Experimental pancreatic allotransplantation in large animals. The role of donor kidney and cyclosporine in modifying rejection.

Experiments were carried out in outbred dogs and pigs to evaluate the relative immunogenicity of pancreatic islets and segmental pancreas grafts, and whether these could be ameliorated by transplanting a kidney simultaneously from the same donor animal. Various immunosuppressive regimens were also studied. Pancreatic islet allografts never normalized blood glucose in totally pancreatectomized recipients despite the use of cyclosporine (CsA) in high doses (40 mg/kg/day) and the simultaneous transplantation of a kidney from the same donor. These grafts which never "took" contrast sharply with the experience of pancreatic islet autografts prepared in the same way and inoculated into the spleen, which in all nine instances normalized blood glucose in pancreatectomized recipients. Segmental transplants were performed in swine with duct drainage into the jejunum. Totally pancreatectomized pigs died at 7.8 +/- 1.0 days. In recipients suppressed with low-dose azathioprine (Az) and prednisone (Pred) pancreas grafts alone were rejected in 12.9 +/- 10 days. Synchronous pancreas and kidney transplants treated similarly extended the mean survival of pancreatic grafts to 20 +/- 10 days--which, however, was not significant (P less than 0.1 greater than 0.05). Mean survival time of pancreatic grafts in recipients receiving CsA at 20 mg/kg/day and prednisone 1 mg/kg/day was 14 +/- 6.3 days. The combination of CsA 20 mg/kg/day, Az 2 mg/kg/day, and Pred 1 mg/kg/day prolonged the mean survival time to 39.8 +/- 22 days. These results allow us to conclude that: crude preparations of islet tissue invariably capable of normalizing blood sugar at day 4 when used as autografts failed to "take" despite the existence of alternative sources of antigen present in a well vascularized kidney from the same donor, and despite very high dosages of CsA; triple immunosuppressive therapy had synergistic effects on pancreatic allograft survival; and simultaneous transplantation of kidney and pancreas had little effect on survival times of the pancreas or the kidney.

The clinical significance of retroperitoneal fibrosis.

A total of 481 cases of retroperitoneal fibrosis (RPF) presented in the literature have been reviewed. Ten additional cases from this hospital have been added. One etiological factor, methysergide, has been implicated in 12.4 percent of cases, but the majority remain unexplained. Characteristically, the patient will be male (2:1 ratio), in his 50's (30.9 percent), with vague lower back pain (34.2 percent) or possibly flank pain (34.0 percent). Physical examination usually will be unrevealing. The patient's serum chemistry probably will show some degree of azotemia (55.4 percent) and perhaps anemia (13.6 percent). The intravenous pyelogram characteristically shows bilateral hydroureteronephrosis (67.6 percent) or unilateral hydroureteronephrosis (20.3 percent) associated with medial deviation of the ureter due apparently to external compression of the ureter. Methysergide should be discontinued if implicated. Laparotomy for ureteral compression characteristically will reveal a dense, rubbery plaque in the retroperitoneum. Generous frozen section biopsies show fibrosis, usually with some chronic inflammation, suggestive of RPF. Careful inspection of retroperitoneal nodes and liver may reveal the presence of malignancy in 7.9 percent of patients. In the absence of malignancy, the ureters should lyse fairly freely and peristasis may return. If no malignancy is present on permanent sections of biopsy material, the patient can be given a fairly optimistic prognosis (cumulative mortality rate, 9 percent). Suboptimal improvement probably is an indication for steroid therapy and surgical re-exploration may become indicated. In these cases further search for malignancy should be undertaken.

Splenic abscess--presentation, diagnosis, and treatment.

Splenic abscess is an unusual entity. In the last 30 years at the Johns Hopkins Hospital, only 11 patients have been treated for clinically overt splenic abscess. Generally presenting with fever, leukocytosis, and left-sided upper abdominal pain in the setting of generalized sepsis, the majority had a distant source of bacteremia or an underlying defect in splenic architecture or function. Prior to 1970, diagnosis was one of exclusion, and delay in treatment was frequent. Recently, diagnosis has been facilitated by splenic scintiscans, ultrasonography, and computerized axial tomography. These techniques now afford earlier, objective evidence of splenic involvement. Although splenectomy controls local splenic suppuration, the ultimate prognosis rests on the underlying process predisposing the patient to development of splenic infection.

Surgical rates in the United States: 1966 to 1978.

A dominant belief throughout the last half of the 1970s was that operative rates in the United States continued to show steady increases. This strongly suggested that an excessive number of operations were being performed. Unsubstantiated statements regarding surgical rates have been accepted at face value, and little critical analysis of the situation has occurred. This study utilizes data from the National Center for Health Statistics as the basis for an in-depth analysis of surgical rates in the United States from 1966 to 1978. All rates have been age-sex standardized. During the 13-year study period, operative rates increased by 26%. The major portion of that growth took place between 1966 and 1974. After that time, the rates leveled off and increased by only 2%. General surgery, gynecology, otorhinolaryngology, and urology have demonstrated decreasing rates of operation since 1974. Neurosurgery, ophthalmology, and cardiac surgery experienced sustained increases in growth during the study years. From 1966 through 1978 there was a steady growth in the total number of surgeons practicing within any given specialty. Through this study we were unable to document any correlation between the number of surgeons practicing a specialty and an increase in that specialty's surgical rates. The belief that operative rates will inevitably rise as the total number of surgeons increases is not supported by this report.

Training of care givers for our aging population.

We cannot rely on geriatricians, internists, and family practitioners alone in the medical community to provide all of the geriatric care. Even though there are alternatives to the use of specialists, we cannot afford to ignore the largest group of current physician trainees who will provide a great deal of geriatric medical care in the future. We need to help make the basic principles of geriatric care part of every training program for every resident, whether in general or specialty programs.

Splenic abscess.

A review of autopsy files and clinical case reports demonstrates two categories of splenic abscess. First, the abscesses discovered at postmortem usually are multiple, small manifestations of widespread, lethal infection in immunologically crippled hosts. A clinical diagnosis seldom is made. Second, the splenic abscesses encountered by the clinician are usually solitary, large, and challenge his diagnostic skills. Recognition is of vital importance, for therapy can be highly successful. Left untreated, the mortality rate is very high. The features, clinical management, and pathogenesis of splenic abscesses are discussed.

Steroid administration and acute pancreatitis: studies with an isolated, perfused canine pancreas.

Steroid administration has been suspected of causing acute pancreatitis for over 20 years. Clinical and experimental data, however, have failed to firmly establish the association or to uncover a pathogenic mechanism. Utilizing an isolated, ex vivo, perfused, canine pancreas preparation, the acute effects of large doses of steroids on the pancreas were evaluated. Using a dose of 200 mg of methylprednisolone, there were no significant differences between the control and steroid-treated preparations in terms of gross appearance, weight gain, serum amylase, or pancreatic secretion over a 4 hour perfusion period. When the dose of methylpredisolone was increased to 400 mg, again there were no significant differences in gross appearance, weight gain, or serum amylase during a 3 hour perfusion period. However, pancreatic secretion was initially depressed in the steroid-treated preparations. Following a maximal secretory stimulus (secretin), secretion markedly increased during the fourth hour of perfusion, but again was significantly less in the steroid-treated glands. Viscosity of pancreatic secretions was significantly increased in the steroid-treated glands. These studies suggest that steroids have a mild inhibitory effect on pancreatic secretion, which might be mediated through an increase in viscosity.

Experimental pancreatitis: influence of secretory state of the pancreas.

The influence of the secretory state of the pancreas on the development of pancreatitis in an isolated, ex vivo, perfused canine pancreas model was evaluated. Free fatty acid infusion was used to induce pancreatitis, and secretin, glucagon, and atropine were administered to influence the secretory state. Despite a 40-fold difference in hourly secretory output, the development of pancreatitis as judged by weight gain, hemoconcentration, amylase value, and arterial blood pressure response was similar in the stimulated, basal, and suppressed states. This study casts further doubt on the role of hypersecretion in the pathogenesis of acute pancreatitis.

The use of sclerotherapy for treatment of postmastectomy wound seromas.

Five patients who developed seromas following mastectomy with lymph node dissection were treated with aspiration of the seromas and instillation of a sclerosant solution containing tetracycline. All seromas resolved promptly without infection, flap necrosis, or recurrence. The technique is recommended for treatment of this postoperative complication.

A pathogenesis for alcoholic pancreatitis.

Twelve patients with prior episodes of alcoholic pancreatitis and hyperlipemia were admitted to a metabolic ward during a quiescent period. By lipid feeding (316 to 894 Gm. per day), significant hypertriglyceridemia (greater than 600 mg. per 100 ml.) was induced in 11 of the 12 patients. Seven of the 11 patients with hypertriglyceridemia developed abdominal pain similar to but not as severe as that experienced during prior attacks of pancreatitis. Four of the seven patients with abdominal pain developed serum amylase elevations, and, of the remaining three, one had a serum lipase elevation and one a urinary amylase elevation. Alcohol ingestion is known to increase serum triglyceride levels in many individuals. A prior study demonstrated that 41 percent of the patients presenting to our hospital with alcoholic pancreatitis had serum triglyceride elevations. The data from the present study suggest that increased serum triglycerides act as an important intermediary in the pathogenesis of acute pancreatitis in some alcoholic patients.

The application and interviewing process for surgical house officership.

The application and interviewing procedure for surgical house officership is an important process to both the medical student and the clinical department. Up-to-date, informative, and honest appraisals of the training programs under evaluation must be obtained. A survey was undertaken to compare and contrast students' and surgical department members' perceptions of nationwide surgical residency application procedures. It is concluded from this sampling that the majority of medical students applying to university-sponsored surgical training programs and the training institutions themselves generally are satisfied with the present application and interviewing experience. Certain areas in need of reform were elucidated, and the following recommendations are offered to aid in the development of a more effective process: (1) if possible, the descriptive information brochure should be updated on a yearly basis and must be comprehensive in scope; (2) when "en masse" interviewing is conducted, it should be held on a number of dates during the year, not just one, and a limited time for "walk-in" interviews should be allowed; (3) an opportunity should be available for the spouse or fiance'(e) to accompany the applicant; (4) an interviewer should prepare for an interview by having read the applicant's file beforehand; and (5) the interviewing schedule should be arranged so that the applicant is able to meet either the department chairperson and/or program director.

Acute pancreatitis with hyperlipemia: studies with an isolated perfused canine pancreas.

Clinical evidence suggests that in many settings hypertriglyceridemia can initiate an episode of acute pancreatitis. Hydrolysis of triglycerides by pancreatic lipase with the local release of large quantities of free fatty acids (FFAs) has been proposed as the pathogenetic mechanism. To gather information to evaluate this mechanism an isolated, ex vivo, perfused pancreatic preparation was used. Control preparations remained normal in gross appearance, gained little weight (18 gm), extracted oxygen and glucose and released carbon dioxide, and continued to secrete during a 4 hour perfusion period. Serum amylase remained normal (972 CU/100 ml) as did FFAs (1.11 mEq/liter). When triglycerides were added to the perfusate to increase the serum triglycerides to 1,600 mg%, the glands became edematous, hemorrhagic, and gained considerable weight (52 gm) during the 4 hour perfusion period. Serum amylase became markedly elevated (2,624 CU/100 ml), as did the serum FFA (29.19 mEq/liter). When FFAs were added directly to the perfusate, the glands became edematous, hemorrhagic, and gained weight (90 gm), but did so much more rapidly than when triglycerides were added. These studies add support to the concept that hypertriglyceridemia can initiate pancreatic injury. Furthermore, they suggest that the mechanism may be through the release of FFAs.

The role of ischemia in acute pancreatitis: studies with an isolated perfused canine pancreas.

Recent clinical studies have suggested that ischemia may be an important factor in the pathogenesis of acute pancreatitis. The effects of ischemia on the pancreas were investigated utilizing the isolated perfused canine pancreas. Six control glands were perfused with autologous blood with an arterial Po2 ranging from 250 to 350 mm Hg. During the 4-hour perfusion period, gross appearance remained normal, weight gain was minimal (7 gm), and mean amylase levels (853 Caraway units [CU]/dl) remained within normal limits (less than or equal to 1,000 CU/dl). Lowering the arterial Po2 (range 30 to 60 mm Hg) in six glands while maintaining the flow at control levels elicited no significant change. Similarly, decreasing the flow (25% of control) with the arterial Po2 at 250 to 350 mm Hg produced no significant change in gross appearance, weight gain, or mean amylase levels. Combining low flow and low arterial Po2 in six glands also elicited no significant change as compared with controls. Four glands were subjected to total ischemia for 1 hour before being perfused. The glands became hyperemic, but mean weight gain (13 gm) and mean amylase levels (740 CU/dl) wee similar to those of controls. In contrast, in six glands subjected to total ischemia for 2 hours gross edema developed during the subsequent 4-hour perfusion. Mean weight gain (52 gm) and mean amylase levels (1,825 CU/dl) were significantly higher than in controls. These experimental data demonstrate that in the isolated perfused canine pancreas severe ischemia can produced significant injury. They therefore support the hypothesis that ischemia can clinically initiate acute pancreatitis.

The use of intraperitoneal xenon for early diagnosis of acute mesenteric ischemia.

We evaluated the technique of intraperitoneal use of xenon Xe 133, previously described for the diagnosis of early intestinal strangulation obstruction in rats and dogs, for the recognition of acute mesenteric vascular occlusion in these animals. 133Xe was injected intraperitoneally into five groups of six rats: control, sham operation, superior mesenteric artery (SMA) ligation, superior mesenteric vein ligation, and portal vein ligation. Residual gamma-activity was monitored by external counting and camera imaging. At 30 minutes after injection, the activity was significantly higher in the rats from the three groups with vascular ligation than in the control and sham operation animals (P less than 0.001). gamma-Camera images reflected these findings, with positive images only in the rats that underwent vascular ligation. "Blinded" readings of the 30 sets of scans confirmed the diagnostic accuracy of the images. Results were essentially the same in a second series of experiments in eight control dogs and six dogs with balloon occlusion of the SMA. Concentrations of isotope in ischemic intestine ranged from 10(3) to 10(5) times the levels in adjacent normal bowel. These levels and the positive images appeared early, prior to the development of tissue necrosis. The intraperitoneal use of 133Xe therefore continues to show promise for the recognition of patients with early intestinal ischemia.

Management of hemobilia associated with transhepatic internal biliary drainage catheters.

Hemobilia developed as a complication in nine patients with transhepatic biliary drainage catheters. Arteriography revealed pseudoaneurysms of the hepatic artery in five patients and hepatic arterio-portal venous fistulas in three patients. In one patient no arteriographic abnormality was seen. Seven of eight patients were treated successfully with angiographic embolization of the bleeding site. Hemobilia stopped spontaneously in one patient without therapeutic intervention.

Mesocaval shunts for the control of bleeding esophageal varices.

Results in 44 patients with esophageal bleeding who underwent a mesocaval shunt utilizing a prosthetic graft are presented. Portal hypertension was secondary to alcoholic cirrhosis in 30 patients, to chronic active hepatitis in eight, to primary biliary cirrhosis in four, to cirrhosis secondary to inflammatory bowel disease in one, and to portal vein thrombosis following splenectomy in one. Thirty-six shunts were performed during the emergent or semiemergent time period, and only eight were performed electively. Sixteen of the patients were Child's class A, 16 were class B, and 12 were class C. There were no hospital deaths in the emergency shunt group (of eight patients); there was a 12% mortality rate for patients undergoing semiemergency shunts (two of 17 patients) and a 42% mortality rate for patients who had emergency shunts (eight of 19 patients). Death was related more closely to hepatic reserve, however, than to timing of the shunt. Among the 32 class A and B patients, there were only three deaths in hospital (9%), as compared with seven deaths among the 12 class C patients (58%). Portal-systemic encephalopathy was high in the period immediately after operation (13 of 34 patients, 38%), but it was a chronic problem following discharge from the hospital in only three of 34 patients (9%). The mesocaval shunt is a safe, effective procedure for the control of variceal bleeding in class A and class B patients in any time period, but it carries a high operative mortality risk in the class C patient when it is performed as an emergency operation.

Transhepatic decompression of the biliary tree in Caroli's disease.

Caroli's disease, defined as a congenital cystic dilatation of the intrahepatic segmental bile ducts, has responded poorly to conventional methods of treatment. Medical treatment has not been useful, and the various surgical procedures that have been proposed have met with limited success. The course of this disease is characterized by recurrent episodes of cholangitis, liver failure, and hemorrhage from esophageal varices. Two cases of Caroli's disease are presented. Both failed to respond to standard forms of internal and/or external drainage. However, one of the patients has been asymptomatic for 4 years after insertion of a silicone rubber transhepatic stent, despite suffering from recurrent cholangitis and other symptoms for more than 20 years previously. We therefore propose the use of a silicone rubber transhepatic stent as a possible approach to the treatment problem posed by Caroli's disease.

Metabolic studies following intrahepatic autotransplantation of pancreatic islet grafts.

A patient with chronic pancreatitis underwent 95% pancreatectomy and islet autotransplantation. The pancreatic tissue was prepared by mincing and collagenase digestion, and then embolized into the liver via the portal vein. The patient has been followed with metabolic studies for 1 year. Fasting normoglycemia returned 3 weeks following operation. Intravenous glucose tolerance tests revealed K values that were similar before operation (1.06), and 3 weeks (0.96) and 4 months (1.09) after operation. Four months after islet transplantation, peripheral, portal, and hepatic vein insulin levels were determined simultaneously following an infusion of glucose (0.25 gm/kg) into the portal vein. During a 10-minute interval, right hepatic vein insulin increased fourfold, left hepatic vein insulin increased twofold, and peripheral vein insulin doubled. During this time portal vein insulin remained constant. In addition, significant levels of pancreatic glucagon were present in both hepatic veins, but were undetectable in the portal vein. At 6 months the patient became hyperglycemic and subsequently has required insulin therapy. Restudy at 10 months following islet transplantation revealed a marked drop in K value (0.34), and no evidence of graft function in the liver. These studies represent convincing evidence of transplanted intrahepatic islet cell function for a 6-month period following operation. The grafts for unknown reasons ceased to function at 6 months.

Some effects of Bunnell suture on otherwise uninjured tendons in subhuman primates.

An experimental study was performed in rhesus monkeys (M. mulatta) to examine the contribution of Bunnell tendon suture to the production of postoperative tendon adhesions. It was found that Bunnell suture used with atraumatic technique caused a significant depression of in vitro tendon surface plasminogen activator activity, allowing the in vivo persistence and fibrous organization of fibrinous postoperative adhesions to sutured areas. Bunnell suture also produced coagulation necrosis of the sutured area of tendon. Collagen, which replaced the destroyed areas, was oriented randomly and frequently was continuous with surface tendon adhesions to surrounding connective tissues. Bunnell suture appears to be a cause of tendon adhesions in subhuman primates. The importance of fibrin and depressed local fibrinolysis in the relationship of tendon ischemia and adhesion formation is discussed.

Aspiration pneumonia: beneficial and harmful effects of positive end-expiratory pressure.

With an ex vivo, isolated, ventilated, perfused canine pulmonary lobe, the effects of various levels of positive end-expiratory pressure (PEEP) were evaluated following acid injury. Following intrabronchial instillation of hydrochloric acid, eight lobes were ventilated with 5 cm of H2O of PEEP, 12 lobes with 10 cm of PEEP, and eight lobes with 15 cm of PEEP during a 4 hour perfusion period. Blood flow was kept constant in all preparations. Lobes with 5 cm of PEEP developed a 39% intrapulmonary shunt and increased their weight by 220%. When PEEP was increased to 10 cm, weight gain was similar (184%), but shunting decreased markedly, to 7%. When PEEP was increased further to 15 cm, shunting remained low (13%), but weight gain increased markedly, to 411% of the initial lobe weight. This study demonstrates the beneficial effects of PEEP in aspiration pneumonia, but it also points out that increasing levels of PEEP can magnify acid-pulmonary injury by causing a further increase in interstitial and intralveolar edema.