened the artery. Eighteen angiographies performed 9.6 +/- 7.9 days after therapy showed a normal left ventricle in eight patients, moderate hypokinesia in seven, and severe hypokinesia in three. Time from first symptom to therapy was shorter in the patients receiving intravenous therapy (p less than 0.01). Coronary artery bypass grafting and four resections after left ventricular aneurysm were performed without operative death. Two patients receiving intracoronary therapy died in the hospital, and one died 2 months later from arrhythmias. Freedom from angina and rehabilitation (New York Heart Association Class I) were achieved in 69.5% of patients receiving intracoronary streptokinase and in 75% of patients receiving intravenous streptokinase. Thus streptokinase-induced thrombolysis salvages myocardium, and the intravenous route seems as effective as the intracoronary. Advantages of the former are earlier administration that might increase myocardial salvage, no invasive procedure, and lesser cost.

Quinidine syncope is an unpredictable side effect of quinidine administrateion which has a mortality rate of 11.5 per cent when managed with conventional drugs and direct-current countershock. In 2 patients with quindine syncope, the arrhythmias were effectively controlled within 30 minutes following the slow infusion of 150 mg. of bretylium tosylate. This control is contrasted with 2 cases managed in the conventional manner. Bretylium tosylate is a quaternary amine with unique antifibrillatory properties and appears to have a significant role in the management of these arrhylmias.

99mTechnetium macroaggregated albumin has successfully been used to define severe postoperative pulmonary vasoconstriction in a four-month-old boy with D-transposition of the great vessels who had undergone a Blalock-Hanlon surgical atrial septectomy. Radionuclide imaging documented clinically suspected pulmonary vasoconstriction and led to the successful use of tolazoline (Priscoline) to reverse the vasoconstriction with improved pulmonary blood flow patterns.