Synergies of THESEUS with the large facilities of the 2030s and guest observer opportunities.

The proposed THESEUS mission will vastly expand the capabilities to monitor the high-energy sky. It will specifically exploit large samples of gamma-ray bursts to probe the early universe back to the first generation of stars, and to advance multi-messenger astrophysics by detecting and localizing the counterparts of gravitational waves and cosmic neutrino sources. The combination and coordination of these activities with multi-wavelength, multi-messenger facilities expected to be operating in the 2030s will open new avenues of exploration in many areas of astrophysics, cosmology and fundamental physics, thus adding considerable strength to the overall scientific impact of THESEUS and these facilities. We discuss here a number of these powerful synergies and guest observer opportunities.

The importance of a thick cement mantle depends on stem geometry and stem-cement interfacial bonding.

The thickness of the cement mantle around the femoral component of total hip replacements is a contributing factor to aseptic loosening and revision. Nevertheless, various designs of stems and surgical tooling lead to cement mantles of different thicknesses. Opinion is divided on whether a thick mantle enhances implant longevity. This study investigates the effect of cement mantle thickness on accumulated damage in the cement, and how this is influenced by the presence or absence of a proximal collar and on whether the stem-cement interface remains bonded. Three-dimensional finite element simulations incorporating creep and non-linear damage accumulation were performed to investigate cracking in the cement mantles around Stanmore Hips under physiologically informed stair-climbing and gait loads. Cement mantle thickness, stem-cement interfacial bonding, and collar design were varied to assess the interactive effects of these parameters. In all cases, damage levels were three to six times higher when the stem-cement interface remained bonded. Cement mantle thickness had little effect on cement damage accumulation around debonded collared stems but was critical in both bonded and collarless cases, where a thicker mantle reduced cement cracking. Damage around a smooth debonded stem with a collar is thus much less sensitive to cement thickness than around bonded or collarless stems.

High cancer mortality rates from childhood leukemia and young adult Hodgkin's disease and lymphoma in the New Jersey-New York-Philadelphia Metropolitan Corridor, 1950 to 1969.

In comparison to the United States as a whole and to their total population age-adjusted rates, the New Jersey-New York-Philadelphia Metropolitan Region was found to have excessively high childhood leukemia and high young adult Hodgkin's disease and lymphoma cancer mortality rates in the period from 1950 to 1969.

Transient bacteremia following endoscopic injection sclerotherapy of esophageal varices.

The incidence of transient bacteremia following endoscopic injection sclerotherapy of esophageal varices was evaluated in 18 patients subjected to 40 sessions of injection sclerotherapy. Blood cultures were obtained before sclerotherapy and at five minutes, 30 minutes, and 24 hours after sclerotherapy. The injectors as well as the endoscope were cultured before and after the procedure. Blood cultures were positive in two patients after injection sclerotherapy (Enterobacter cloacae and Staphylococcus species, coagulase-negative, respectively) for an incidence of 5% of transient bacteremia. Pseudomonas aeruginosa was the most frequent bacteria isolated from the injector after sclerotherapy. We conclude that the incidence of transient bacteremia after sclerotherapy is no higher than routine upper-intestinal endoscopy.

Rapid alterations in substrate profiles after partial hepatectomy in the rat.

We compared alterations in circulating levels of insulin and glucagon and metabolic fuels in response to partial (70%) hepatectomy (HP) and sham hepatectomy (SHP) in fasting rats and in unanesthetized, fasting control rats. Within 15 minutes, animals in the HP group were hypoglycemic compared with the SHP and control groups. After 30 minutes, the insulin concentration and the insulin-glucagon molar ratio (IGR) rose in the HP group. After four hours, animals in the HP group were hyperglycemic compared with the SHP and control animals. Comparison of the lipid and amino acid profiles suggested use of these substrates by eight hours. The levels of branched-chain amino acids, although depressed early after HP, were markedly elevated later, when the IGR in the HP group had normalized. The acute loss of hepatic mass by limiting gluconeogenesis may be the cause of hypoglycemia and also could alter the plasma IGR because of the different hepatic clearance rates of these hormones. A switch to lipid and protein as metabolic fuels appears to follow these early changes.

Factors that affect the outcome of peripheral arterial embolization.

To find the factors that significantly affected prognosis in patients with peripheral arterial thromboembolism, we reviewed a 12-year experience at two hospitals. Sixty-one patients had 67 embolectomies. Operative treatment and management preserved the limbs in 75.8%. Mortality was 22.4%. Outcome was favorably affected when age was less than 60 years and when arteriosclerotic heart disease was absent, and was adversely affected when common femoral emboli were present and hematocrit level elevated. Duration of symptoms did not affect outcome. Our treatment of patients with peripheral embolism is based on the effect of certain intrinsic factors on the formation of distal thrombus. These factors may be more important than duration of symptoms. Immediate, complete heparinization is recommended to arrest thrombosis, and to allow both for proper emphasis on treatment on the often-associated cardiopathy and for attention to hydration and acid-base balance. This preoperative plan of therapy should produce maximal limb salvage with reduced operative mortality.

Beta-adrenergic blockade increases the hepatic extraction of glucose in sepsis.

To determine the relationship between hepatic glucose clearance and elevated epinephrine levels in sepsis, dogs with gangrenous cholecystitis were anesthetized and received either propranolol hydrochloride (mean dose, 0.29 mg/kg) or saline solution before intraduodenal glucose injection (2.5 g/kg). The amounts of glucose, insulin, and glucagon in the portal vein, the hepatic artery, and the hepatic vein were determined from the concentrations and the blood flows in these vessels over a two-hour period. Normal dogs served as controls. The amounts of glucose, insulin, and glucagon reaching the livers of both septic groups were the same. However, propranolol treatment increased the percent of glucose extracted by the liver without affecting the extractions of insulin or glucagon. Propranolol reverses the limitation of hepatic glucose extraction in sepsis by a direct effect. Whether the extracted glucose is utilizable as an energy substrate needs to be established.

Preoperative fasting improves survival after 90% hepatectomy.

OBJECTIVE: To assess whether alterations in preoperative fatty acid oxidation and gluconeogenesis induced by fasting will affect survival and liver regeneration following 90% hepatectomy in the rat. DESIGN: In a randomized, controlled trial, Wistar rats (N = 157) were separated into two groups. Rats in the first group fasted for 24 hours. Rats in the second group were allowed to eat ad libitum until the time of operation. These groups were further randomized to receive either 20% glucose or tap water ad libitum postoperatively. INTERVENTIONS: Ninety percent hepatectomy; 24-hour fast; 5% glucose feeding. MAIN OUTCOME MEASURES: Survival, DNA synthesis in the hepatic remnant along with glucokinase activity (GKA) and glycogen content, serum ketone bodies (KB), free fatty acid (FFA), glucose, and ad libitum glucose consumption (GC) were serially quantified. RESULTS: Fasting rats that were offered glucose (fasted/glucose) after hepatectomy demonstrated better survival at 48 hours than the rats that were fed before the procedure and given glucose following hepatectomy (fed/glucose), 95% vs 52% (P < .05). The fasted/glucose group also had a greater peak rate of DNA synthesis (550 +/- 110 vs 275 +/- 40 disintegrations per minute per 0.001 mg of DNA, P < .05). Survival was poor in both groups when only tap water was offered to the animals after hepatectomy (31% vs 12%). In the fasted/glucose group, GC 1 hour after hepatectomy was greater than that for fed rats (1.3 +/- 0.175 vs 0.73 +/- 0.176 g/h, P < .05), yet GKA was suppressed (3.4 +/- 0.42 vs 8.05 +/- 2.77 nmol/min per milligrams of protein, P < .05). Fasting before hepatectomy and consuming glucose after causes elevations in both FFA (1.26 +/- 0.19 vs 0.82 +/- 0.13 mol/mL., P < .05) and KB (18.96 +/- 2.82 vs 11.4 +/- 3.94 mmol/mL, P < .05). Normal glucose was maintained in the fasted/glucose group, but fell to 63 +/- 14 mg/dL at 8 hours after hepatectomy in the fed/glucose group. CONCLUSIONS: Fasting before hepatectomy shifts energy utilization to fat oxidation and gluconeogenesis, which appears to ameliorate liver failure after hepatectomy in this severe model of hepatic resection.

Efficacy of oral and systemic antibiotic prophylaxis in colorectal operations.

A cooperative Veterans Administration study of the septic complication rate during large-bowel surgery was undertaken in two groups of patients. The first group received oral neomycin and erythromycin base plus parenteral placebo; the second, the oral antibiotics plus parenteral cephalothin sodium. During a five-year period, 1,128 patients were studied. The overall septic complication rate was 7.8% in patients receiving only oral antibiotics, and 5.7% in patients receiving both oral and parenteral antibiotics. This difference was not significant. The only significant finding was a greater incidence of fever of unknown origin in patients receiving only oral antibiotics. None of those patients were treated with additional antibiotics, and all fevers cleared spontaneously. There seems to be no discernible benefit from adding parenteral antibiotic prophylaxis when performing elective colon surgery if appropriate mechanical cleansing and oral neomycin and erythromycin therapy are employed.

Anterior or posterior: does the surgical approach to the hip influence the quality of the femoral cement mantle?

The purpose of this study was to determine whether the surgical approach to the femoral neck during total hip arthroplasty affects the quality of femoral cement mantle in terms of thickness and defects, both of which have been implicated in the development of aseptic loosening. A retrospective radiological review of 50 Stanmore Hip femoral stems inserted using the anterior approach and 50 inserted via the posterior approach was performed, with analysis by zone of cement mantle thickness and number of defects. This study demonstrates that the anterior approach is associated with an increase in the frequency of deficiencies in the cement mantle. We recommend that surgeons using the anterior approach are wary of this increased risk and adopt measures, such as the use of distal centralisers, to minimise its occurrence.

Increased uptake of insulin and glucagon by the liver as a signal for regeneration.

We have determined the pancreatic output and the hepatic uptake, per gram of liver, of insulin and glucagon before and after both a 42 and a 72 per cent hepatectomy in dogs. Pancreatic output and hepatic uptake were determined from the hormonal concentration, as measured by radioimmunoassay, and the blood flows in the portal vein, hepatic artery and hepatic vein measured with an electromagnetic flowmeter. There was no significant difference in the output of either insulin or glucagon by the pancreas after hepatectomy. Likewise, peripheral concentrationof insulin and glucagon did not change significantly. The uptake of each hormone by the liver was a function of the amount delivered to the liver both before and after hepatectomy. After a 72 percent hepatectomy, there was a statistically significant increase in uptake per gram of liver for both insulin and glucagon, p less than 0.005, when compared with the uptake before hepatectomy. During this time, the plasma glucose concentration fell. The immediate increase in the uptake, per gram of remaining liver, of insulin and glucagon may be a signal for regeneration in terms of rapid augmented binding or degradation by liver cell receptor sites.

The morbidity and mortality of emergent operations for colorectal disease.

p6 participants in the Veterans Administration Cooperative Studies Program investigating antibiotic prophylaxis in colorectal operations, 693 consecutive patients (1978-1981) from three hospitals were studied. This report concerns 20% of these patients who presented with either perforation, obstruction, or hemorrhage necessitating emergent surgical intervention on unprepared bowel. The 30-day, in-hospital mortality of the 138 patients undergoing emergency operations was 28%. Elective colorectal procedures during the same period had a six per cent mortality rate. There is a striking difference in the cause of death in prepared patients and those needing emergent surgery. Death in prepared patients was usually of a vascular etiology, while septic-related mortality was present in only one per cent. On the other hand, despite massive doses of antibiotics, fecal diversion, surgical drainage and lavage, abdominal sepsis was documented in 20% and septic related mortality was present in 17% of patients undergoing emergency operations. Early, elective treatment and prevention of obstruction and perforation will improve our results in colorectal disease.

The relative roles of hydrolases of the erythrocyte and other tissues in controlling aspirin survival in vivo.

The rate of aspirin (acetylsalicylic acid, ASA) deacetylation to salicylate in vivo determines the availability of the intact molecule for therapeutically important transacetylation reactions. Experiments were carried out to assess the relative contribution of a previously isolated human erythrocyte ASA esterase to the overall hydrolysis rate in vivo, as opposed to similar enzymes in other tissues. In vitro, the rates of ASA hydrolysis were relatively slow in plasma from humans and dogs. The hydrolysis rates were significantly greater in whole blood in dogs, rabbits, and humans. In human and canine whole blood, the rate of hydrolysis correlated positively with hematocrit. In vivo studies with dogs showed that ASA decay rates conform to a 2-compartment model. After reduction of hematocrit by a mean of 49% in 4 dogs without previous splenectomy, the "availability" of ASA increased. In 4 dogs with previous splenectomy, this measurement was increased even more after comparable hematocrit reduction. In 2 dogs that underwent a sub-total hepatectomy, ASA availability increased by only 35% and 12.8%, respectively. These results suggest a significant role for the erythrocyte esterase in vivo in the dog and possibly in humans.

The clearance capacity of the canine liver for a portal vein endotoxin infusion.

The capacity of the livers of anesthetized dogs to clear a portal vein infusion of Escherichia coli 026 endotoxin was evaluated. Appearance of the endotoxin in arterial blood was quantitated by immunoradiometric assay. Various hemodynamic and metabolic parameters were monitored throughout the infusion to corroborate the development of systemic endotoxemia. Significant amounts of E. coli 026 endotoxin were detected in arterial blood after infusion of 240 micrograms endotoxin. As expected, systemic endotoxemia was associated with decreased cardiac index, mean arterial blood pressure, heart rate, and splanchnic (portal vein) blood flow. Changes in plasma levels of glucose, insulin, and glucagon and in the pancreatic outputs of insulin and glucagon did not occur before the development of severe hypotension and the termination of the study. It was concluded that the liver clearance capacity for endotoxin in the dog is 0.72 microgram/gm liver/hour and that severe hemodynamic alterations develop in this animal model before changes in carbohydrate balance.

Streptococcus pneumoniae meningitis in two patients with peritoneovenous shunts.

We report two patients with cirrhosis and peritoneovenous shunts (LeVeen) in whom fatal Streptococcus pneumoniae sepsis and meningitis developed 10 months and 22 days, respectively, after insertion of the shunts. The association between pneumococcal bacteremia and meningitis is well established. The potential implications of a LeVeen shunt in increasing risk for meningitis are discussed.

Twenty-two year experience with the diagnosis and treatment of intrahepatic calculi.

Intrahepatic cholelithiasis is commonly associated with suppurative cholangitis and occurs equally in males and females. Patients usually present with a history of recurrent symptoms and a differential diagnosis which includes viral hepatitis, pancreatitis, myocardial infarction and perforated ulcer. Cholangiography including stereocholangiography is essential for localizing intrahepatic stones and ductal strictures. The guiding operative principle is to drain all infected bile distal to ducts obstructed with stones or stricture. This may also necessitate a bilioenterostomy with or without partial hepatic resection. Although these procedures are formidable in an acutely ill patient, a more simple but inappropriate choledocholithotomy and t-tube drainage done proximal to an obstructed intrahepatic duct will be ineffective and may result in continued sepsis and death.

Insulin, glucagon and glucose in the regeneration response of the liver.

The effects of intraduodenal glucose load on the hepatic uptake of insulin, glucagon and glucose after a 70 per cent hepatectomy were studies in anesthetized dogs. Dogs without a hepatectomy served as the control study. Data were derived from plasma concentrations in the portal vein, aorta and hepatic vein with simultaneous portal vein and hepatic artery plasma flow measurements. The concentrations of glucose in the arterial blood of dogs after a hepatectomy were less than those for the controls throughout the study, while insulin and glucagon concentrations showed no differences between the groups. Hepatic uptakes of insulin, glucagon and glucose per gram of liver perfused were significantly greater in the hepatectomy group and occurred because the amounts of these substances reaching the liver remnant were the same as those for the controls. The increased uptake of insulin and glucagon after partial hepatectomy may reflect increased binding of these hormones to the liver cell receptors, by which hepatic regeneration is induced. Increased glucose uptake could serve as the substrate for the accelerated anabolic processes.

D-Galactosamine liver injury: absorption of endotoxin and protective effect of small bowel and colon resection in rabbits.

D-Galactosamine is an amino sugar with unique hepatotoxic properties in animals. Although the mechanism of liver injury by galactosamine remains controversial, a role for bacterial endotoxin has been suggested. In the present study, using New Zealand rabbits, we show that the significant increase in serum glutamic oxaloacetic transaminase which followed the injection of 4.25 mmole/kg of D-galactosamine was completely prevented in animals subjected to resection of small bowel and colon. Using an immunoradiometric assay specific for E. coli 026 endotoxin we showed that after instillation of 50 mg of E. coli into the colon, serum levels of this endotoxin were higher in the animals injected with galactosamine than the controls injected with saline. However, the differences in endotoxin concentration between the two groups of animals was statistically significant only at 30 and 60 min. The role of endotoxin in the pathogenesis of galactosamine liver injury is reviewed and discussed.

The hemodynamic effects of the sclerosant sodium morrhuate in dogs.

The hemodynamic effects of systemic administration of 5 per cent sodium morrhuate was evaluated in normal dogs. Dogs in the control group were injected with 2 per cent benzyl alcohol with pH adjusted to 9.5. Animals injected with sodium morrhuate had a significant reduction in cardiac output, arterial blood pressure, portal vein and hepatic artery flows. These changes occurred primarily in the first 30 minutes of observation. In response to the reduction of the hepatic blood flow, there was an increase in portal vein pressure and resistance.