Porcine encephalomyocarditis virus persists in pig myocardium and infects human myocardial cells.

Recent advances toward using pig tissues in human transplantation have made it necessary to determine the risk of transmitting zoonotic viruses from pigs to humans or vice versa. We investigated the suitability of the porcine encephalomyocarditis virus (EMCV) model for such studies by determining its ability to persist in pigs, escape detection by routine serological methods, and infect human cells. Intraperitoneal inoculation of 5-week-old pigs with EMCV-30, a strain isolated from commercial pigs, resulted in acute cellular degeneration, infiltration of lymphocytes, and apoptosis in myocardium in 13 of 15 (86.7%) pigs during the acute phase of disease (3 to 21 days postinfection), followed by less-severe lymphocytic infiltration and apoptosis in 5 of 10 (50%) pigs during the chronic phase of the disease (day 45 to 90 postinfection). In the brain, lymphocytic infiltration, neuronal degeneration, and gliosis were observed in 26 to 33% of pigs in the acute phase of disease whereas perivascular cuffing was the predominant feature during chronic disease. EMCV antigens and RNA were demonstrated in the myocardium and brain during the chronic phase of disease. Analysis of 100 commercial pigs that were negative for EMCV antibodies identified two pig hearts positive for EMCV RNA. Porcine EMCV productively infected primary human cardiomyocytes as demonstrated by immunostaining using a monoclonal antibody specific for EMCV RNA polymerase, which is expressed only in productively infected cells, and by a one-step growth curve that showed production of 100 to 1,000 PFU of virus per cell within 6 h. The findings that porcine EMCV can persist in pig myocardium and can infect human myocardial cells make it an important infectious agent to screen for in pig-to-human cardiac transplants and a good model for xenozoonosis.

Radioisotopic pulmonary lobectomy: feasibility study in dogs.

In search for an alternate treatment for inoperable cancer of the lung in humans, we investigated the possibility that introduction of radioactive material into a selected lobe of the canine lung would effectively destroy that lobe without systemic effects or radiation injury to adjacent organs. Ten million ion exchange microspheres labeled with 740 MBq of phosphorus-32 (32P) were injected through a catheter placed in a selected lobar branch of a pulmonary artery in 12 anesthetized dogs. Six additional dogs served as controls and received 10 million microspheres not labeled with 32P. Organs were harvested from 1 wk to 12 mo after injection and examined grossly and histologically. There was progressive organization and contraction of each necrosed 32P treated lobe which was reduced to a scarred remnant by 12 mo, whereas only minimal inflammatory changes occurred in controls. Of the 32P injected dose, 94% remained in injected lobe, 4%-5% in nontargeted lobes and less than 0.08% in blood. Radioactivity in liver, kidneys, spleen, heart, and bone marrow was less than 0.1% for each organ. Thus, large doses of radiation in the order of 1,500 Gy can be effectively delivered to a selected lobe to produce a "radioisotopic pulmonary lobectomy."

Baron Dominique Jean Larrey (1766-1842). Father of modern military surgery, innovater, humanist.

There is no question that Baron Larrey was the first modern military surgeon. The high morale of Napolean's troops, which contributed to the success of his armies, was in a major way dependent on Larrey's superb medical care of the wounded. It was Napoleon's brilliance to recognize this and to give Larrey free rein. Beginning in the Civil War, when ambulances first brought in the wounded to receive surgical care at the Battle of Antietam (1862), down to World War II and the Vietnam War, his principles were increasingly followed by the U.S. Army Medical Corps. In Vietnam a true "flying ambulance," the medical helicopter, was obviously the final perfection of Larrey's ambulance volante. Perhaps his dedicated humanism in the care of the wounded soldier was his best characteristic and the one that should be followed most carefully today. Even in this era of great ethical concerns for the sick and wounded, Larrey's principles set the highest of standards for all.

Options in the management of perforations of the esophagus.

A study of 90 cases of esophageal perforation in the antibiotic era emphasizes individualized treatment and options of therapy based on a fundamental understanding of modifying pathophysiologic factors. If the patient is seen during the first 24 hours, surgical repair and irrigating tube drainage continue to be the treatment of choice in the thoracic and abdominal regions, with certain exceptions. The exceptions include small perforations proved by a thin media esophagram or esophagoscopy without pleural involvement or constitutional symptoms. Such patients may be treated nonoperatively, with gastric drainage, antibiotics, and parenteral alimentation. However, for large perforations with extensive contamination of the mediastinum and pleura, an esophageal exclusion operation may be life saving. In the cervical region, irrigating tube drainage may be just as effectual as repair and drainage. In patients seen after 24 hours, size of the perforation and the amount of mediastinopleural infection, rather than the time that has elapsed, dictate optimal treatment.

Alteration of lymphocyte transformation response to herpes simplex virus infection by acyclovir therapy.

To evaluate the effect of acyclovir (ACV) therapy on the cellular immune response, we sequentially followed 43 patients with culture-proven first episodes of genital herpes simplex virus (HSV) infection. Twenty-three patients who were treated with ACV and 20 who received placebo had blood obtained weekly during the first 6 weeks after onset of lesions and had their in vitro lymphocyte transformation (LT) response to inactivated HSV antigens measured. The mean stimulation index to HSV antigens at week 3 among patients treated with systemic ACV was 3.5 +/- 0.64 compared to 18.4 +/- 6.89 in their placebo-treated counterparts (P less than 0.05). The mean time to the development of the peak LT response to HSV antigens was 4.3 weeks in systemic-treated versus 3.4 in placebo-treated patients (P less than 0.05). The time to the development of the peak in vitro LT response to HSV antigens and the height of that response were, however, similar between topical ACV- and topical placebo-treated patients. The geometric mean HSV-2-neutralizing titer in convalescent sera was 5.4 in recipients of systemic ACV compared to 10.0 in patients treated with systemic placebo (P less than 0.05). The LT response to HSV antigen was also measured at the first recurrence in 11 patients. No differences were found in the time to first recurrence, lesion duration, number of lesions, or mean stimulation index response to inactivated HSV antigens between the six patients treated with systemic ACV during their primary episode and the five given placebo during their primary episode. Systemic ACV therapy appears to diminish the peak in vitro LT response to inactivated HSV antigens as well as to delay the time to development of that peak response. However, the cell-mediated immune response to subsequent episodes appears similar.

The failing myocardium. Historical notes.

The management of the failing myocardium was primarily empirical for centuries, until Withering introduced foxglove (digitalis) in 1785 as an effective medication. Gradually, the medical treatment included, besides digitalis preparations, the use of diuretics to reduce excessive sodium and water retention; limiting salt and water intake; and the administration of drugs to combat vasoconstriction, irregular rhythms, and hypertension. Cardiac surgery emerged for the correction of mechanical lesions while relieving the strain on the myocardium, first in patients with congenital heart diseases and then in those with acquired disease, by closed and then open techniques. In arresting the heart for more precise surgery, the combination of hypothermic and potassium-induced arrest proved to be minimally damaging to the myocardium. However, the search goes on. Mechanical cardiac assist apparatus have been successful in buying time for salvage of patients with failing myocardia refractory to conventional methods. Heart and, more recently, heart-lung transplantations are now having long-term survival. The opportunity for me to present these historical notes is a great privilege , since I have been involved in the problems of heart surgery for more than four decades.

Ribonucleic acid-protein cross-linking within the intact Escherichia coli ribosome, utilizing ethylene glycol bis[3-(2-ketobutyraldehyde) ether], a reversible, bifunctional reagent: identification of 30S proteins.

To obtain detailed topographical information concerning the spatial arrangement of the multitude of ribosomal proteins with respect to specific sequences in the three RNA chains of intact ribosomes, a reagent capable of covalently and reversibly joining RNA to protein has been synthesized [Brewer, L.A., Goelz, S., & Noller, H. F. (1983) Biochemistry (preceding paper in this issue)]. This compound, ethylene glycol bis[3-(2-ketobutyraldehyde) ether] which we term "bikethoxal", possesses two reactive ends similar to kethoxal. Accordingly, it reacts selectively with guanine in single-stranded regions of nucleic acid and with arginine in protein. The cross-linking is reversible in that the arginine- and guanine-bikethoxal linkage can be disrupted by treatment with mild base, allowing identification of the linked RNA and protein components by standard techniques. Further, since the sites of kethoxal modification within the RNA sequences of intact subunits are known, the task of identifying the components of individual ribonucleoprotein complexes should be considerably simplified. About 15% of the ribosomal protein was covalently cross-linked to 16S RNA by bikethoxal under our standard reaction conditions, as monitored by comigration of 35S-labeled protein with RNA on Sepharose 4B in urea. Cross-linked 30S proteins were subsequently removed from 16S RNA by treatment with T1 ribonuclease and/or mild base cleavage of the reagent and were identified by two-dimensional polyacrylamide gel electrophoresis. The major 30S proteins found in cross-linked complexes are S4, S5, S6, S7, S8, S9 (S11), S16, and S18. The minor ones are S2, S3, S12, S13, S14, S15, and S17.

Ribonucleic acid-protein cross-linking within the intact Escherichia coli ribosome, utilizing ethylene glycol bis[3-(2-ketobutyraldehyde) ether], a reversible, bifunctional reagent: synthesis and cross-linking within 30S and 50S subunits.

We have used the reversible, bifunctional reagent ethylene glycol bis[3-(2-ketobutyraldehyde) ether] to cross-link RNA to protein within intact ribosomal subunits from Escherichia coli. Here we describe the synthesis of this compound (termed bikethoxal) and demonstrate its ability to form covalent attachments between RNA and protein in the 5S RNA-L18 complex and within 30S and 50S ribosomal subunits. The reagent is a symmetrical dicarbonyl compound and reacts with guanine in single-stranded RNA and with arginine in protein. RNA-protein cross-links generated with this reagent are stable, as demonstrated by the comigration of 35S-labeled ribosomal proteins with ribosomal RNA on neutrally buffered sodium dodecyl sulfate (SDS)-agarose gels. However, the cross-linked product is unstable in mildly basic conditions, allowing the identification of the linked macromolecules by conventional techniques. The reagent is potentially capable of cross-linking any combination of single-stranded RNA, single-stranded DNA, or protein; it should prove a useful probe of the RNA-protein proximities within the E. coli ribosome, since the SDS-agarose gel system we describe provides a rapid method of optimizing this RNA--protein cross-linking reaction.

The contributions of the Second Auxiliary Surgical Group to military surgery during World War II with special reference to thoracic surgery.

The outstanding scientific and surgical accomplishments of the Second Auxiliary Surgical Group in the Mediterranean Theater of Operations and the 7th Army in World War II were not exceeded by any other group in the United States Army Medical Corps. In the final 921-page report to the Surgeon General with 550 tables, 8801 severely wounded casualties out of a total of 22,000 treated were reviewed. In addition, the major portion of three books on war surgery and over 60 scientific articles were written by this group. The contributions in thoracic surgery that focused attention on physiologic principles and limited the indications for thoracotomy have stood the test of time. The author made the original description of the reaction of the lung to severe trauma of the brain, abdomen, and extremities by the development of "the wet lung of trauma" (RDS), while his introduction of a hand-operated, intermittent positive pressure oxygen respirator to treat the advanced form of this syndrome (pulmonary edema) ushered in a new form of treatment. Long-term, follow-up studies by the author confirm the validity of the physiologic approach to the treatment of thoracic trauma.

A historical account of the "wet lung of trauma" and the introduction of intermittent positive-pressure oxygen therapy in world war II.

During World War II, my associates and I observed for the first time in medical history that casualties with severe brain, thoracic, abdominal, and extremity trauma, who had persistent "wet" respiration (wet lung of trauma), were most difficult to resuscitate, withstood operation poorly, and had the highest mortality. The etiology appeared to be ineffectual cough and persistent bronchopulmonary fluid from hemorrhage, pulmonary transudates resulting from anoxia, airway obstruction, and unknown causes secondary to trauma, some of which have been discovered since then. Our treatment consisted of assisting cough, transnasal tracheobronchial aspiration and oxygenation, bronchoscopy, and tracheostomy. To treat the advanced form, pulmonary edema, I devised an effectual hand-operated intermittent positive-pressure oxygen machine, which has been supplanted by elegant automatic volume- and pressure-regulated devices. Through the use of the intermittent positive-pressure breathing machines, most hospitals have developed thriving departments of respiratory therapy. Better physiological monitoring and use of intermittent mandatory ventilation and positive end-expiratory pressure have improved the care, but our basic principles of treatment are still the standards of respiratory therapy.

Acute gastric volvulus. A study of 25 cases.

Twenty-five patients with acute gastric volvulus were studied. The two types, organoaxial and mesenteroaxial, are compared with respect to clinical characteristics, diagnosis, pathogenesis and treatment. An understanding of the varied features, including both thoracic and abdominal manifestations, is essential to early recognition and prompt treatment. In addition to Borchardt's triad, this study suggests three important features: (1) minimal abdominal findings when the stomach is in the thorax; (2) a gas-filled viscus in the lower chest or upper abdomen shown by chest radiography (Figure 8), and (3) obstruction at the site of volvulus shown by emergency upper gastrointestinal series. The high incidence of strangulation (28 percent) in this series attests to the urgency of this condition and is a compelling reason for the elective repair of paraesophageal hiatal hernias whenever possible.

History of surgery of the esophagus.

The progress of esophageal surgery from the beginning of medical history through five historical eras, up to the second half of the 20th century, is reviewed. Progress was slow from the first surgical repair of the esophagus in ancient Egypt in 2500 B.C. until the end of the 19th century, when scientific discoveries made possible the solid beginnings of abdominal surgery. Thoracic surgery followed in the 20th century, with rapid strides in World War II. These wartime advances stimulated an interest in esophageal surgery in the postwar era, when operative techniques became well standardized and surgery of the esophagus was placed on a par with that of other parts of the gastrointestinal tract. Because of the limitations of time and space, much important material has had to be left out. Yet it is hoped that this brief historical overview will put in perspective the important advances of the second half of this century, which will be presented by our distinguished speakers. It has been a privilege for me to have had a part in the development of this type of surgery and to share these ideas with you.

Aortoesophageal fistula.

With the advent of cardiovascular and bypass procedures, aortoesophageal fistula has progressed from the stage of a pathologic curiosity to a treatable lesion. Although the causes of aortoesophageal fistula are varied, a remarkably consistent clinical picture emerges from study of this condition. Chiari's triad of midthoracic pain, sentinel hemorrhage, and a symptom-free interval followed by fatal exsanguination remains the most important clinical finding today. Although contrast esophagography, esophagoscopy, and aortography are important diagnositc aids, immediate left thoracotomy may be the only means of making the diagnosis and saving the patient when hemorrhage is profuse. In most cases (80 per cent of the present series) there is a symptom-free period varying from hours to days from the original sentinel hemorrhage to the final exsanguination. This permits the informed surgeon trained in cardiovascular technics an opportunity to salvage some of these patients. The various methods of aortic and esophageal repair are discussed.