Nutrient content and stoichiometry of pelagic Sargassum reflects increasing nitrogen availability in the Atlantic Basin.

The pelagic brown macroalgae Sargassum spp. have grown for centuries in oligotrophic waters of the North Atlantic Ocean supported by natural nutrient sources, such as excretions from associated fishes and invertebrates, upwelling, and N2 fixation. Using a unique historical baseline, we show that since the 1980s the tissue %N of Sargassum spp. has increased by 35%, while %P has decreased by 44%, resulting in a 111% increase in the N:P ratio (13:1 to 28:1) and increased P limitation. The highest %N and δ15N values occurred in coastal waters influenced by N-rich terrestrial runoff, while lower C:N and C:P ratios occurred in winter and spring during peak river discharges. These findings suggest that increased N availability is supporting blooms of Sargassum and turning a critical nursery habitat into harmful algal blooms with catastrophic impacts on coastal ecosystems, economies, and human health.

Intermittent Access to Ethanol Induces Escalated Alcohol Consumption in Primates.

BACKGROUND: Escalation of voluntary alcohol drinking is characteristic of alcohol addiction and can be induced in rodents using intermittent access to alcohol. This model has been used to evaluate candidate therapeutics, but key systems involved in the transition into alcohol addiction, such as CRF, differ in their organization between rodents and primates. We examined the ability of an intermittent access schedule to induce escalation of voluntary alcohol drinking in non-human primates and used this model to assess the role of corticotropin releasing hormone (CRF) signaling in this process. METHODS: Four young adult male rhesus macaques were given access to an 8.4% alcohol solution every other weekday (EOD; M, W, F), while four other young adult males were given the same solution every weekday (ED; M-F). Subjects were then administered a CRF1 antagonist, antalarmin. RESULTS: EOD increased alcohol intake by up to 50% over baseline, with a more pronounced increase immediately following reintroduction of alcohol. For the morning/daytime sessions, EOD subjects increased their consumption by 83% over baseline. Differences between ED and EOD schedules emerged quickly, and EOD-induced escalation resulted in pharmacologically active BAC's. EOD-induced alcohol consumption was insensitive to CRFR1 blockade by antalarmin, but subjects with high CSF levels of CRF were more responsive. CONCLUSIONS: Similar to what has been observed in rodents, intermittent access results in an escalation of voluntary alcohol drinking in non-human primates. In contrast to findings in rats, recruitment of the CRF system does not seem to be involved in the escalated alcohol drinking observed under these conditions, though individual differences in CRF system activity may play a role.

Excessive mortality in young free-ranging male nonhuman primates with low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations.

BACKGROUND: The purpose of this study was to assess the impact of central serotonin turnover rate on survival to adulthood among nonhuman primates living in a large, free-ranging colony. METHODS: The rate of mortality was ascertained over a 4-year period after obtaining blood and cisternal cerebrospinal fluid (CSF) samples from 49 free-ranging, 2-year-old prepubertal male rhesus monkeys. Cerebrospinal fluid was assayed for 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, 3-methoxy-4-hydroxyphenylgycol, and homovanillic acid. Blood plasma was assayed for adrenocorticotropic hormone, cortisol, and testosterone. Following the sampling of body fluids, records of scars and wounds and aggressive encounters were used to rank the subjects from low to high in aggressiveness. Direct observations of aggressive behavior were collected from 27 of the subjects over a 3-month period. RESULTS: Four years later, 6 of the 49 subjects were known to be dead and an additional 5 had been missing for more than 2 years and were presumed dead. The CSF 5-HIAA concentrations were predictive of which subjects died, with 46% of the subjects with low CSF 5-HIAA concentrations dead or presumed dead. None of the subjects from the highest CSF 5-HIAA concentration quartile were dead or missing. Indeed, 91% of the dead subjects came from the 2 lowest quartiles of CSF 5-HIAA concentrations. Direct observations of aggressive behavior showed that dead or missing subjects had initiated escalated aggression, a measure of unrestrained aggression that has a high probability of trauma or injury, at a higher rate than subjects that were known to be alive. The cause of death could be ascertained for 6 of the 11 missing subjects. The 4 subjects that were known to die as a consequence of aggressive encounters came from the lowest quartile of CSF 5-HIAA concentrations and had been rated as more aggressive during their initial capture. Subjects captured more than once possessed lower CSF 5-HIAA concentrations, were rated as more aggressive, and were more likely to suffer early death than those captured only once. CONCLUSION: These findings suggest that low CSF 5-HIAA concentrations quantified early in life is a powerful biological predictor of future excessive aggression, risk taking, and premature death among nonhuman primate males.

Salivary prolactin as a marker for central serotonin turnover.

Central nervous system (CNS) serotonin deficits have been linked to many pathological behaviors in both human and nonhuman primates. The plasma prolactin response to fenfluramine has been widely used to assess CNS serotonin functioning in humans. Prolactin is also found as an integrated measure in saliva. We hypothesized that salivary prolactin concentrations would correlate positively with cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) in rhesus monkeys. Twenty-seven adult male and female rhesus macaques (Macaca mulatta) were sampled for concurrent saliva, blood, and CSF. Saliva and blood serum were assayed for prolactin concentrations, and CSF was assayed for 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). Salivary prolactin concentrations were positively correlated with CSF 5-HIAA concentrations. No other relationships between any of the measures, including that between salivary prolactin and serum prolactin, were found to be statistically significant. These findings suggest the possibility of using salivary prolactin concentrations as an index of CNS serotonin turnover in humans.

Plethysmographic pulse wave amplitude and future leg arteriosclerosis.

A low pulse wave amplitude during calf plethysmography at 55 years of age was previously found to be associated with an increased mortality and incidence of myocardial infarction. In order to test the hypothesis that a low pulse wave amplitude is associated with an increased risk of future leg atherosclerosis as well, we have studied the relationship between a low ankle-brachial pressure index (ABPI; < 0.9) at 68 years of age and the pulse wave amplitude at 55 years of age in that same cohort. The prevalence of a low pulse wave amplitude (< or = 5 mm; lowest quintile) among men with a low ABPI (42%) was more than twice as high as it was among men who had a normal ABPI (19%) (P < 0.001). No association was found between a low ABPI and the plethysmographically recorded leg blood flow at 55 years of age. A low pulse wave amplitude might reflect early symptom-free arteriosclerosis, or age-dependent non-arteriosclerotic loss of vessel wall elasticity. The relationship between a low pulse wave amplitude and a low ABPI remained when controlling for smoking, hypertension and hyperlipidaemia. It is concluded that pulse wave measurement by plethysmography contributes information to improve leg atherosclerotic risk assessment in individuals exposed to known risk factors.

Social anchorage and blood pressure in elderly men--a population study.

The present study was designed to test the hypothesis that there is an independent association between the three concepts of psychosocial factors, social network, social support, social influence and blood pressure (see Materials and methods for definition). The study sample chosen (n = 621) comprised a randomly selected group of half the male residents of Malmö born in 1914, 500 (80.5%) of whom participated. A study based on a model with clearly defined criteria was used to measure the different aspects of social network, social support and social influence. In multiple regression analysis, social anchorage (a subconcept of social network) was shown to have an association with both systolic (P = 0.03) and diastolic blood pressure (P less than 0.001), when adjustments for social class, marital status, medication for hypertension, alcohol consumption, smoking habits, body mass index (BMI) and physical activity were made. Social anchorage is a concept on a structural level, that describes to what degree the individual belongs to and is anchored within formal and informal groups in society. As such, it may contribute to a deeper understanding of mechanisms behind high blood pressure and could thus be significant in the field of health promotion.

The effects of fasting on the quality of liver preservation by simple cold storage.

Although livers can be successfully preserved for 24 hr or more, often the transplanted livers have poor or no (primary nonfunction) function. The quality of the liver does not appear dependent upon the time of preservation but may be dependent upon the condition of the donor. In this study we have investigated the effects of fasting on the quality of livers for transplantation. Rabbits were fasted (48 hr) and livers preserved in the UW solution for 6-8 hr. Functions of the liver were analyzed by isolated perfusion for 2 hr. Also, pigs were fasted for 72 hr, livers preserved for 12 hr, and viability determined by orthotopic transplantation. Fasting depleted the liver glycogen by 85% but had no effect on ATP or glutathione concentrations. Rabbit livers from fasted animals produced similar amounts of bile, released similar concentrations of lactate dehydrogenase (LDH) and aspartate amino transaminase (AST) into the perfusate, maintained similar concentrations of ATP and glutathione in the tissue, and had a similar intracellular K:Na ratio after 24-hr preservation when compared to livers from fed animals. After 48-hr preservation, livers from fasted animals were less viable than livers from fed animals, including: reduced bile production (2.0 +/- 0.3 vs. 5.0 +/- 0.9 ml/2 hr, 100 g), greater release of LDH (3701 +/- 562 units vs. 1123 +/- 98 units) and AST, less ATP (0.326 +/- 74 vs. 0.802 +/- 160 nmol/g), less glutathione (0.303 +/- 13 vs. 0.933 +/- 137 nmol/g), and a lower K:Na ratio (1.5 +/- 0.9 vs. 7.4 +/- 0.6). Pigs receiving livers from fed animals preserved for 12 hr had better survival (5/6, 83%) than livers from fasted animals (3/6, 50%). The results show that the nutritional status of the donor can affect the outcome of liver preservation and transplantation. Increased injury in livers from fasted animals may be due to the loss of glycogen that may be an essential source of energy in the initial posttransplant period. In clinical liver transplantation the nutritional status of the donor may be an important factor in the initial function of the liver, and methods to increase the nutritional status of the donor may be important in increasing the quality of livers.

Kupffer cells depress hepatocyte protein synthesis on cold storage of the rat liver.

The causes of liver failure after transplantation are multifactorial. An understanding of the mechanisms of injury to the liver could help to define methods to improve preservation and transplantation. We measured protein synthesis by 3H-leucine incorporation into acid precipitable protein in rat liver tissue slices, isolated hepatocytes, and isolated perfused liver (IPL) after cold storage for 24 or 48 hr in University of Wisconsin (UW) solution. Some rats were pretreated with dexamethasone prior to liver harvest. Protein synthesis was depressed in all in vitro models after 24 hr storage. The percent decrease was greater in tissue slices and IPL (about 70% decrease relative to fresh livers) than in isolated hepatocytes (about 30% decrease). Dexamethasone pretreatment improved protein synthesis significantly after 24 hr preservation in tissue slices and in IPL, but had no significant effect on protein synthesis in isolated hepatocytes. The greater loss of protein synthesis in tissue slices and IPL compared with that in isolated hepatocytes was considered in relation to the presence of Kupffer cells in the former systems and lack of Kupffer cells in the isolated cell suspensions. Kupffer cells generate cytotoxins that could cause injury to metabolically depressed hepatocytes or endothelial cells. Dexamethasone has been shown to modulate Kupffer cell inhibition of hepatocyte functions. The results suggest that preservation damage to hepatocytes sensitizes them to further damage on reperfusion by Kupffer cell-generated agents.

A comparison of histidine-lactobionate and UW solution in 48-hour dog liver preservation.

Many modifications of the UW solution have been reported to yield successful results in rat liver preservation and transplantation. One solution used histidine, in combination with lactobionate (HL-I), and gave superior preservation of the rat liver when compared with the UW solution. In this study we have compared the HL-I solution with 90 mM histidine, HL-II solution with 30 mM histidine, and the UW solution in dog liver preservation and transplantation. Dog livers were preserved for 48 hr in one of the three solutions and transplanted. The peak AST and ALT values were highest in livers preserved in HL-I, intermediate in UW solution, and lowest in HL-II. However, there were no significant differences among survival rates (average 5-7 days per group), posttransplant serum concentration of liver enzymes (AST, ALT, LDH, and alk-phos), clotting factors (PT and PTT), bilirubin, and fibrinogen concentration for each group. Dogs were sacrificed or died within 5-7 days due to rejection in nonimmunosuppressed dogs. Also, rat livers were preserved in the HL-II solution or in a solution in which histidine was replaced by isoleucine (IL-I). Isoleucine is an amino acid with a molecular mass similar to that of histidine, but is not as good a hydrogen ion buffer as histidine at the pH used for liver preservation (7.4). The buffer capacity of the IL-I solution was similar to the UW solution, but about one-half as much as the HL-II solution. Rats receiving a liver preserved for 30 hr in HL-II or IL-I were 100% viable. Rats receiving a liver preserved for 40-44 hr in HL-II or IL-I showed less survival (33% and 25%, respectively). This shows that histidine can be effectively replaced by isoleucine in a preservation solution and gives equivalent preservation results. Thus, the mechanism of improvement of liver preservation with histidine is not due to its action as a hydrogen ion buffer. These studies show that, although the HL solutions are superior for preservation of the rat liver, they are not superior to the UW solution for preservation of the dog liver. However, as others have shown in the rat liver transplant model, a simplified UW solution (HL-II) appears effective in dog liver preservation. The dog liver transplant model remains a more appropriate model for testing new preservation solutions prior to initiation of clinical trials.

An analysis of the components in UW solution using the isolated perfused rabbit liver.

The isolated perfused rabbit liver model has been used to determine the essential components of the UW solution for hepatic preservation by simple cold storage. Livers were stored on ice for 48 hr after initial flushing with the solution being tested, and then reperfused at 38 degrees C in an isolated perfusion circuit; bile flow and enzyme (SGOT, SGPT, and LDH) release during a 2-hr period were recorded. All solutions tested contained phosphate (25 mM) as a buffer and magnesium sulfate (5 mM). Sodium can be substituted for potassium without adverse effects. Lactobionate, raffinose and glutathione cannot be omitted; all other components can be eliminated without altering the effectiveness of the solution in this model.

Seventy-two-hour preservation of the canine liver by machine perfusion.

The UW solution effectively preserves the dog liver for up to 48 hr by simple cold storage. This solution contains lactobionate as the primary impermeant. Another solution developed for machine perfusion of the kidney is similar to the UW solution but contains gluconate in place of lactobionate. In this study the UW gluconate solution was used for the continuous hypothermic machine perfusion of dog livers for 72 hr. Dog livers were continuously perfused at 5 degrees C through the portal vein at a pressure of 16-18 mm Hg and transplanted. Seven of 8 dogs survived for 7 or more days following orthotopic transplantation. The livers functioned as well as those preserved for 48 hr by cold storage in the UW solution as indicated by various liver-function tests. Successful machine perfusion was only achieved when the perfusate contained a high concentration of potassium (125 mM) but not with a high concentration of sodium (125 mM). This study demonstrates the feasibility of machine-perfusion preservation of the liver that yields longer preservation of equal quality compared to simple cold storage. For the development of truly long-term preservation (5 or more days) and better quality short-term preservation, machine perfusion may be the method of choice.

Donor nutritional status--a determinant of liver preservation injury.

In liver transplantation, the quality of the liver is determined by a number of factors including donor nutritional status. Livers from fasted donors appear to tolerate long-term preservation better than livers from fed donors. In this study we repeated earlier results and obtained 31% (4/13) survival after 40-hr preservation of livers from fed donor Brown Norway rats and 67% (8/12) survivors with donor livers from 4-day-fasted rats (P = 0.154). The explanation for this improvement is not known but may be due to inactivation of Kupffer cells due to nutritional depletion of the liver. Kupffer cell activation has been one explanation advanced to explain how cold storage injuries livers during reperfusion (transplantation). In this study, we have measured how donor fasting affects Kupffer cell function (phagocytosis of colloidal carbon) after preservation of the rat liver. In addition, we measured how enhancing liver glycogen by feeding glucose to the rat donors affected outcome and liver functions tested by isolated perfusion after 24- and 40-hr cold storage of the liver. Preservation did not cause inactivation or activation of Kupffer cell phagocytosis of colloidal carbon. In livers with 0-hr preservation, colloidal carbon uptake was 3.1 +/- 0.2 mg/g/hr, after 40-hr preservation uptake was 3.8 mg/g/hr (P < 0.05 vs. 0 hr) (fed) and 2.7 +/- 0.3 mg/g/hr (fasted, P, 0.05 vs. 0-hr and 40-hr-fed). Thus, the improved survival obtained with livers from fasted donors does not appear related to inactivation of Kupffer cell phagocytosis. Although livers from fasted donors showed improved survival, there was extensive hepatocellular injury as indicated by large LDH release from the livers after 40-hr cold storage as tested by isolated perfusion. LDH released into the perfusate increased from 35.8 +/- 10.1 U/L (fed, 40-hr CS) to 301 +/- 65 U/L (fasted, 40-hr CS) after 1-hr reperfusion. AST release showed a similar pattern and bile production was suppressed more in livers from fasted donors than fed donors. Feeding rats glucose elevated liver glycogen and significantly reduced hepatocellular injury as measured by LDH release and AST release in the isolated perfused liver after 40-hr cold storage. Feeding rats glucose (40% in drinking water for 4 days) also improved survival: fed+glucose = 85% survival versus 31% survival with no glucose and fasted+glucose = 92% survival versus 67% survival with no glucose. These results show that both extensive donor fasting and glucose feeding enhanced outcome in orthotopic liver transplantation. This dilemma (both fasting and feeding improved survival) are discussed in terms of how the interactions between Kupffer cells and hepatocytes affect liver viability. Donor fasting is probably impractical clinically as a method to improve the donor liver, but elevating liver glycogen by glucose supplementation is possible and may lead to improved preservation and outcome in liver transplantation.

Effect of glycine in dog and rat liver transplantation.

Glycine has been shown to protect renal tubule cells and hepatocytes from ischemia, ATP depletion, and cold storage injury. Glycine may be a useful additive to organ preservation solutions or suppress reperfusion injury by infusion into recipients of liver transplantation. In this study, the effects of glycine on survival and postoperative liver injury were studied in the rat and dog orthotopic transplant model. Rat livers preserved for 30 hr in the University of Wisconsin (UW) solution were 50% viable (3 of 6 survivors for 7 days). When glutathione was replaced by 10 mM glycine, survival increased to 100% (6 of 6). There was a significant reduction in hepatocellular injury at the end of preservation (lactate dehydrogenase [LDH] in the pretransplant flush-out of the liver was lower in the glycine group) and after transplantation (serum LDH concentration 6 hr after transplant was lower in the glycine group). In the dog, omission of glutathione from the UW solution resulted in 33% survival (48-hr preservation model) versus 100% survival with glutathione. Replacing glutathione in the UW solution by glycine did not improve survival (33% after 48 hr of preservation). However, when glycine was given to recipients of livers preserved in the UW solution for 24 or 48 hr, there was a decrease in the degree of hepatocellular injury. After 48 hr of preservation, peak aspartate aminotransferase, alanine aminotransferase, and LDH were reduced by about 45-55% when glycine was given to the recipient. Although the differences, with and without glycine treatment of the recipients, did not reach statistical significance, there was a noticeable reduction in hepatocellular injury with glycine. There was 100% survival of dogs in the groups that received livers preserved with the UW solution plus or minus glycine infusion. Hepatamine, a parenteral nutrition solution containing glycine and other amino acids increased hepatocellular injury (higher concentrations of aspartate aminotransferase, alanine transferase, and LDH versus control 48-hr preserved livers), although all dogs survived. This study shows that glycine is cytoprotective when administered to recipients of livers preserved for 24 or 48 hr and suppresses hepatocellular injury, as reflected in a reduction in the concentration of serum enzymes. However, the differences, with and without glycine, were, at best, marginal and further studies are needed to determine whether glycine would make a significant improvement in liver preservation and prevent primary nonfunction.

Effect of oxidized and reduced glutathione in liver preservation.

Glutathione spontaneously oxidizes in the UW solution for organ preservation and reduced glutathione (GSH) is converted to oxidized (GSSG) glutathione. To determine the effects of the oxidized or reduced forms of glutathione on liver preservation dog livers were preserved for 24 and 48 hr with the UW solution containing either GSH or GSSG. After 24 hr of preservation the form of glutathione did not affect survival or the postoperative course of the animals. All animals survived (three per group) with near-normal liver functions by the third to fifth postoperative day. When preservation was extended to 48 hr survival was 100% (6/6) with GSH and 29% (2/7) with GSSG. The dogs that died developed primary nonfunction of the liver. This study shows that GSH is an important component of the UW solution for 48-hr preservation of the dog liver. The presence of GSSG does not prevent successful 24-hr preservation of the liver, which has been confirmed in clinical studies. However, for 48-hr preservation GSH is required and GSSG is not suitable.

Preservation of dog liver, kidney, and pancreas using the Belzer-UW solution with a high-sodium and low-potassium content.

The UW solution developed for cold storage of the liver, pancreas, and kidney was used in a modified form in this study and tested in the orthotopic transplantation of dog livers, kidneys, and pancreases preserved for 48 hr. The modification was the alteration of the concentrations of potassium and sodium. The original UW solution contained 120 mM K+ and 30 mM Na+. In this study the Na+ was 140 mM and the K+ only 9 mM, all other agents were identical to the original UW solution. Six of 11 dogs survived with livers preserved for 48 hr. The five deaths were due to technical complications and unrelated to preservation failure. Postoperative AST and partial thromboplastin time (PTT) values were lower (statistically significant on days 1, 3, and 4) in livers preserved in the high Na+ UW solution than as previously shown in the high-k+ UW solution. Other measures of liver function (bilirubin and fibrinogen) were similar between the high-Na+ and high-K+ groups. Six dogs survived with kidneys preserved for 48 hr in the high-Na+ UW solution. The results were comparable to those obtained with the high K+ solution. Four of six dogs survived for up to 28 days with pancreases preserved for 48 hr. The two deaths were due to technical complications unrelated to preservation failure. Three of the four dogs had normal blood glucose values for one month, and intravenous glucose tolerances test on day 7 and 28 were identical to those obtained in pancreases preserved with the high-K+ UW solution. The high-Na+ version of the UW solution appears equally or slightly more effective for 48-hr organ preservation than the original high-K+ UW solution. The use of a high-Na+ UW solution reduces the problems of hyperkalemic cardiac arrest in in situ flushing of the donor for multiple organ harvesting and in transplantation of the liver. Thus, with this solution livers do not need to be flushed with a low K+-containing solution prior to transplantation.

Preservation of the canine liver for 24-48 hours using simple cold storage with UW solution.

The results of a series of 29 orthotopic liver transplants in the dog are described. The livers were preserved in a new cold storage fluid, UW solution, and were successfully transplanted after periods of storage of 24, 30, 36, and 48 hr. All six animals transplanted after 24 hr survived beyond 5 days after transplantation and had excellent graft function. Four of six survived for at least 5 days after 30 hr of cold storage, and five of five after 36 hr. Five of six consecutive dogs that received transplants that had been cold-stored for 48 hr survived for 5 or more days. This solution represents a substantial advance over all existing cold storage solutions for liver preservation.

Important components of the UW solution.

The UW solution for preservation of the liver, kidney, and pancreas contains a number of components, and the importance of each of these has not been fully resolved. In the studies reported here the importance of glutathione and adenosine is demonstrated in isolated cell models (rabbit renal tubules and rat liver hepatocytes) of hypothermic preservation and reperfusion and in dog renal transplantation. Glutathione in the UW solution is necessary for the preservation of the capability of the cell to regenerate ATP and maintain membrane integrity. Adenosine in the UW solution provides the preserved cell with substrates for the regeneration of ATP during the reperfusion period following cold storage. The omission of GHS from the UW solution results in poorer renal function in the 48 hr dog kidney preservation-transplant model. The role of other components of the UW solution is discussed including lactobionic acid; other impermeants; and the colloid, hydroxyethyl starch. It is concluded that the development of improved preservation solutions will require a more detailed understanding of the mechanism of injury due to cold storage and, once obtained, solutions more complex than the UW solution may be required for improved long-term storage of organs.

Donor brain death reduces survival after transplantation in rat livers preserved for 20 hr.

BACKGROUND: Eighty percent of donor organs come from donors who have suffered brain trauma (brain-dead donors). This unphysiological state alters the hemodynamic and hormonal status of the organ donor. This can cause organ injury, which has been suggested to alter the immunological or inflammatory status of the organ after transplantation, and may lead to increased sensitivity of the organ to preservation/transplantation injury. In this study we asked the question: does brain death cause injury to the liver that decreases successful liver preservation? METHODS: The rat liver transplant model was used to compare survival in rats receiving a liver from a brain-dead donor versus a non-brain-dead donor. Brain death was induced by inflation of a cranially placed balloon catheter. The rats were maintained normotensive with fluid infusion for 6 hr. The livers were flushed with University of Wisconsin (UW) solution and immediately transplanted or cold stored for 20 hr before transplantation. RESULTS: Recipient survival with immediately transplanted livers or those stored for 20 hr was 100% with livers from non-brain-dead donors. However, survival decreased when livers were procured from brain-dead donors. Survival was 75% (6/8) when storage time was 0 hr and 20% (2/10) when the liver was cold stored for 20 hr before transplantation. CONCLUSION: This study shows that brain death induces alterations in the donor liver that make it more sensitive to preservation/reperfusion injury than livers from donors without brain death. The mechanism of injury to the liver caused by brain death is not known. Because most livers used clinically for transplantation come from brain-dead donors, it is possible that poor function of these livers is due to the intrinsic condition of the donor organ, more than the quality of the preservation. Methods to treat the brain-dead donor to improve the quality of the liver may be needed to allow better preservation of the organ and to give better outcome after liver transplantation.

Risk factors for carotid artery stenosis: an epidemiological study of men aged 69 years.

Four hundred and seventy-eight men born in 1914 and residing in the city of Malmö, Sweden, underwent ultrasonic Doppler examination of the carotid arteries in 1982/83. The known risk factors for vascular disease--blood pressure, lipids, glucose, hematocrit, alcohol consumption and Body Mass Index were also measured. A moderate stenosis (diameter reduction 30-59%) of the internal carotid artery was found in 95 men (20%); 15 men (3%) had a greater than or equal to 60% stenosis of the internal carotid artery, while 7 (1.5%) had complete unilateral occlusion. Smoking was found to be significantly related to severe carotid artery disease. There was also a significant correlation between maximum flow velocity in the internal carotid artery and triglycerides. Those quitting smoking before the age of 50 had the same incidence of internal carotid artery disease as non-smokers, while those quitting later in life had a slightly higher incidence than life-long smokers.

Design and synthesis of inhibitors of adenosine and AMP deaminases.

Nucleosides and nucleotides which are able to undergo covalent hydration in the aglycone ring system are potential inhibitors of the enzymes adenosine deaminase (ADA) and AMP deaminase, respectively. Calculations of the enthalpy of covalent hydration and of enzyme binding energy have been used to design new inhibitors of ADA. The ribosyl triazolotriazine 16, which was synthesized as a result of these calculations, exists predominantly as the covalent hydrate 18 in water and is a potent inhibitor of mammalian ADA (IC(50) 50 nM).