Comparison of two devices for the treatment of keloid scars with the use of intralesional cryotherapy: An experimental study.

BACKGROUND: Intralesional (IL) cryotherapy is a new technique for the treatment of keloid scars, in which the scar is frozen from inside. Two cryodevices are available, which were recently evaluated. Both devices showed promising results, but differed in clinical outcome. To explain these differences, more understanding of the working mechanism of both devices is required. OBJECTIVE: This experimental study was designed to investigate and compare the thermal behavior of an argon gas- and a liquid nitrogen-based device. Thermal behavior constitutes: (1) minimum tissue temperature (°C), (2) the freezing rate (°C/min). The thermal behavior was measured inside and on the outer surface of the scar. Both devices were tested ex vivo and in vivo. RESULTS: Ex vivo, when determining the maximum freezing capacity, the argon gas device showed a higher end temperature compared to the liquid nitrogen device (argon gas: -120°C, liquid nitrogen: -140°C) and a faster freezing rate (argon gas: -1300°C/min, liquid nitrogen: -145°C/min). In vivo, measured inside the keloid, the argon gas device showed a lower end temperature than the liquid nitrogen device (argon gas: -36.4°C, liquid nitrogen: -8.1°C) and a faster freezing rate (argon gas: -14.7°C/min, liquid nitrogen: -5°C/min). The outer surface of the scar reached temperatures below -20°C with both devices as measured with the thermal camera. CONCLUSION: In conclusion, the argon gas device displayed a lower end temperature and a faster freezing rate in vivo compared to the liquid nitrogen device. Although this resulted in lower recurrence rates for the argon gas device, more hypopigmentation was seen compared to the liquid nitrogen device following treatment. Finally, the low outer surface temperatures measured with both devices, suggest that some hypopigmentation following treatment is inevitable.

Sarcopenic obesity is associated with adverse clinical outcome after cardiac surgery.

BACKGROUND & AIMS: Both undernutrition - low fat free mass (FFM) - and obesity - high fat mass (FM) - have been associated with adverse outcome in cardiac surgical patients. However, whether there is an additional effect on outcome of these risk factors present at the same time, that is sarcopenic obesity (SO), is unknown. Furthermore, the association between SO and muscle function is unidentified. METHODS AND RESULTS: In 325 cardiac surgical patients, we prospectively analysed the association between preoperative FFM and FM, measured by bioelectrical impedance spectroscopy, and postoperative adverse outcomes, and their correlation with muscle function - handgrip strength (HGS). SO was associated with postoperative infections (28.2% vs. 5.3%, adj. odds ratio (OR): 7.9; 95% confidence interval (CI): 1.2-54.1; p=0.04). Further, a low FFM index (FFMI; kgm(-2)) was associated with postoperative infections (18.5% vs. 4.7%, adj. OR: 6.6; 95% CI: 1.7-25.2; p=0.01) while a high FM index (FMI; kgm(-2)) was not. Both components of SO, FFMI and FMI, correlated with HGS (FFMI: r=0.570; p<0.001, FMI: r=-0.263; p<0.001). CONCLUSION: SO is associated with an increased occurrence of adverse outcome after cardiac surgery. Our results suggest an additional risk of a low FFMI and high FMI present at the same time. Furthermore, SO is characterised by less muscle function. We advocate determining body composition in cardiac surgical patients to classify and treat undernourished patients, in particular those who are also obese.

4-1BB-mediated expansion affords superior detection of in vivo primed effector memory CD8+ T cells from melanoma sentinel lymph nodes.

We have been studying the re-activation of tumor-associated antigen (TAA)-specific CD8(+) T cells in sentinel lymph nodes (SLN) of melanoma patients upon intradermal administration of the CpG-B oligodeoxynucleotide PF-3512676. To facilitate functional testing of T cells from small SLN samples, high-efficiency polyclonal T cell expansion is required. In this study, SLN cells were expanded via classic methodologies with plate- or bead-bound anti-CD3/CD28 antibodies and with the K562/CD32/4-1BBL artificial APC system (K32/4-1BBL aAPC) and analyzed for responsiveness to common recall or TAA-derived peptides. K32/4-1BBL-expanded T cell populations contained significantly more effector/memory CD8(+) T cells. Moreover, recall and melanoma antigen-specific CD8(+) T cells were more frequently detected in K32/4-1BBL-expanded samples as compared with anti-CD3/CD28-expanded samples. We conclude that K32/4-1BBL aAPC are superior to anti-CD3/CD28 antibodies for the expansion of in vivo-primed specific CD8(+) T cells and that their use facilitates the sensitive monitoring of functional anti-tumor T cell immunity in SLN.

The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients.

Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42+/-0.06 versus 0.73+/-0.2micromol/L, respectively; p<0.001). Both ADMA (B=3.5; 95% CI: 0.5-6.5; p=0.023) and SDMA (B=1.7; 95% CI: 0.7-2.7; p=0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p=0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p=0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed.

Immunological consequences of laparoscopic versus open transhiatal resection for malignancies of the distal esophagus and gastroesophageal junction.

BACKGROUND/AIM: Surgery remains the only curative therapy for esophageal cancer. The objective of the current study was to evaluate the impact of laparoscopic transhiatal esophagectomy versus open transhiatal esophagectomy on both inflammatory and immunological responses. METHODS: Seventeen patients undergoing laparoscopic or open surgery were included in the study. The postoperative inflammatory response was assessed by measuring WBC count and CRP, IL-6, IL-8, soluble TNF I and II receptor, and elastase levels. The postoperative immune function was assessed by measuring the monocyte HLA-DR expression. LPS-binding protein (LBP) and bactericidal/permeability-increasing protein (BPI) were measured to evaluate bacterial translocation. RESULTS: The IL-6 level increased significantly more in the patients who received open surgery as compared with the laparoscopic group. Both LBP and BPI increased predominantly in the laparoscopic group as compared with the group who received open surgery. No difference was found in HLA-DR expression between the two groups. CONCLUSION: Although both laparoscopic and conventional esophageal resections result in an activation of the inflammatory response, this study suggests that this response could be less pronounced after the laparoscopic approach. However, in the laparoscopic group higher LBP and BPI levels were seen, suggesting an increased endotoxemia. We postulate that the persistently elevated abdominal pressure results in a loss of mucosal barrier function, resulting in bacterial translocation. The cellular acidification of the cells of the peritoneum induced by CO(2) insufflation, however, blunts the expected inflammatory response.

[Low prognostic importance of non-radical melanoma excision and the presence of melanoma cells in the re-excision specimen to overall and disease-free survival of melanoma patients]. / Weinig prognostische betekenis van niet-radicale melanoomexcisie en van melanoomcellen in het re-excisiepreparaat voor totale en ziektevrije overleving van melanoompatiënten.

OBJECTIVE: To determine in patients with skin melanoma whether disease-free and overall survival are associated with the tumour excision type and the presence of residual tumour cells in the re-excision specimen. DESIGN: Prospective and descriptive. METHOD: In the period August 1993-August 2004, 471 patients were diagnosed with stage I/II skin melanoma after partial or non-partial removal of a pigmented skin lesion, followed by re-excision and a sentinel node biopsy at Amsterdam Free University Medical Centre, the Netherlands. All patients were followed prospectively with a mean follow-up of > 5 years. Patients were divided into two groups according to (a) the type of primary excision (radical excision, narrow/radical excision, non-radical excision biopsy and incisional biopsy) and (b) the presence or absence of residual tumour cells in their re-excision specimen. Survival analysis was done using Cox proportional hazard model adjusted for the 8 known most important determinants of melanoma. RESULTS: Of the 471 patients, the primary excision was radical in 279 patients and narrow/radical in 109 patients; 52 patients underwent a nonradical excision and 31 patients an incisional biopsy. Re-excision was carried out in 441 patients and in 41 of them residual tumour cells were present in the re-excision specimen. Neither the diagnostic biopsy type nor the presence oftumour cells in the re-excision specimen were connected with disease-free or overall survival in the melanoma patients. CONCLUSION: Non-radical diagnostic biopsies were not negatively associated with overall and disease-free survival in melanoma patients.

The prognostic value of severe malnutrition in the development of nonthyroidal illness in head and neck cancer patients.

BACKGROUND: Thyroid hormone metabolism is modulated by starvation and overfeeding but also by dietary composition. Unfortunately, little is known about the effect of malnutrition on disease-induced nonthyroidal illness (NTI). In this study, we investigated whether the degree of NTI after surgery differed between severely malnourished and well-fed patients with head and neck cancer. METHODS: Plasma levels of the thyroid hormones 3',5-triiodothyronine (T(3)), reverse T(3) (rT(3)), free T(4) (FT(4)), and thyrotropin (TSH) were measured on the first day before the operation and on the first, fourth, and seventh day after the operation in 16 malnourished patients who were admitted for intentional curative surgery of T1-T4 carcinomas of the head and neck. Six well-fed head and neck cancer patients eligible for surgical treatment served as a control group. RESULTS: In the malnourished group, rT(3) showed a significant increase, whereas T(3) and FT(4) decreased significantly due to the operation. TSH showed no significant change. During the postoperative course, it took 7 days until rT(3) and 4 days until T(3) and FT(4) were restored to their preoperative value. In contrast, well-fed patients did not develop NTI. CONCLUSIONS: This study shows that peri- and postoperative rT(3), T(3), and FT(4) levels change significantly in malnourished patients compared with well-fed patients. Therefore, it can be concluded that nutrition status of patients undergoing major head and neck surgery should be optimized in order to prevent the development of NTI.

[Perioperative nutrition]. / Perioperatieve voeding.

Illness is associated with involuntary weight loss, which is often the result of malnutrition. The undernourished surgical patient runs a higher risk of postoperative morbidity and mortality. For this reason, perioperative nutrition is an important part of a patient's therapy. Supplying substrates for wound healing and maintaining existing organic structures are the major goals of nutrition. It is recommended that extremely malnourished patients be fed at least 7 days prior to surgery. It would seem sensible to give a carbohydrate-rich beverage up to 2 hours before surgery, both to decrease preoperative anxiety and to reduce postoperative insulin resistance. The Dutch tradition of fasting patients before surgery is difficult to defend any longer because this policy impairs patients' state of health as a result of which they are not optimally prepared for the surgical induced stress response. The postoperative recovery of all surgical patients can be improved by an early postoperative start of enteric nutrition. When the enteric administration of food turns out to be impossible, total parenteral nutrition can be given to bridge a long period without food.

The interval between primary melanoma excision and sentinel node biopsy is not associated with survival in sentinel node positive patients - An EORTC Melanoma Group study.

BACKGROUND: Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe. AIM: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. METHODS: Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. RESULTS: Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both <47 days and ≥47 days interval: 3.00 mm (1.90-5.00 mm) vs 3.00 mm (1.90-4.43 mm) (p = 0.402). Sentinel node tumor burden was significantly higher in patients operated ≥47 days (p = 0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS. CONCLUSIONS: Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients.

Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results.

PURPOSE: Although sentinel lymph node (SLN) status is part of the new American Joint Committee on Cancer staging system, there is no final proof that the SLN procedure in melanoma patients influences outcome of disease. This study investigated the accuracy of the SLN procedure and clinical outcome in melanoma patients after at least 60 months of follow-up. PATIENTS AND METHODS: Between 1993 and 1996, 209 patients with stage I/II cutaneous melanoma underwent selective SLN dissection by the triple technique. If the SLN contained metastatic disease, a completion lymphadenectomy was performed. Survival analyses were performed using the Kaplan-Meier approach. Factors associated with survival were analyzed using the Cox proportional hazards regression model. RESULTS: The success rate was 99.5%. Median follow-up was 72 months. Forty patients (19%) had a positive SLN. The false-negative rate was 9%. Five-year overall survival was 87% for the entire group and 92% and 67% for SLN-negative and SLN-positive patients (P <.0001), respectively. All patients with a positive SLN and a Breslow thickness < or = 1.00 mm survived, and SLN-positive patients with a Breslow thickness less than 2.00 mm tend to have a better prognosis compared with SLN-negative patients with a Breslow thickness greater than 2.00 mm. SLN status (P =.002), Breslow thickness (P =.002), and lymphatic invasion (P =.0009) were all found to be independent prognostic factors for overall survival. CONCLUSION: With a success rate of 99.5% and a false-negative rate of 9% after long-term follow-up, the triple-technique SLN procedure is a reliable and accurate method. Survival data seem promising, although a therapeutic effect is still questionable. As shown in this study, not all SLN-positive patients have a poor prognosis.

Preoperative supplementation with a carbohydrate mixture decreases organ dysfunction-associated risk factors.

BACKGROUND & AIMS: Recently, both asymmetrical dimethylarginine and IL-6 have been suggested to be associated with the induction and severity of single and multiple organ dysfunction. The aims of the present study were to elucidate if these factors were increased in an ischemia reperfusion (IR) model and whether pre-operative carbohydrate supplementation can reduce the risk factors along with the IR injury. METHODS: One group of male Wistar rats was fasted for 16 h (water ad libitum) prior to clamping the superior mesenteric artery (IR fasted n=14). A second group had ad libitum access to a carbohydrate solution prior to clamping (IR fasted CHO group n=11). Sham-fasted animals, which only received laparotomy and no clamping, served as controls (n=4). RESULTS: Plasma urea and ALAT activity were both increased in the IR fasted animals when compared to the sham rats (P=0.007 and P<0.02, respectively). Furthermore, it was shown that IR fasted rats had increased ADMA and IL-6 concentration in plasma when compared to sham animals (P<0.02). Moreover, the GSH level in lung was significantly decreased in the IR fasted animals (P=0.014). IR CHO supplemented showed no significant increase of ALAT activity and decrease of lung GSH. Furthermore, significantly lower plasma urea, ADMA and IL-6 concentration was seen in the IR CHO supplemented group when compared to the IR fasted rats (P=0.028, P<0.01 and P<0.02, respectively). The liver glycogen concentration in IR fasted rats was 48% of that IR rats supplemented the carbohydrate mixture. CONCLUSION: The present rat intestinal ischemia reperfusion model not only induces organ injury indicated by the classical parameters such as plasma urea and ALAT activity, but also increased plasma IL-6 and ADMA and decreased lung GSH concentration in IR fasted rats. Pre-operative supplementation with the carbohydrate mixture significantly lowered the plasma urea, IL-6 and ADMA concentrations and maintained lung GSH concentration. This indicates that pre-operative carbohydrate supplementation reduces post-operative organ injury.

Preoperative fasting: an outdated concept?

Recent studies have shown that fasting during the preoperative period for elective surgery induces a metabolic state that seems unfavorable for patients. Results from animal studies indicate that rapid depletion of liver glycogen before surgery leads to mobilization of muscle glycogen after surgery, in turn leading to reduced muscle strength. Depletion of liver glycogen also influences the function of the mononuclear phagocytic system (MPS), which is located predominantly in the liver. The MPS is essential in restricting endotoxin, which may translocate from the gut. In addition, surgery per se puts a substantial physical strain on the patient, and fasting may adversely affect the metabolic response to surgery. This paper presents experimental and clinical data that, when combined together, prove that fasting before surgery has adverse consequences for the patient.

[Three patients with a Spitz naevus that later turned out to be a melanoma]. / Drie patiënten met op Spitz-naevus gelijkende afwijkingen die later een melanoom bleken te zijn.

A melanocytic lesion was removed from each of three patients: 2 men aged 37 and 65 and 1 woman aged 45. The preferred diagnosis was 'Spitz naevus'. Subsequently, all three developed regional (sub)cutaneous and/or lymph node metastases, indicating that the lesions were melanomas. The histopathological distinction between Spitz naevus and melanoma is often very difficult. Classical Spitz naevi can be diagnosed correctly only if the entire lesion is available for histological examination. Incompletely removed lesions should be re-excised for further examination. Some melanomas resemble Spitz naevi, but can be recognised on the basis of well-defined histological indicators of malignancy. Some melanocytic lesions, however, cannot be categorised with confidence as being either benign (Spitz naevus) or malignant (spitzoid melanoma). Thus, a group of lesions with inconclusive histology remains and has been designated as 'atypical Spitz tumour' or 'Spitz tumour of uncertain malignant potential'. Generally, such lesions are best treated as melanomas.

Flavonoids: a review of probable mechanisms of action and potential applications.

The aim of this review, a summary of the putative biological actions of flavonoids, was to obtain a further understanding of the reported beneficial health effects of these substances. Flavonoids occur naturally in fruit, vegetables, and beverages such as tea and wine. Research in the field of flavonoids has increased since the discovery of the French paradox,ie, the low cardiovascular mortality rate observed in Mediterranean populations in association with red wine consumption and a high saturated fat intake. Several other potential beneficial properties of flavonoids have since been ascertained. We review the different groups of known flavonoids, the probable mechanisms by which they act, and the potential clinical applications of these fascinating natural substances.

Effect of perioperative nutrition, with and without arginine supplementation, on nutritional status, immune function, postoperative morbidity, and survival in severely malnourished head and neck cancer patients.

BACKGROUND: Malnourished head and neck cancer patients are at increased risk of postoperative complications. OBJECTIVE: We studied the effect of perioperative, arginine-supplemented nutritional support on nutritional status, immune status, postoperative outcome, and survival in severely malnourished (weight loss >10% of body weight) head and neck cancer patients undergoing major surgery. DESIGN: Forty-nine patients were randomly assigned to receive 1) no preoperative and standard postoperative tube feeding, 2) standard preoperative and postoperative tube feeding, or 3) arginine-supplemented preoperative and postoperative tube feeding. RESULTS: Patients in both prefed groups received approximately 9 d of preoperative tube feeding, resulting in energy intakes of 110% and 113% of calculated needs (compared with 79% in the control group; P = 0.007). Compared with no preoperative feeding, preoperative enteral nutrition did not significantly improve nutritional status or any of the studied biochemical or immunologic indexes. Major postoperative complications occurred in 53%, 47%, and 59% of patients in study groups 1, 2, and 3 (NS). A trend was seen toward better survival in the arginine-supplemented group (P = 0.15). Secondary analysis showed that survivors had better human leukocyte antigen-DR expression on monocytes (P = 0.05) and higher endotoxin-induced cytokine production (P = 0.010 for tumor necrosis factor alpha and P = 0.042 for interleukin 6) at the start of the study than did patients who died. CONCLUSIONS: Nine days of preoperative tube feeding, with or without arginine, did not significantly improve nutritional status, reduce the surgery-induced immune suppression, or affect clinical outcome in severely malnourished head and neck cancer patients. Patients supplemented with arginine-enriched nutrition tended to live longer. Some markers of immune function may distinguish patients with good or bad prognoses.

Gut endotoxin restriction improves postoperative hemodynamics in the bile duct-ligated rat.

BACKGROUND: Postoperative hemodynamic disturbances in obstructive jaundice are associated with complications such as shock and renal failure. Gut-derived endotoxemia may underlie these complications. Recently, we have shown that cholestyramine treatment prevents gut-derived endotoxemia in bile duct-ligated (BDL) rats (Houdijk APJ, Boermeester MA, Wesdorp RIC, Hack CE, van Leeuwen PAM: Tumor necrosis factor unresponsiveness following surgery in bile duct-ligated rats. Am J Physiol 271: G980-G986, 1996). METHODS: The effect of cholestyramine on systemic hemodynamics and organ blood flows after a laparotomy was studied in 2 wk BDL rats using radioactive microspheres. RESULTS: Compared with sham-operated rats, postoperative BDL rats had 1) lower blood pressure (p < .05) and heart rate (p < .001) with higher cardiac output (p < .05), 2) lower splanchnic blood flow (p < .05), 3) lower renal blood flow (p < .01), and 4) higher splanchnic organ and renal-vascular resistances. Cholestyramine treatment in BDL rats prevented the postoperative decrease in blood pressure by increasing cardiac output (p < .01). In addition, cholestyramine maintained splanchnic blood flow at sham levels (p < .05). Furthermore, cholestyramine also prevented the fall in renal blood flow after surgery in BDL rats. CONCLUSION: Gut endotoxin restriction using cholestyramine treatment maintained normal blood pressure, improved splanchnic blood flow, and completely prevented the fall in renal blood flow in BDL rats. Reducing the gut load of endotoxin in patients with obstructive jaundice scheduled for abdominal surgery may prevent postoperative hemodynamic complications.

Arginase release from red blood cells: possible link in transfusion induced immune suppression?

Arginine stimulates lymphocyte function and is degraded by arginase, an enzyme that is abundantly present in red blood cells. Arginase impairs lymphocyte function and responses in vitro. Leakage of arginase from stored red blood cells may be involved in the lymphocyte dysfunction associated in allogenic blood transfusion. In the present study, arginase activity was determined in bags of red cells stored for transfusion. Buffy coat depleted red blood cells were obtained routinely from four healthy donors and stored in bags for a maximum period of five weeks at 4 degrees C. The bags were sampled for determination of arginase, lactate dehydrogenase, and potassium. In addition, a random sample of 36 bags of red blood cells about to be transfused to patients were studied. Levels of arginase, lactate dehydrogenase, and potassium showed a time dependent increase in the bags of the four donors. This time dependent increase in arginase activity could be confirmed in the additional bags sampled (P < 0.0001, r = 0.78). The results for the first time show that arginase is released from red blood cells during storage for transfusion. Arginase infusion may play an important role in the immune suppression observed after blood transfusion.

Paradoxical changes in organ blood flow after arginase infusion in the non-stressed rat.

Arginine (ARG) is the precursor of nitric oxide (NO), a potent vasodilator. Arginase (ASE) is released following hepatocellular damage, resulting in low plasma ARG levels. The effect of ASE infusion on hemodynamics was studied. Rats received a 20 min ASE or saline infusion, and systemic hemodynamics and organ blood flow were studied, at 30 and 270 min, using radiolabeled microspheres. Compared with control, ASE resulted (30 min) in 1) undetectable ARG levels; 2) higher mean arterial pressure and total peripheral resistance (both p < .05); 3) higher blood flow to the heart, kidneys, stomach, small intestine (all p < .05), and spleen (p < .001); and 4) lower vascular resistance in the heart, kidneys, stomach, and small intestine (all p < .05) and in the spleen (p < .005). At 270 min, ASE rats had similar organ blood flow and higher nitrate levels in urine and plasma (both p < .05) compared with control. We conclude that ASE reduces ARG levels with simultaneous increase in mean arterial pressure and total peripheral resistance. Higher nitrate production, suggesting higher NO formation in the presence of low ARG plasma levels, is paradoxical but could explain the higher blood flow in some organs. The increased total peripheral resistance during higher nitrate formation suggests regional differences in dependency of NO production on plasma ARG levels.

Reduced arginine plasma levels are the drive for arginine production by the kidney in the rat.

In bile duct ligated rats, arginase (ASE) release from damaged hepatocytes results in low arginine (ARG) levels despite maximal renal ARG production. Plasma ARG levels were restored by reducing gut-derived endotoxemia that lowered circulating ASE activity although maintaining increased renal production. From this it was not clear if the higher renal ARG production was induced by the low grade endotoxemia or the low arginine plasma levels. The separate and combined influence of both factors on ARG metabolism was studied in the rat. Male Wistar rats received either bovine liver ASE, to lower ARG levels, or saline (SAL). Following the ASE or SAL infusion, rats were randomized to receive a low dose endotoxin (LPS) or SAL infusion. In ASE/SAL- and ASE/LPS-treated rats, ARG levels were lower compared with SAL/SAL (p<.005) and SAL/LPS (p<.005). The increased ARG production by the kidneys and gut proved to be independent of LPS but related to reduced ARG plasma levels (both p<.05 when compared with SAL/SAL and SAL/LPS). Metabolism of related amino acids was not explanatory. The study concluded that a low grade endotoxemia did not influence the metabolism of ARG by the gut, kidney, and liver. Reductions in ARG plasma by ASE treatment, irrespective a low dose endotoxin, were the drive for ARG production by the gut and the kidney.

Pharmacokinetics of a recombinant amino terminal fragment of bactericidal/permeability increasing protein (rBPI21) after liver surgery in rats and humans.

Major liver resections are associated with considerable morbidity and mortality. Gut-derived bacteria and bacterial endotoxin (LPS) are considered to play a central role in the pathophysiology of these complications. Like human BPI, rBPI21 binds to LPS from Gram-negative bacteria. By binding and clearing of LPS, rBPI21 can inhibit a number of endotoxin-induced humoral and cellular responses. Because of this capacity, rBPI21 could partially compensate for the loss of hepatic mononuclear phagocytic system function after liver resection. However, the liver is also thought to be an important organ for the clearance of BPI, and reduction of liver mass could result in a decreased clearance and exceedingly high plasma levels of rBPI21. In this study we therefore investigated the pharmacokinetics of rBPI21 in rats and in patients undergoing a major liver resection. Rats were administered an intravenous (i.v.) bolus of rBPI21 after undergoing a 60% or 80% hepatectomy (with sham-operated controls). Patients undergoing a hemihepatectomy and healthy volunteers received rBPI21 or placebo by continuous i.v. infusion for 48 h. Plasma concentrations were measured by sandwich ELISA. In rats, 60% hepatectomy did not consistently change the clearance of rBPI21, whereas 80% hepatectomy decreased the clearance of rBPI21 severalfold. In hemihepatectomized patients, the clearance of rBPI21 after major hepatectomy was also slower, when compared with healthy volunteers, but this difference had disappeared within 24 h. Our data indicate that the administration of rBPI21 in patients undergoing liver resection is well tolerated and does not result in exceedingly high plasma levels. Additional studies on the efficacy of rBPI21 in the prevention of complications after hepatectomy are needed.