Biomedical subjects
Publications and source records attributed to N J Espat.
Esophageal leiomyoma represents 70-80% of all benign esophageal tumors but only approximately 0.5% of all esophageal neoplasms; optimal surgical treatment consists of local resection. We present the first reported robotic-assisted thoracoscopic resection of two patients with esophageal leiomyoma using the daVinci Surgical System. Operative technique and technical considerations are presented.
OBJECTIVE: Many substances have been investigated for attenuation of spinal cord injury after acute trauma; however, pharmacologically only steroid administration has shown clinical benefits. This study attempts to characterize local spinal cord histologic response to human dose equivalent (HDE) intravenous methylprednisolone (MP) administration in a rodent model of acute spinal cord injury. DESIGN: Forty-eight Sprague-Dawley rats were divided equally into control and experimental groups. Each group was subdivided into eight sets of three animals each, according to postinjury intervals. Paraplegia after lower thoracic laminectomy was achieved using a standardized weight drop technique. INTERVENTION: Within one hour, experimental animals were treated with HDE MP followed by 23-hour continuous infusion of HDE MP. Spinal cords were harvested at variable intervals postinjury and prepared for histologic/immunohistochemistry examination. MAIN OUTCOME MEASUREMENTS: Edema, necrosis, and glial fibrillary acidic protein (GFAP) positivity in the specimens from treated/control groups were graded by microscopy and immunohistochemistry staining and compared in a blinded manner by a qualified neuropathologist and senior authors. RESULTS: Minimal differences were observed between control and MP-treated animals at zero and four hours. At eight hours, increased white matter and medullary edema was evident in control versus MP-treated rats. This trend continued through twelve, sixteen, twenty-four, forty-eight, and seventy-two hours. No difference was observed in the astrocytic response to injury by GFAP immunohistochemistry between the groups. CONCLUSIONS: Histologically, MP reduces the development of severe edema and preserves spinal cord architecture adjacent to the site of injury. In contrast, MP does not alter the development of spinal cord necrosis or astrocytic response at the zone of injury.
Technical improvement in perioperative morbidity and mortality with improved long-term survival associated with pancreaticoduodenectomy for patients with pancreatic carcinoma has clearly established a role for this operation when performed with curative intent. Most patients with pancreatic adenocarcinoma will not be candidates for surgical resection of their disease. These patients will experience significant symptoms potentially requiring surgical and nonsurgical palliative interventions to treat unrelieved cancer-associated pain, obstructive jaundice, or the development of GOO. The primary goal for palliative interventions should be to relieve symptoms with minimal morbidity and to maintain or improve the quality of life for patients with an expected limited survival.
The vast majority of patients developing obstructive jaundice will have an underlying malignancy. When the etiology of the obstruction cannot be defined prior to operative intervention, identification of a non-malignant process will occur only subsequent to a major operation. The clinical course of a patient with complete distal common bile duct obstruction as the result of pancreatic heterotopia is discussed. This uncommon diagnosis prompted a review of the literature on this subject enabling this detailed discussion inclusive of the embryology, prevalence and clinical presentations of this entity. Our review further identified a varied group of other non-malignant causes of biliary obstruction that may be mistakenly interpreted to represent biliary or pancreatic malignancy.
OBJECTIVES: Plasma proinflammatory, anti-inflammatory cytokine, and soluble tumor necrosis factor (TNF) receptor concentrations were examined in hospitalized patients after abdominal and thoracoabdominal aortic aneurysm (TAAA) repair, with and without left atrial femoral bypass. Changes in plasma cytokine concentrations were related to the duration of visceral ischemia and the frequency rate of postoperative, single, or multiple system organ dysfunction (MSOD). DESIGN: Prospective, observational study. SETTING: Two academic referral centers in the United States and The Netherlands. PATIENTS: We included 16 patients undergoing TAAA repair without left atrial femoral bypass, 12 patients undergoing TAAA repair with left atrial femoral bypass, and nine patients undergoing infrarenal aortic aneurysm repair. MEASUREMENTS AND MAIN RESULTS: Timed, arterial blood sampling for proinflammatory and anti-inflammatory cytokine and soluble TNF receptor concentrations (p55 and p75), and prospective assessment of postoperative single and MSOD. Plasma appearance of TNF-alpha, interleukin (IL)-6, IL-8, and IL-10 peaked 1 to 4 hrs after TAAA repair, and concentrations were significantly elevated compared with infrarenal abdominal aortic aneurysm repair (p < .05). Left atrial femoral bypass significantly reduced the duration of visceral ischemia (p < .05) and the systemic TNF-alpha, p75, and IL-10 responses (p < .05). Plasma TNF-alpha concentrations >150 pg/mL were more common in patients with extended visceral ischemia times (>40 mins). Additionally, patients with early peak TNF-alpha concentrations >150 pg/mL and IL-6 levels >1,000 pg/mL developed MSOD more frequently than patients without these elevated plasma cytokine levels (both p < .05). CONCLUSIONS: Thoracoabdominal aortic aneurysm repair results in the increased plasma appearance of TNF-alpha, IL-6, IL-8, IL-10, and shed TNF receptors. The frequency and magnitude of postoperative organ dysfunction after TAAA repair is associated with an increased concentration of the cytokines, TNF-alpha, and IL-6 and the increased plasma levels of these cytokines appear to require extended visceral ischemia times.
Local tumor recurrence after complete resection may be due to treatment factors or represent a manifestation of tumor biology. The association of local tumor recurrence, distant metastases, and death in patients undergoing treatment for extremity soft tissue sarcoma (STS) has been described but continues to be enigmatic. After definitive multimodality treatment for extremity STS, local tumor recurrence is associated with development of distant metastasis, and metastases are implicated in subsequent disease-specific death. The relationship is an enigma, and the causality is unclear. Conversely, for patients with retroperitoneal STS, a direct relationship between local tumor recurrence and disease-specific death has been shown. In this article, current concepts are analyzed and reviewed.
BACKGROUND: Laparoscopic staging is an effective and accurate means of staging pancreatic cancer. But, the frequency of subsequent surgical bypass to treat biliary or gastric obstruction in laparoscopically staged patients with unresectable adenocarcinoma is unknown. The development of biliary and gastric obstruction in patients with unresectable pancreatic adenocarcinoma has been reported to occur in as many as 70% and 25% of patients, respectively. Previously, staging for patients with pancreatic cancer was achieved by laparotomy and the anticipated high rate for these patients to develop obstruction led to prophylactic bypass procedures. As laparoscopic staging for pancreatic cancer becomes a standard modality, the need for prophylactic bypass procedures in these patients needs to be examined. STUDY DESIGN: Analyses of laparoscopically staged patients (n = 155) with unresectable, histologically proved pancreatic adenocarcinoma, from a single institution treated between 1993-1997 were performed. The frequency of surgical bypass in a prospective cohort of patients with unresectable pancreatic adenocarcinoma who did not undergo open enteric or biliary bypass at the time of laparoscopic staging was determined. RESULTS: Laparoscopic staging revealed that 40 patients had locally advanced disease and 115 had metastatic disease. Median survival for patients with locally advanced and metastatic disease was 6.2 and 7.8 months, respectively. Postlaparoscopy followup revealed that 98% (152 of 155) of these patients did not require a subsequent open surgical procedure to treat biliary or gastric obstruction. CONCLUSIONS: These results do not support the practice of routine prophylactic bypass procedures. As such, we propose that surgical biliary bypass can be advocated only for those patients with obstructive jaundice who fail endoscopic stent placement, and gastroenterostomy should be reserved for patients with confirmed gastric outlet obstruction.
The acute phase response to inflammation is mediated in part by the endogenous production of pro-inflammatory cytokines. Interleukin 6 (IL-6) and members of its superfamily, including ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF) have been implicated as primary mediators of the hepatic acute phase response. In the present report, mice suffering a turpentine-induced myositis were passively immunized with antibodies against either IL-6, CNTF or LIF. Passive immunization against IL-6 attenuated the anorexia and completely prevented the hypoalbuminaemia, and increases in the serum concentration of the acute phase reactants, amyloid P, amyloid A and seromucoid. In contrast, passive immunization against either CNTF or LIF failed to modulate the anorexia, weight loss or hepatic acute phase protein responses. The findings suggest that IL-6, but not other members of its superfamily, is primarily responsible for the hepatic acute phase response, and contributes to the anorexia, associated with turpentine-induced myositis.
Specialized diets enriched in the amino acids glutamine and arginine have been shown to benefit surgical patients. In the liver, glutamine supports glutathione biosynthesis, arginine regulates nitric oxide synthesis, and both of these amino acids serve as precursors for ureagenesis, gluconeogenesis, and acute phase protein synthesis. The effects of a diet enriched with glutamine and arginine on hepatic plasma membrane transport activity have not been studied in humans. We hypothesized that feeding supradietary amounts of these nutrients would enhance the activities of the specific carriers which mediate their transmembrane transport in the liver. We fed surgical patients (n = 8) and rats (n = 6) one of three diets: a) a regular diet, b) an enteral liquid diet containing arginine and glutamine, or c) an enteral diet supplemented with pharmacologic amounts of glutamine and arginine. Diets were isocaloric and were administered for 3 days. Hepatic plasma membrane vesicles were prepared from rat liver and from human wedge biopsies obtained at laparotomy. The transport of glutamine and arginine by rat and human vesicles was assayed. Vesicle integrity and functionality were verified by osmolarity plots, enzyme marker enrichments, and time courses. Provision of both a standard enteral liquid diet and one enriched with glutamine and arginine increased the activities of Systems N (glutamine) and y+ (arginine) in rat and human liver compared to a control diet. The diet supplemented with glutamine and arginine was the most effective in increasing transport activity. We conclude that the liver responds to diets enriched with specific amino acids by increasing membrane transport activity. This adaptive response provides essential precursors for hepatocytes which may enhance hepatic synthetic functions during catabolic states. This study provides insights into the mechanisms by which enteral nutrition regulates nutrient transport at the cellular level and may provide a biochemical rationale for the use of formulas which are enriched with conditionally essential nutrients.
OBJECTIVE: The present study was designed to evaluate whether pre-existing hepatic dysfunction (cirrhosis) leads to increased morbidity and mortality, in part through an inappropriate in vivo tumor necrosis factor-alpha response. SUMMARY BACKGROUND DATA: Vibrio vulnificus is the most commonly isolated member of the noncholera Vibrio sp., responsible for fulminant and frequently fatal septicemia. A strong clinical association exists between hepatic dysfunction and increased morbidity and mortality from Vibrio sp. infection. However, the underlying mechanism behind this association has not been fully delineated. METHODS: Cirrhosis was induced in C57BL/6 (15 to 20 g) mice using thrice-weekly injections of carbon tetrachloride (CCl4) for 7 weeks. Either a 7.0 to 9.5 X 10(7) (low dose) or a 0.8 to 1.2 X 10(9) colony-forming unit (high dose) of V. vulnificus was administered through a mini-laparotomy incision via transgastric puncture into both cirrhotic and control animals. RESULTS: Mortality in cirrhotic mice to low- and high-dose Vibrio infection was 88% (7/8) and 100% (8/8), respectively, whereas mortality in control animals was 0% (0/8) and 12% (1/8), respectively (p<0.01). Tumor necrosis factor-alpha mRNA could be detected by reverse transcriptase polymerase chain reaction in livers and lungs from infected animals 2 and 4 hours after Vibrio administration in both control and cirrhotic animals. Lung and liver tumor necrosis factor-alpha bioactivity, however, was significantly lower in cirrhotic animals infected with Vibrio when compared with controls. Serum tumor necrosis factor-alpha was only sporadically detected in both groups of Vibrio-infected animals. When cirrhotic mice challenged with a low dose of Vibrio sp. were pretreated with 1.0 mg/kg body weight of a novel tumor necrosis factor-alpha receptor immunoadhesin, the increased mortality was completely prevented. CONCLUSIONS: Cirrhotic mice show increased mortality to Vibrio infection, and this increased mortality is dependent on an in vivo tumor necrosis factor-alpha response.
Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 (IL-6) superfamily, has recently been shown to induce several inflammatory responses when administered to healthy animals, including induction of fever and a hepatic acute phase protein response. In the present report, 250 micrograms.kg body wt-1.day-1 of recombinant rat CNTF or murine IL-6 were repeatedly administered to healthy mice over a 7-day period in an effort to compare biological responses. In addition to its in vivo capacity to elicit a hepatic acute phase response, administration of CNTF, but not IL-6, produced profound anorexia and lean tissue wasting in mice. In C57B1/6 mice, 7 days of CNTF administration led to a 21% loss in carcass protein content, resulting from carcass protein breakdown rates being increased 218% over freely fed controls (both P < 0.01). Protein synthesis rates in carcass protein were also increased in CNTF-treated mice compared with both freely fed animals and mice pair-fed equivalent quantities of food. In contrast, administration of equivalent quantities of murine IL-6 had no effect on food intake or body weight in mice, although IL-6 produced a similar hepatic acute phase response, as determined by increases in serum amyloid P and seromucoid fraction and increases in total hepatic protein synthesis. However, when CNTF was coincubated with extensor digitorum longus muscles from juvenile rats in vitro, rates of total muscle and myofibrillar protein degradation and muscle protein synthesis were unchanged. We conclude that CNTF can regulate in vivo both skeletal muscle remodeling as well as the distant anorexia and hepatic acute phase protein responses. In the case of skeletal muscle, these actions are both indirect and independent of the associated anorexia. These properties of CNTF are distinct from IL-6, which when administered to the mouse at these doses is neither anorexigenic nor cachexia producing.
Anticytokine therapies have been promulgated in gram-negative sepsis as a means of preventing or neutralizing excessive production of proinflammatory cytokines. However, systemic administration of cytokine inhibitors is an inefficient means of targeting excessive production in individual tissue compartments. In the present study, human gene transfer was used to deliver to organs of the reticuloendothelial system antagonists that either inhibit tumor necrosis factor-alpha (TNF-alpha) synthesis or block its interactions with cellular receptors. Mice were treated intraperitoneally with cationic liposomes containing 200 micrograms of either a pCMV (cytomegalovirus)/p55 expression plasmid that contains the extracellular domain and transmembrane region of the human p55 TNF receptor, or a pcD-SR-alpha/hIL-10 expression plasmid containing the DNA for human interleukin 10. 48 h later, mice were challenged with lipopolysaccharide (LPS) and D-galactosamine. Pretreatment of mice with p55 or IL-10 cDNA-liposome complexes improved survival (p < 0.01) to LPS-D-galactosamine. In additional studies, intratracheal administration of IL-10 DNA-liposome complexes 48 h before an intratracheal LPS challenge reduced pulmonary TNF-alpha levels by 62% and decreased neutrophil infiltration in the lung by 55% as measured by myeloperoxidase activity (both p < 0.05). Gene transfer with cytokine inhibitors is a promising option for the treatment of both the systemic and local sequelae of septic shock.
The clinical syndrome of cachexia is characterized by anorexia, continued losses of lean body mass, and altered carbohydrate and lipid metabolism. As early as the 1930s, this "chronic wasting" syndrome had been identified as the most frequent immediate cause of death in patients with cancer [Warren: Am J Med Sci 184:610-619, 1932]. At present, controversy remains as to the benefit of supplemental parenteral or enteral feedings in the nutritional repletion of cachectic cancer patients, since only selected patient groups have demonstrated clear benefit from their administration [Copeland et al.: Cancer 43:2108-2116, 1979; Copeland et al.: Cancer Res 37:2451-2456, 1977; Terepka and Waterhouse: Am J Med 20:225-238, 1956]. Despite having these advanced nutritional modalities firmly in our therapeutic armamentarium, the progression of cachexia in the nutritionally depleted cancer patient often continues unabated, and our ability to intervene successfully remains limited. This review proposes that host: tumor interactions lead to a nonspecific inflammatory response mediated in part by the chronic production and release of proinflammatory cytokines, including interleukin-1, tumor necrosis factor alpha, interleukin-6 and interferon-gamma, which antagonize the anabolic signals associated with enteral and parenteral nutrition support. Cytokine-mediated alterations can explain the inability of adequate dietary nitrogen and calories to result in lean tissue repletion. Based on this proposal, interrupting proinflammatory cytokine production or target organ action may be an appropriate therapeutic objective to improve nutrient utilization in patients with tumors.
Octreotide, a somatostatin analogue that inhibits the release of most gut peptides, hastens the resolution of experimental postoperative ileus, suggesting that gut peptides mediate this process. We studied the role of two gut peptides involved in the control of normal gut motility, vasoactive intestinal peptide (VIP), and substance P (SP), in the initiation and maintenance of postoperative small bowel ileus in rats by preoperative administration of VIP and SP receptor antagonists, (VIP-ra and SP-ra). Thirty male Sprague-Dawley rats (300-350 g) underwent laparotomy. One half underwent placement of a duodenal catheter for transit studies while the other half had serosal electrodes placed on the proximal jejunum for myoelectric recordings. Six days later, animals were separated into three treatment groups of five each. Control animals were pretreated with ip saline, while the others received either VIP-ra or SP-ra prior to standardized laparotomy. Following abdominal closure, [Na51]CrO4 was injected into the duodenum and the animals were sacrificed 25 min later. The small bowel was then excised and divided into 10 equal segments. Small bowel transit was calculated as the geometric center of [Na51]CrO4 distribution. The interval until the return of migrating myoelectric complexes (MMCs) was determined in animals with intestinal electrodes. VIP-ra-treated rats demonstrated a 67% improvement in the geometric center of radiolabel relative to controls and SP-ra-treated rats had a 23% improvement (3.67 +/- 0.06 VIP-ra vs 2.69 +/- 0.09 SP-ra vs 2.20 +/- 0.09 control, P < 0.01). MMCs returned 180 +/- 17 min in controls vs 99 +/- 14 min in VIP-ra-treated rats (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Septic shock following gram-negative infection is a leading cause of mortality in critically ill patients, accounting for nearly 200,000 deaths a year. The exaggerated production of tumor necrosis factor-alpha (TNF alpha) is known to contribute to hemodynamic collapse and the hematological dyscrasia associated with gram-negative sepsis. Although previous studies have shown TNF alpha antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated that administration of a novel construct of two modified soluble p55 receptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in non-human primates. Nine adult female and male baboons (Papio anubis), weighing 10-17 kg, were anesthetized and invasively monitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 (n = 3), 5.0 mg/kg body wt PEG-BP-30 (n = 3), or placebo (n = 3). One hour after pretreatment, animals were infused with 5-10 x 10(10) CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters and throughout the study to obtain total and differential white blood cell and platelet counts and cytokine levels (TNF alpha, IL-1 beta, IL-6, IL-8). E. coli bacteremic baboons receiving only placebo demonstrated a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuated declines in blood pressure and leukocyte numbers.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: The liver of the host with cancer requires increased amounts of amino acids to support the synthesis of glucose and key defense proteins. To study the effect of the growing tumor on hepatic amino acid uptake, the authors measured hepatic transport activity in tumor-bearing rats and in rats at various times after tumor resection. METHODS: Fischer-344 rats were implanted subcutaneously with methylcholanthrene-induced fibrosarcoma cells (MCA sarcoma). When the tumors reached 10% of body weight, hepatic amino acid transport activity was assayed or the animals underwent surgical removal of the tumor. In animals that underwent tumor excision, livers were removed at 1, 3, or 5 days post-resection, and hepatic plasma membrane vesicles (HPMVs) were prepared. Nontumor-bearing pair-fed rats undergoing sham implantation or sham resection served as controls. System N (glutamine), System A (MeAIB), and System y+ (arginine) transport activity were assayed, which allowed the authors to compare differences in tumor-induced rates of transport and the influence of resection on transport activity. RESULTS: System A transport activity was unaltered by tumor growth. In contrast, the presence of the growing tumor increased arginine and glutamine uptake by the liver. Hepatic glutamine transport remained elevated for 5 days after tumor resection, although by postoperative day 5 there was a trend toward normalization. In contrast, arginine transport remained increased by twofold onpost-resection day 1 and had normalized by postoperative day 3. The enhanced arginine transport was a result of an increase in maximal transport velocity (Vmax) rather than a change in carrier affinity. CONCLUSIONS: Increases in hepatic amino acid transport normalize within several days of tumor resection, indicating a key role for the tumor in the induction of this response. The observation that hepatic glutamine transport activity remains augmented after tumor resection longer than any other transporter studied suggests a key role for this amino acid in overall hepatic nitrogen metabolism and may partially explain the persistent glutamine depletion that is characteristic of the tumor-bearing host.
BACKGROUND: Arginine plays a pivotal role in regulating ureagenesis, polyamine biosynthesis, and nitric oxide production, metabolic pathways that may be stimulated in the liver of the tumor-bearing host. Normally, plasma arginine is excluded from the hepatocyte intracellular space by the low basal activity of its membrane transporter. We hypothesized that progressive malignant disease is associated with an increase in carrier-mediated arginine transport across the hepatocyte plasma membrane. METHODS: Twenty-four adult Fischer 344 rats were implanted subcutaneously with fibrosarcomas (TBR) and were studied when the tumors were small [10 +/- 1% of body weight (BW)], medium-sized (15 +/- 1% of BW), and large (25 +/- 1% of BW). Groups of control rats (n = 24) were pair-fed to match carcass weights of the three TBR groups. Livers were excised, and hepatocyte plasma membrane vesicles (HPMVs) were prepared by Percoll density gradient centrifugation. Arginine transport by HPMVs was assayed by a rapid mixing/filtration technique. Vesicle purity and functionality were assessed by membrane enzyme marker enrichments and transportability into an osmotically active space. RESULTS: Arginine uptake by HPMVs was mediated by both saturable carrier-mediated (System y+) and nonsaturable (diffusion) components. The time course of arginine uptake in HPMVs in the three groups showed similar equilibrium transport rates, indicating similar vesicle sizes. The presence of the growing tumor resulted in a 40-120% increase in System y(+)-mediated arginine transport in HPMVs. This response was dependent on tumor size and was due to a stimulation of carrier Vmax, suggesting an increase in the number of functional System y+ carriers in the hepatocyte plasma membrane. The Na(+)-dependent transport of the System A analog MeAIB was also increased, but only in rats with large tumors. CONCLUSIONS: Tumor growth results in a progressive increase in hepatic arginine transport, a response mediated primarily by an increase in the activity of System y+. This accelerated transport may amplify the availability of arginine to support key arginine-dependent metabolic pathways in the hepatocyte.
Anorexia, net proteolysis of skeletal muscle and consumption of body fat are hallmarks of the cachexia syndrome associated with chronic disease states. While inanition contributes to cachexia, this wasting diathesis has little in common with simple starvation. The cachexia syndrome is characterized by progressive weight loss and depletion of lean body mass in excess to that resulting from comparable caloric restriction. Accelerated mobilization and consumption of host protein stores from peripheral tissues occurs to support gluconeogenesis and acute phase protein synthesis [1, 2]. In contrast, simple starvation is associated with a relative sparing of lean tissue with the preferential consumption of fat. While the clinical manifestations of cachexia are readily apparent, identification of the specific mechanisms responsible for the development of cachexia remains an enigma. In recent years, interest has focused on the role that the immune system plays in the development of cachexia. Investigators initially hypothesized that the chronic production of two inflammatory cytokines, tumour necrosis factor alpha (TNF alpha) and/or interleukin-1 (IL-1), could explain the host non-specific responses resulting in cachexia [3-5]. Other pro-inflammatory cytokines, including interleukin-6 (IL-6) [6, 7] and interferon-gamma [8, 9], have been more recently proposed to be involved in this complex process. Although no consensus exists for the exclusive role of any one cytokine in the pathogenesis of cachexia, there is growing acceptance that the progression of cachexia results in part from the inappropriate release of one or more pro-inflammatory cytokines [10, 11]. In the present review, the current role of TNF alpha as a mediator of cachexia is examined.