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.

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.

In vitro potency assay for yellow fever vaccines: comparison of three vero cell lines sources.

Quality control of Yellow Fever vaccines performed by Control Authorities prior to marketing vaccines batches requires in vitro potency assays. The two currently available methods are the plaque formation assay and the cytopathic effect assay based on the use of porcine kidney PS cells or monkey kidney Vero cells. Among several sources of variation in virus titration, the cell systems are considered as important issues and Quality Assurance strongly recommends working with cell banks from certified suppliers. The aim of our study was to compare the behaviour and the sensitivity of three Vero cell sources obtained from ATCC, WHO and EP used at different passage levels in a plaque formation test. The conclusion of this work was that the yellow fever live attenuated virus titration, adapted in Vero cell lines appeared as a reliable method applicable for routine in vitro potency assay. The comparison of Vero cell lines, originated from three different sources, showed that they could be equally used as substrates by laboratories having the basic facility of cell culture, without influence on the final viral titre.

Parameters for using mannan-MUC1 fusion protein to induce cellular immunity.

We have previously reported preclinical studies in mice of the human mucin 1 (MUC1) antigen covalently linked to the yeast cell-wall mannan polysaccharide (MFP), and shown strong cellular responses of the T1 type using mice. We now describe the optimum parameters for administration of MFP to obtain cellular immunity [as measured by the cytotoxic T cell precursor (CTLp) frequency]. In dose/response studies, in which 1 microg-150 microg was given by the i.p. route, it was clear that doses of 1-7 microg led to cellular and not humoral immunity; at doses above 7 microg humoral immunity prevailed with little cellular immunity increasing doses giving greater amounts of antibody. The most favoured routes of administration were intraperitoneal or intradermal immunisation, which were substantially better than i.m., i.v.; s.c. administration was the worst. Three immunisations were necessary for a maximum cellular response, further immunisation decreasing the CTLp frequency. Six different adjuvants were used with MFP [complete and incomplete Freund's adjuvant (CFA, IFA) Alum, Adjuprime, muramyl dipeptide (MDP) and glutaminyl-muramyl dipeptide (GMDP)]; Alum, GMDP, MDP and IFA moderately increased the CTLp frequency, IFA being the best. Even though preclinical studies of the immunogen in mice may not necessarily mirror the behaviour of the immunogen in humans, these studies demonstrate the factors to be taken into account for phase I/II clinical trials.

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.

Fibrin seal--an alternative to suture repair in experimental pulmonary surgery.

Fibrin seal (FS) a biological tissue adhesive was evaluated as a sealant of lung parenchyma. New Zealand White (NZW) rabbits underwent a right upper lobe wedge resection. The defect was repaired with FS, suture (S), or a combination of S and FS (SFS). Five rabbits from each treatment group were sacrificed on postoperative Days 1, 3, and 14. The ventilatory pressure required to produce air leak was measured and the wet weight of normal vs hemorrhagic lung tissue determined. Although leak pressure was lowest in FS on Day 1 (P less than 0.05), leak pressure was equal to S and SFS of Day 3 and highest on Day 14 (P less than 0.01). FS-treated lungs had less hemorrhagic tissue than S and SFS (P less than 0.0001). Microscopically S and SFS repairs had large areas of hemorrhagic necrosis while FS showed minimal changes. We conclude that FS is an effective sealant of lung parenchyma.

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.

Paradoxical effects of glucose feeding on liver regeneration and survival after partial hepatectomy.

Although glucose is regularly administered to patients after partial hepatic resection, its contribution to survival and/or liver regeneration is unclear. To examine this question fed and anesthetized rats underwent 68% or 90% hepatectomy and received either oral 20% glucose solution or tap water (controls) ad lib for 24 h. Survival was compared by life table analysis and the regeneration response measured by 3H-thymidine uptake into liver deoxyribonucleic acid (DNA). Profound hypoglycemia (60 +/- 8 mg/dl) following 90% hepatectomy in controls was corrected by glucose feeding (99 +/- 25 mg/dl) and survival was enhanced (75 +/- 0.09% vs. 42 +/- 0.1%, p less than 0.01). No deaths occurred in the 68% hepatectomy groups wherein untreated hypoglycemia was not as severe (106 +/- 6 mg/dl). However, after 68% hepatectomy glucose adversely affected the regeneration response. We conclude that glucose feeding corrected the life threatening hypoglycemia following 90% hepatectomy. Prophylactic glucose administration after 68% hepatectomy reduced the liver regeneration response. Selective glucose administration to prevent lethal hypoglycemia may provide optimal survival and conditions for regeneration.

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.

Tissue impedance and temperature measurements in relation to necrosis in experimental cryosurgery.

Tissue temperature and impedance were measured in dog skin during freezing in situ. The previously frozen skin was removed by punch biopsies 3 days later to permit microscopic evaluation of the extent of necrosis. The histologic observations were related to the temperature and impedance measurements in an effort to determine the usefulness of the monitoring techniques in clinical cryosurgery. Tissue temperature and impedance have a definite relationship in tissue freezing, but the range of temperatures about any impedance values causes some concern. The tissue biopsies showed that an impedance value of at least 10 Mohms is not always associated with tissue death. In these experiments, there was the usual range of temperatures in relation to tissue death, but tissue temperatures of -30 degrees C and colder were always associated with complete necrosis. It is concluded that tissue temperatures are the more accurate and useful monitoring technique to supplement clinical judgment. However, impedance techniques may also be used to monitor therapy, especially if used primarily to monitor depth of therapy, and if controlled by clinical judgment wary of the inaccuracy of the technique.

Effect of varying freezing and thawing rates in experimental cryosurgery.

Six different freezing/thawing programs, which varied freezing rate, duration of freezing, and thawing rates, were used to investigate the effect of these factors on cell destruction in dog skin. The range of tissue temperatures produced was from -15 to -50 degrees C. The extent of destruction was evaluated by skin biopsies 3 days after cold injury. In single, short freezing/thawing cycles, the temperature reached in the tissue was the prime factor in cell death. Longer freezing time and slow thawing were also important lethal factors which increased destruction of cells. Cooling rate, whether slow or fast, made little difference in the outcome. The experiments suggested that present-day, commonly employed cryosurgical techniques, which feature fast cooling, slow thawing, and repetition of the freeze/thaw cycle, should be modified by the use of maintenance of the tissue in the frozen state for several minutes and slow thawing. Thawing should be complete before freezing is repeated. These modifications in technique will maximize tissue destruction, an important consideration in cancer cryosurgery.

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.

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.

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.

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.

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.

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.