Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein.

Cytokines and growth factors induce tyrosine phosphorylation of signal transducers and activators of transcription (STATs) that directly activate gene expression. Cells stably transformed by the Src oncogene tyrosine kinase were examined for STAT protein activation. Assays of electrophoretic mobility, DNA-binding specificity, and antigenicity indicated that Stat3 or a closely related STAT family member was constitutively activated by the Src oncoprotein. Induction of this DNA-binding activity was accompanied by tyrosine phosphorylation of Stat3 and correlated with Src transformation. These findings demonstrate that Src can activate STAT signaling pathways and raise the possibility that Stat3 contributes to oncogenesis by Src.

Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias.

BACKGROUND: In 1990, when the Program on the Surgical Control of the Hyperlipidemias (POSCH) reported its in-trial results strongly supporting the conclusion that effective lipid modification reduces progression of atherosclerosis, the differences for the end points of overall mortality and mortality from atherosclerotic coronary heart disease (ACHD) did not reach statistical significance. METHODS: The Program on the Surgical Control of the Hyperlipidemias recruited men and women with a single documented myocardial infarction between the ages of 30 and 64 years who had a plasma cholesterol level higher than 5.69 mmol/L (220 mg/dL) or higher than 5.17 mmol/L (200 mg/dL) if the low-density lipoprotein cholesterol level was in excess of 3.62 mmol/L (140 mg/dL). Between 1975 and 1983, 838 patients were randomized: 417 to the diet control group and 421 to the diet plus partial ileal bypass intervention group. Mean patient follow-up for this 5-year posttrial report was 14.7 years (range, 12.2-20 years). RESULTS: At 5 years after the trial, statistical significance was obtained for differences in overall mortality (P = .049) and mortality from ACHD (P = .03). Other POSCH end points included overall mortality (left ventricular ejection fraction > or =50%) (P = .01), mortality from ACHD (left ventricular ejection fraction > or =50%) (P = .05), mortality from ACHD and confirmed nonfatal myocardial infarction (P<.001), confirmed nonfatal myocardial infarction (P<.001), mortality from ACHD, confirmed and suspected myocardial infarction and unstable angina (P<.001), incidence of coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (P<.001), and onset of clinical peripheral vascular disease (P = .02). There were no statistically significant differences between groups for cerebrovascular events, mortality from non-ACHD, and cancer. All POSCH patients have been available for follow-up. CONCLUSION: At 5 years after the trial, all POSCH mortality and atherosclerosis end points, including overall mortality and mortality from ACHD, demonstrated statistically significant differences between the study groups.

Evidence for a rapid stimulation of tyrosine kinase activity by prolactin in Nb2 rat lymphoma cells.

Studies were designed to determine if the activation of tyrosine kinases may be involved in the signal transduction pathway for PRL. Tyrosyl phosphorylation of cellular proteins was evaluated by western blot analysis of Nb2 cell proteins employing an antibody to phosphotyrosine. Physiological concentrations of ovine PRL (oPRL) had a pronounced effect on the tyrosyl phosphorylation of a 121 kDa protein. Increased tyrosyl phosphorylation of the 121 kDa protein was detectable with concentrations of oPRL as low as 0.5 ng/ml. Consistent with oPRL acting through a PRL receptor, hGH also stimulated tyrosyl phosphorylation of the 121 kDa protein when tested at concentrations between 5 and 20 ng/ml. In time course experiments, increased tyrosyl phosphorylation of the 121 kDa protein was apparent after a 5 min incubation with 20 ng/ml hGH, and maintained for at least one h. At higher concentrations of hGH (200 ng/ml), increased phosphorylation of the 121 kDa protein was clearly evident after only 1 min, indicating that tyrosyl phosphorylation of cellular proteins is an early event following ligand binding to the PRL receptor. Increased tyrosyl phosphorylation of proteins of 40, 90 and 55-65 kDa was also evident after incubation with hGH for 10, 10, and 60 min respectively. These findings are consistent with PRL-dependent tyrosine kinase activation being an early and perhaps initiating event in the signal transduction pathway for PRL in Nb2 cells.

Regulation of glucose transport and c-fos and egr-1 expression in cells with mutated or endogenous growth hormone receptors.

To identify mechanisms by which GH receptors (GHR) mediate downstream events representative of growth and metabolic responses to GH, stimulation by GH of c-fos and egr-1 expression and glucose transport activity were examined in Chinese hamster ovary (CHO) cells expressing mutated GHR. In CHO cells expressing wild-type GHR(GHR(1-638)), GH stimulated the expression of c-fos and egr-1, and stimulated 2-deoxyglucose uptake, responses also mediated by endogenous GHR in 3T3-F442A cells. Deletion of the proline-rich box 1 of GHR (GHR(deltaP)) abrogated all of these responses to GH, indicating that box 1, a site of association of GHR with the tyrosine kinase JAK2, is crucial for these GH-stimulated responses. As the C-terminal half of the cytoplasmic domain of GHR is required for GH-stimulated calcium flux and for stimulation of spi-2.1 transcription, GHR lacking this sequence (GHR(1-454)) were examined. Not only did GHR(1-454) mediate stimulation of c-fos and egr-1 expression and 2-deoxyglucose uptake, but they also mediated GH-stimulated transcriptional activation via Elk-1, a transcription factor associated with the c-fos Serum Response Element. Thus, the C-terminal half of the cytoplasmic domain of GHR is not required for GH-stimulated c-fos transcription, suggesting that increased calcium is not required for GH-stimulated c-fos expression. In CHO cells lacking all but five N-terminal residues of the cytoplasmic domain (GHR(1-294)), GH did not induce c-fos or egr-1 expression or stimulate 2-deoxyglucose uptake. Further, in 3T3-F442A fibroblasts with endogenous GHR, GH-stimulated c-fos expression and 2-deoxyglucose uptake were reduced by the tyrosine kinase inhibitors herbimycin A, staurosporine, and P11. Herbimycin A and staurosporine inhibit JAK2 and tyrosyl phosphorylation of all proteins stimulated by GH, whereas P11 inhibits the GH-dependent tyrosyl phosphorylation of only some proteins, including extracellular signal regulated kinases ERK1 and -2, but not JAK2. Taken together, these results implicate association of GHR with JAK2 and GH-stimulated tyrosyl phosphorylation of an additional cellular protein in GH-stimulated glucose transport and c-fos and egr-1 expression. These studies also indicate that, in contrast to spi-2.1, the N-terminal half of the cytoplasmic domain of GHR is sufficient to mediate stimulation of c-fos and egr-1 expression and Elk-1 activation, supporting multiple mechanisms for GH signaling to the nucleus.

Program on the Surgical Control of the Hyperlipidemias (POSCH): design and methodology. POSCH Group.

The Program on the Surgical Control of the Hyperlipidemias (POSCH) is a prospective, randomized, controlled, multi-center, secondary, atherosclerosis intervention trial. POSCH addresses the therapeutic arm of the lipid-atherosclerosis theory, i.e. whether lowering of plasma cholesterol is directly related to a reduction in atherosclerosis risk. In this trial, lipid modification is accomplished by the partial ileal bypass operation. Between 1975 and 1983, 838 patients were randomized into this study. All patients were between 30 and 64 years of age, had survived one and only one electrocardiogram and enzyme-documented myocardial infarction, and had a total plasma cholesterol of at least 220 mg/dl or a low density lipoprotein (LDL)-cholesterol of at least 140 mg/dl if the total plasma cholesterol was between 200 and 219 mg/dl after a minimum of 6 weeks of dietary fat and cholesterol restriction. The primary response variable in POSCH is overall mortality. Secondary endpoints include fatal and non-fatal myocardial infarctions, serial electrocardiographic changes, and, most importantly, sequential coronary arteriography changes. The minimum follow-up is currently planned to be 7 years. Study analyses will be made primarily on the "intention to treat" basis. This paper is the first detailed presentation of POSCH design and methodology. Included are descriptions of study design, implementation, and data collection, including data processing, quality assurance/quality surveillance, and patient safety monitoring. POSCH seeks to demonstrate a significant reduction in overall mortality by lipid modification and to validate the use of coronary arteriographic change as a surrogate endpoint for change in coronary heart disease risk.

Subgroup analyses of the major clinical endpoints in the Program on the Surgical Control of the Hyperlipidemias (POSCH): overall mortality, atherosclerotic coronary heart disease (ACHD) mortality, and ACHD mortality or myocardial infarction.

The Program on the Surgical Control of the Hyperlipidemias (POSCH) was a secondary atherosclerosis intervention trial employing partial ileal bypass surgery as the intervention modality. For this report, we analyzed 105 subgroups in 35 variables in POSCH, chosen predominantly for their potential relationship to the risk of atherosclerotic coronary heart disease (ACHD). We defined potential differential effects as those with: (1) an absolute z-value > or = 2.0 for the subgroup, if the absolute z-value for the overall effect was < 2.0; and (2) an absolute z-value > or = 3.0 for the subgroup and a relative risk < or = 0.5, if the absolute z-value for the overall effect was > or = 2.0. For each of three major POSCH endpoints of overall mortality, ACHD mortality and ACHD mortality or confirmed nonfatal myocardial infarction, we found seven subgroups with a differential risk reduction in the surgery group as compared to the control group. Allowing for identical subgroups for more than one endpoint, there were 13 individual subgroups with differential effects. Of these, seven demonstrated internal consistency across endpoints, and five of these seven displaced external consistency with known ACHD risk factors and for biological plausibility: triglyceride concentration > or = 200 mg/dl; cigarette smoking; overt or borderline diabetes mellitus; a Minnesota ECG Q-QS code of 1-1; and obesity. A greater risk reduction, in comparison to the overall treatment effect, by the reduction of a single risk factor, hypercholesterolemia, in patients with at least two major ACHD risk factors was a provocative and an hypothesis-generating outcome of this analysis. The clinical implications of this finding may lead to more aggressive cholesterol intervention in patients with multiple ACHD risk factors.

Pulsatile perfusion versus conventional high-flow nonpulsatile perfusion for rapid core cooling and rewarming of infants for circulatory arrest in cardiac operation.

Thirty consecutive infants undergoing hypothermia and circulatory arrest for repair of ventricular septal defect, transposition of the great vessels, or atrioventricular canal defects were alternately selected for conventional high flow nonpulsatile perfusion or pulsatile perfusion during core cooling and rewarming. All received morphine anesthesia, 30 mg/kg of Solu-Medrol, and 10 to 15 mcg/kg of phentolamine. Those receiving nonpulsatile flow were perfused at a rate of 160 to 180 cc/kg/min with a roller pump and oxygenator with arterial pressure of 50 to 55 mm Hg. In the pulsatile flow group, a roller pump and oxygenator were used, and an especially constructed Datascope PAD (pulsatile assist device) was interposed in the arterial line to provide pulsatile perfusion with 75/40 mm Hg pressure at slightly reduced flow (150 cc/kg/min). The average rectal, esophageal, and tympanic membrane temperatures were reduced to approximately 16 degrees C prior to circulatory arrest. Following repair, perfusion was resumed until these temperatures returned to 37 degrees C. Cooling and rewarming were enhanced by pulsatile perfusion, with over 30% reduction in total pump time. Additionally, the larger patients in the pulsatile group cooled almost as rapidly as the smaller. The rates of decline and subsequent rise of rectal, esophageal, and tympanic membrane temperatures were equal in the pulsatile group, but the rectal temperature lagged far behind in the nonpulsatile group. Urine production during bypass was 100% greater in the pulsatile group. The plasma free hemoglobin was similar in both groups. The average postrewarming pH was 7.31 in the nonpulsatile group and 7.42 in the pulsatile group. Infants receiving pulsatile flow awakened more quickly, were more alert, and required less postoperative mechanical ventilation. We suggest that pulsatile perfusion for core cooling and rewarming of infants is safe and is more rapid and physiological than conventional high-flow nonpulsatile perfusion.

Teaching law students in the medical schools.

Traditional efforts in the law schools to improve interprofessional communication between the medical and legal professions have been confined to abstract case studies and other academic materials, sometimes augmented with visits and demonstrations by physicians in the classroom. This paper describes one approach to broaden the prespective of law students during their training by permitting them to experience directly the atmosphere of the teaching hospital and the sociology of surgery practice in that environment. The experiment has proved beneficial to the young members of both professions.

Activated clotting time monitoring of intraoperative heparinization: our experience and comparison of two techniques.

The activated clotting time (ACT) has been used clinically for 41/2 years to monitor the adequacy of intraoperative heparinization in both cardiopulmonary bypass (CPBP) and peripheral vascular surgery (PVS) patients. Since January, 1976, we have operated on 440 PVS patients in our institutions, of whom 255 had intraoperative monitoring of heparinization by means of the ACT test; an additional 185 patients received heparin according to an empiric protocol. An automated machine for determining the ACT (Hemochron) had been used on the last 28 patients in the ACT group. We conclude that: (1) the ACT is an acurate method of monitoring anticoagulation during PVS, (2) the Hemochron is a simple and effective machine to perform the ACT, (3) values obtained by the Hemochron generally exceed those of the ACT done by hand by approximately 20 seconds at lower levels of heparin and are equal at higher levels of heparin, (4) supplemental heparin was required in 22% of our patients to maintain their ACT values at twice control values, (5) the response to heparin is twofold: an initial sensitivity or resistance followed by an independent and variable rate of consumption, and (6) the ACT is a useful method for predicting inadequate heparin reversal or heparin rebound at the conclusion of the operation.

The relative merits of the heparin-bonded shunt vs. femerofemoral bypass for aortic arch injury.

Six patients with traumatic aortic arch injuries have been repaired with distal aortic perfusion maintained with femerofemoral bypass (three patients) and the heparin-bonded ascending aorta-to-femoral artery shunt (three patients). The two groups are compared regarding pre- and postoperative changes in blood urea nitrogen, creatinine and platelet counts, as well as required blood replacement, days in the hospital, and rapidity of setting up the technique of distal aortic perfusion. No significant difference in the two techniques was demonstrated regarding the above parameters. Both the heparin-bounded shunt and femoral vein-to-femoral artery bypass with the pump oxygenator provide acceptable spinal cord and renal protection. The two techniques should be equally rapid and safe for the larger institution employing cardiopulmonary bypass procedures on a routine basis. The heparin-bounded shunt, however, may provide a more rapid and reliable means of lower aortic perfusion for the smaller institution with less available means of cardiopulmonary bypass support.

The Program on the Surgical Control of the Hyperlipidemias: a status report.

The Program on Surgical Control of the Hyperlipidemias (POSCH) is a multicentered secondary coronary heart disease intervention trial utilizing maximal plasma lipid reduction as achieved by the partial ileal bypass operation. With over 500 patients recruited into this trial at present, the 4-year sequential lipid changes are statistically highly significant and include an approximate 30% plasma total cholesterol and 40% low density lipoprotein (LDL)-cholesterol reduction, with a slight increase in the high density lipoprotein (HDL)-cholesterol and a marked increase in the HDL-cholesterol:LDL-cholesterol ratio of about 75% or higher. A definitive answer to the lipid-atherosclerosis theory corollary--whether a decrease in the plasma cholesterol engenders a reduction in the incidence or severity of atherosclerotic cardiovascular disease--can be expected from these marked lipid changes in POSCH.

Treatment of corrosive burns of the esophagus.

Forty patients with caustic ingestion have been treated between 1955 and 1975. Strong alkali was the corrosive in 95%, and 80% were under 10 years old. Early esophageal stricture developed in 18 patients four weeks after lye ingestion. Among these, esophageal bougienge restored an adequate lumen in two patients with short, soft annular strictures, and right colon interposition was used for esophageal subsitution in ten who had long, dense strictures. We recommend early diagnostic esophagoscopy, to the uppermost level of burn injury only, to determine the presence and severity of the esophageal injury. If esophagoscopy reveals esophageal burn injury, corticosteroid and antibiotic therapy are continued. If no burn injury is visualized, the patient is spared unnecessary treatment. Long, dense strictures unresponsive to bougienage place the patient at risk from instrumental perforation, and these patients should undergo colon interposition through a substernal extrapleural tunnel.

Ureteral obstruction secondary to iliac artery aneurysm.

A patient with an unusual unilateral ureteral obstruction secondary to mechanical obstruction by a common iliac artery aneurysm in association with an abdominal-aortic aneurysm is presented. A diagnosis of ureteral obstruction should be suspected in a patient with flank or abdominal pain and an infra-umbilical (iliac) aneurysm. Treatment is directed toward the aneurysm. The aneurysmal wall attachments to the ureter should be left undisturbed.

Adult respiratory distress syndrome.

Basic scientists and clinicians have written numerous articles on the diverse causes of adult respiratory distress syndrome (ARDS). There is no specific diagnostic test for ARDS; the condition is characterized by interstitial lung edema, reduction in lung compliance, alveolar and small airway closure, decrease in functional residual capacity, and persistent hypoxia with increasing amounts of pulmonary blood flow coursing through nonventilated or poorly ventilated alveoli. Recent studies have emphasized the roles of macrophages and polymorphonuclear neutrophils in lung defense and injury. Advances in understanding the pathophysiology of ARDS have produced little significant change in the clinical management of the syndrome. There is no specific treatment for ARDS. The cornerstone of therapy is the early recognition and elimination of initiating factors such as sepsis. ARDS is not a single disease process, but appears to represent a final common pathway for the manifestation of a variety of lung injuries. The goal of therapy is to eliminate the predisposing condition and support the patient. New modes of ventilatory and pharmacologic therapy are presented.

The role of profundaplasty in revascularization of the lower extremity.

Profundaplasty has been performed on 112 limbs (88 primary and 24 secondary) in eighty-five men. Seventy-six limbs had incapacitating claudication, twenty-three rest pain, and thirteen either gangrene or ischemic ulceration. In thirty-six limbs treated by profundaplasty alone there were no deaths but five subsequently had amputation for ischemic pain. In the seventy-six limbs treated by profundaplasty plus other operative augmentation there were three operative deaths and one late death; three required further operative surgery and in four amputation was necessary. Oblique arteriographic films of the femoral area are essential for evaluation of the profunda femoris artery. Both radionuclide and Doppler pressure studies confirmed physical and arteriographic findings. The latter would appear superior because of ease of availability and cost. After profundaplasty alone and aortofemoral bypass there was a moderate increase in calf blood flow, but in only those with a patent superficial femoral artery did blood flow and pressure studies return to within normal limits. Profundaplasty is an important addition to the armamentarium of the vascular surgeon in dealing with arteriosclerotic insufficiency of the lower extremities.

Congenital dilatation of the bile ducts.

Our experience with five cases of cystic dilatation of the extrahepatic bile ducts is reported and compared with the literature. The following conclusions have been reached: (1) The etiology of this anomaly is primarily congenital but may involve an acquired component. (2) Diagnosis should be suspected when any of the triad of abdominal pain, right upper quadrant mass, or jaundice is present. (3) The diagnosis can usually be made in infants based on the clinical picture and routine radiologic studies. (4) Retrograde cholangiopancreatography is a useful tool in making the diagnosis in older children and adults. (5) Roux-en-Y choledochocystojejunostomy is the procedure of choice for type I cysts, excision for type II, and choledochocystoduodenostomy for type III.

Symptomatic nonparasitic liver cysts.

Based on our experience with four cases of liver cysts and review of the literature, the following conclusions are reached: (1) Diagnosis can be established with routine and special radiologic studies. (2) Laparotomy is indicated for patients with symptoms or uncertain diagnosis. (3) Surgical management should be guided by cyst size, location, and content. (4) Definitive surgical treatment is indicated only for cysts larger than 10 cm.

Arterial embolectomy in the leg. Results in a referral hospital.

The clinical characteristics and course of 90 patients in whom 121 arterial emboli occurred from 1968 to 1978 were reviewed. The factor that correlated most significantly with a favorable outcome was the interval from onset of symptoms until arterial embolectomy was performed. The results of embolectomy were excellent in the patients operated on within 6 hours of symptoms (amputation rate 4 percent, mortality rate 15 percent), but less favorable in the patients operated on within 6 to 12 hours of onset of symptoms (amputation rate 27 percent, mortality 40 percent). Mortality (48 percent) and amputation (52 percent) rates in the patients operated on 12 to 48 hours after onset of symptoms were excessive. It is recommended that immediate embolectomy be performed in all potentially viable extremities in patients who present within 12 hours of symptoms, but that after 12 hours only those limbs with obvious viability (not paralyzed or anesthetic) should be operated on. Alternatives for the remainder are high dose intravenous heparinization or expedient amputation. In patients who present greater than 60 hours after the onset of symptoms, embolectomy can be performed with low morbidity and mortality.

The good ol' days is now: trends in operative experience of general surgical residents over 25 years.

To define the changing trends in operative experience of general surgery residents, the records of all residents completing our training program from 1964-1987 were reviewed. Except for a slight decline in operative experience in head and neck and gastric surgery, the experience in other primary component procedures either remained stable (major breast, esophagus, intestine, colon, pancreas, spleen and endocrine) or increased (minor breast, anorectal, hernia, biliary, vascular and trauma). A rich experience in secondary component procedures was maintained in thoracic, pediatric and plastic surgery, all of which are services within the department of surgery. A relatively low but stable experience in gynecology, neurosurgery, orthopaedics and urology has been reported, which did not change when these disciplines became separate departments. Finally, there has been a dramatic increase in endoscopic procedures performed in the surgery department despite the presence of endoscopic services in other departments. It is believed that such an institutional review of surgical resident caseload over time will be of help not only to program directors but also to accrediting and certifying organizations concerned with surgical training programs and their graduates.

Operative correction of proximal blocks of the subclavian or innominate arteries.

Ninety-four operations were performed on 90 individuals with occlusive disease of the subclavian or innominate arteries during the past 17 years. The left subclavian was occluded in 71, the right in 10, and the innominate in 9. Presenting symptomatology was neurological in 34, arm ischemia in 30 and combined in 26. Blood pressure was reduced by 30 mmHg on the involved side in all. An extrathoracic approach was used in 78 and a transthoracic approach in 16. Early mortality 18.7% and morbidity 18.7% was associated with the transthoracic approach. Long subcutaneous axillo-axillary and axillo-carotid are prone to thrombosis and skin erosion. Carotid-subclavian grafts used in 64 remain patent, occasionally become infected (4.7%), are associated with a low mortality and do not develop "carotid steal". When associated with vascular insufficiency of the lower extremity (44%) the brachiocephalic lesion should be corrected first.