The first polluted river? Repeated copper contamination of fluvial sediments associated with Late Neolithic human activity in southern Jordan.

The roots of pyrometallurgy are obscure. This paper explores one possible precursor, in the Faynan Orefield in southern Jordan. There, at approximately 7000cal. BP, banks of a near-perennial meandering stream (today represented by complex overbank wetland and anthropogenic deposits) were contaminated repeatedly by copper emitted by human activities. Variations in the distribution of copper in this sequence are not readily explained in other ways, although the precise mechanism of contamination remains unclear. The degree of copper enhancement was up to an order of magnitude greater than that measured in Pleistocene fluvial and paludal sediments, in contemporary or slightly older Holocene stream and pond deposits, and in the adjacent modern wadi braidplain. Lead is less enhanced, more variable, and appears to have been less influenced by contemporaneous human activities at this location. Pyrometallurgy in this region may have appeared as a byproduct of the activity practised on the stream-bank in the Wadi Faynan ~7000years ago.

Risk of malignancy in resected cystic tumors of the pancreas < or =3 cm in size: is it safe to observe asymptomatic patients? A multi-institutional report.

Recent international consensus guidelines propose that cystic pancreatic tumors less than 3 cm in size in asymptomatic patients with no radiographic features concerning for malignancy are safe to observe; however, there is little published data to support this recommendation. The purpose of this study was to determine the prevalence of malignancy in this group of patients using pancreatic resection databases from five high-volume pancreatic centers to assess the appropriateness of these guidelines. All pancreatic resections performed for cystic neoplasms < or =3 cm in size were evaluated over the time period of 1998-2006. One hundred sixty-six cases were identified, and the clinical, radiographic, and pathological data were reviewed. The correlation with age, gender, and symptoms (abdominal pain, nausea and vomiting, jaundice, presence of pancreatitis, unexplained weight loss, and anorexia), radiographic features suggestive of malignancy by either computed tomography, magnetic resonance imaging, or endoscopic ultrasound (presence of solid component, lymphadenopathy, or dilated main pancreatic duct or common bile duct), and the presence of malignancy was assessed using univariate and multivariate analysis. Among the 166 pancreatic resections for cystic pancreatic tumors < or =3 cm, 135 cases were benign [38 serous cystadenomas, 35 mucinous cystic neoplasms, 60 intraductal papillary mucinous neoplasms (IPMN), 1 cystic papillary tumor, and 1 cystic islet cell tumor], whereas 31 cases were malignant (14 mucinous cystic adenocarcinomas and 13 invasive carcinomas and 4 in situ carcinomas arising in the setting of IPMN). A greater incidence of cystic neoplasms was seen in female patients (99/166, 60%). Gender was a predictor of malignant pathology, with male patients having a higher incidence of malignancy (19/67, 28%) compared to female patients (12/99, 12%; p < 0.02). Older age was associated with malignancy (mean age 67 years in patients with malignant disease vs 62 years in patients with benign lesions (p < 0.05). A majority of the patients with malignancy were symptomatic (28/31, 90%). Symptoms that correlated with malignancy included jaundice (p < 0.001), weight loss (p < 0.003), and anorexia (p < 0.05). Radiographic features that correlated with malignancy were presence of a solid component (p < 0.0001), main pancreatic duct dilation (p = 0.002), common bile duct dilation (p < 0.001), and lymphadenopathy (p < 0.002). Twenty-seven of 31(87%) patients with malignant lesions had at least one radiographic feature concerning for malignancy. Forty-five patients (27%) were identified as having asymptomatic cystic neoplasms. All but three (6.6%) of the patients in this group had benign disease. Of the patients that had no symptoms and no radiographic features, 1 out of 30 (3.3%) had malignancy (carcinoma in situ arising in a side branch IPMN). Malignancy in cystic neoplasms < or =3 cm in size was associated with older age, male gender, presence of symptoms (jaundice, weight loss, and anorexia), and presence of concerning radiographic features (solid component, main pancreatic duct dilation, common bile duct dilation, and lymphadenopathy). Among asymptomatic patients that displayed no discernable radiographic features suggestive of malignancy who underwent resection, the incidence of occult malignancy was 3.3%. This study suggests that a group of patients with small cystic pancreatic neoplasms who have low risk of malignancy can be identified, and selective resection of these lesions may be appropriate.

Covered self-expandable metal stents in pancreatic malignancy regardless of resectability: a new concept validated by a decision analysis.

BACKGROUND AND STUDY AIMS: The current treatment model for the management of malignant biliary obstruction is to place a plastic stent for unstaged pancreatic cancer. In patients with unresectable disease but a life expectancy of more than 6 months, self-expandable metal stents (SEMS) are favored because of their more prolonged patency. We analyzed the efficacy and cost-effectiveness of covered SEMS (CSEMS) in patients with pancreatic cancer and distal biliary obstruction without regard to surgical resectability. PATIENTS AND METHODS: Between March 2001 and March 2005, 101 consecutive patients with obstructive jaundice secondary to pancreatic cancer underwent placement of a CSEMS. Patients with resectable tumor were offered pancreaticoduodenectomy. A model was developed to compare the costs of CSEMS and polyethylene and DoubleLayer stents. RESULTS: A total of 21 patients underwent staging laparoscopy, of whom 16 had a resection (76%). The 85 patients who did not have a resection had a mean survival of 5.9 months (range 1-25 months) and a mean CSEMS patency duration of 5.5 months (range 1-16 months). Life-table analysis demonstrated CSEMS patency rates of 97% at 3 months, 85% at 6 months, and 68% at 12 months. In a cost model that accounted for polyethylene and DoubleLayer stent malfunction and surgical resections, initial CSEMS placement (3177 euros per patient) was a less costly intervention than either DoubleLayer stent placement (3224 euros per patient) or polyethylene stent placement with revision (3570 euros per patient). CONCLUSIONS: Covered SEMS are an effective treatment for distal biliary obstructions caused by pancreatic carcinoma. Their prolonged patency and removability makes them an attractive option for biliary decompression, regardless of resectability. The strategy of initial covered SEMS placement might be the most cost-effective strategy in these patients.

Endoscopic ultrasound drainage of pancreatic pseudocyst: a prospective comparison with conventional endoscopic drainage.

BACKGROUND AND STUDY AIMS: Pancreatic pseudocysts are a complication in up to 20% of patients with pancreatitis. Endoscopic management of pseudocysts by a conventional transenteric technique, i. e. conventional transmural drainage (CTD), or by endoscopic ultrasound-guided drainage (EUD), is well described. Our aim was to prospectively compare the short-term and long-term results of CTD and EUD in the management of pseudocysts. PATIENTS AND METHODS: A total of 99 consecutive patients underwent endoscopic management of pancreatic pseudocysts according to this predetermined treatment algorithm: patients with bulging lesions without obvious portal hypertension underwent CTD; all remaining patients underwent EUD. Patients were followed prospectively, with cross-sectional imaging during clinic visits. We compared short-term and long-term results (effectiveness and complications) at 1 and 6 months post procedure. RESULTS: 46 patients (37 men) underwent EUD and 53 patients (39 men) had CTD. The mean age of the entire group was 50 +/- 13 years. There were no significant differences between the two groups regarding short-term success (93% vs. 94%) or long-term success (84% vs. 91%); 68 of the 99 patients completed 6 months of follow-up. Complications occurred in 19% of EUD vs. 18% of CTD patients, and consisted of bleeding in three, infection of the collection in eight, stent migration into the pseudocyst in three, and pneumoperitoneum in five. All complications but one could be managed conservatively. CONCLUSIONS: No clear differences in efficacy or safety were observed between conventional and EUS-guided cystenterostomy. The choice of technique is likely best predicated by individual patient presentation and local expertise.

Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells.

Focal adhesion kinase (FAK) has been implicated in the regulation of cell migration. In addition, FAK expression is increased in a number of highly metastatic tumor cell lines. Therefore, we investigated the role of FAK in regulating migration of prostate carcinoma cell lines with increasing metastatic potential. We show that highly tumorigenic PC3 and DU145 cells exhibit intrinsic migratory capacity, while poorly tumorigenic LNCaP cells require a stimulus to migrate. Increased metastatic potential of PC3 and DU145 cells correlates with increased FAK expression, overall tyrosine phosphorylation and activity, as measured by autophosphorylation of tyrosine 397. However, in PC3 and DU145 cells, FAK autophosphorylation is adhesion dependent whereas a second site of tyrosine phosphorylation, tyrosine 861, a Src specific site, is uncoupled from adhesion-dependent signaling events. Finally, inhibiting the FAK/Src signal transduction pathway by over expressing FRNK (Focal adhesion kinase-Related Non-Kinase), an inhibitor of FAK activation, or treatment with PP2, a Src family kinase inhibitor, significantly inhibited migration of prostate carcinoma cell lines, demonstrating that tumor cell migration continues to be dependent on signals emanating from this pathway.

Outpatient laparoscopic cholecystectomy: patient outcomes after implementation of a clinical pathway.

OBJECTIVE: To determine the success of a clinical pathway for outpatient laparoscopic cholecystectomy (LC) in an academic health center, and to assess the impact of pathway implementation on same-day discharge rates, safety, patient satisfaction, and resource utilization. SUMMARY BACKGROUND DATA: Laparoscopic cholecystectomy is reported to be safe for patients and acceptable as an outpatient procedure. Whether this experience can be translated to an academic health center or larger hospital is uncertain. Clinical pathways guide the care of specific patient populations with the goal of enhancing patient care while optimizing resource utilization. The effectiveness of these pathways in achieving their goals is not well studied. METHODS: During a 12-month period beginning April 1, 1999, all patients eligible for an elective LC (n = 177) participated in a clinical pathway developed to transition LC to an outpatient procedure. These were compared with all patients undergoing elective LC (n = 208) in the 15 months immediately before pathway implementation. Successful same-day discharges, reasons for postoperative admission, readmission rates, complications, deaths, and patient satisfaction were compared. Average length of stay and total hospital costs were calculated and compared. RESULTS: After pathway implementation, the proportion of same-day discharges increased significantly, from 21% to 72%. Unplanned postoperative admissions decreased as experience with the pathway increased. Patient characteristics, need for readmission, complications, and deaths were not different between the groups. Patients surveyed were highly satisfied with their care. Resource utilization declined, resulting in more available inpatient beds and substantial cost savings. CONCLUSIONS: Implementation of a clinical pathway for outpatient LC was successful, safe, and satisfying for patients. Converting LC to an outpatient procedure resulted in a significant reduction in medical resource use, including a decreased length of stay and total cost of care.

Xenografting human colon cancers.

Xenografting of human tumors has been used to produce samples which are enriched for neoplasia and optimal for subsequent molecular analyses. Molecular studies of xenograft tumors generated from both human colon and pancreatic adenocarcinomas have led to the discovery of important genetic alterations underlying these malignancies (e.g., Smad4, Smad2) (1,2). Moreover, analysis of pancreatic xenografts helped facilitate the discovery of BCRA2 through identification of homozygous deletions ( 3 ). Furthermore, xenografted tumors have facilitated the discovery of distinctive allelic loss patterns in pancreatic and stomach adenocarcinomas (4,5). Comparative genomic hybridization analysis of xenografted human gastric cancers has demonstrated consistent DNA copy number changes, including both gains and losses of chromosomal regions (6).

Adhesion signaling through integrins.

Tumor cell interactions with the local microenvironment influence a range of cellular activities. A ubiquitous and important ";signal"; for tumor cells is the surrounding protein stroma, the extracellular matrix (ECM). This protein network varies in composition and structure throughout the body and within tissues, having a profound effect on the cells interacting with it. Input from these proteins regulates normal and tumor cell functions including adhesion, motility, proliferation, apoptosis, and differentiation.

Genetic syndromes and genetic tests in colorectal cancer.

Our understanding of the biology of colon cancer has matured to the point that it is a useful general paradigm for understanding solid tumor development. Recent advances provide insight into the genetic alterations underlying the development of colon cancer. These insights provide unique opportunities for genetic testing in predisposed, asymptomatic patients that can direct screening efforts and their clinical management. This review examines several inherited colon cancer predispositions, well described clinically for a century, that are now amenable to genetic testing. Additional discussion focuses on colon cancer predisposition traits that occur with high frequency but low penetrance characteristics. Finally, genetic tests for tumor markers that potentially have prognostic or therapeutic implications are reviewed.

Association of infiltrating lobular carcinoma with positive surgical margins after breast-conservation therapy.

OBJECTIVE: To determine whether infiltrating lobular carcinoma (ILC) is associated with high positive-margin rates for single-stage lumpectomy procedures, and to define clinical, mammographic, or histologic characteristics of ILC that might influence the positive-margin rate, thereby affecting treatment decisions. SUMMARY BACKGROUND DATA: Infiltrating lobular cancer represents approximately 10% of all invasive breast carcinomas and is often poorly defined on gross examination. METHODS: A group of 47 patients with biopsy-proven ILC undergoing breast-conservation therapy (BCT) at the University of Virginia Health Sciences Center between 1975 and 1999 was compared with a group of 150 patients with infiltrating ductal cancer undergoing BCT during the same time period. The pathology of the lumpectomy specimen was reviewed for each patient to confirm surgical margin status. Office and surgical notes as well as mammography reports were examined to determine whether the lesions were deemed palpable before and during surgery. Patients were stratified according to age, family history, tumor size, tumor location, and histologic features of the tumor. RESULTS: The incidence of positive margins was greater in the ILC group compared with the infiltrating ductal cancer group. Patient age, family history, and preoperative palpability of the tumor did not correlate with surgical margin status. Of the mammographic features identified, including spiculated mass, calcifications, architectural distortion, and other densities, only architectural distortion predicted positive surgical margin status. Tumor grade, tumor size, lymph node status, and receptor status were not predictive of surgical margin status. CONCLUSIONS: For patients with ILC, BCT is feasible, but these patients are at high risk of tumor-positive resection margins (51% incidence) after the initial resection. Only the mammographic finding of architectural distortion was identified as a preoperative marker reliably identifying a subgroup of ILC patients at especially high risk for a positive surgical margin. For all patients with ILC considering BCT, careful counseling about the potential need for a second procedure to treat the positive margin should be included in the treatment discussion.

Identification of integrin-stimulated sites of serine phosphorylation in FRNK, the separately expressed C-terminal domain of focal adhesion kinase: a potential role for protein kinase A.

Focal adhesion kinase (pp125(FAK)) is a protein tyrosine kinase that is localized to focal adhesions in many cell types and which undergoes tyrosine phosphorylation after integrin binding to extracellular matrix. In some cells the C-terminal non-catalytic domain of pp125(FAK) is expressed as a separate protein referred to as FRNK (FAK-related, non-kinase). We have previously shown that overexpression of FRNK inhibits tyrosine phosphorylation of pp125(FAK) and its substrates as well as inhibiting cell spreading on fibronectin. In this report we identify Ser148 and Ser151 as residues in FRNK that are phosphorylated after tyrosine phosphorylation of pp125(FAK) and in response to integrin binding to fibronectin. Tyrosine phosphorylation of pp125(FAK) appears to be an early event after integrin occupancy, and serine phosphorylation of FRNK occurs significantly later. Treatment of fibroblasts with a series of protein kinase A inhibitors delayed serine phosphorylation of FRNK as well as cell spreading on fibronectin and tyrosine phosphorylation of pp125(FAK). However, these PKA inhibitors are unlikely to delay cell spreading simply by preventing serine phosphorylation of FRNK, as overexpression of FRNK containing mutations of Ser148 and Ser151 either singly or jointly to either alanine or glutamate residues did not significantly alter the ability of FRNK to act as an inhibitor of pp125(FAK).

Laparoscopic percutaneous jejunostomy for long term enteral access.

BACKGROUND: Patients suffering from upper gastrointestinal pathology may require jejunal feeding for adequate nutrition. A laparoscopically guided percutaneous jejunostomy offers a minimally invasive means of obtaining such feeding access. METHODS: Laparoscopic jejunostomy was performed in 32 patients. The most common indications were gastroparesis (n = 16), neurological deficits (n = 7), and proximal obstruction (n = 5). The proximal jejunum was affixed to the abdominal wall using intracorporeal and extracorporeal transabdominal sutures, allowing safe insertion of an 18-Fr Silastic dual-lumen tube. RESULTS: Laparoscopic jejunostomy was successfully completed for 28 patients; the procedure was converted to an open operation in four cases. Three of these four were among 14 patients undergoing the procedure who had a history of previous abdominal surgery. Major complications were observed in seven patients, including one reoperation and one death from aspiration pneumonia. Tube feeding was accomplished in all patients; progression to full enteral feeding proceeded without interruption in 20 patients. CONCLUSION: Laparoscopic jejunostomy can be performed with relative safety. Morbidity, though high, is usually related to preexisting disease. Previous abdominal surgery is not necessarily a contraindication to laparoscopic jejunostomy.

Correlation of peripheral blood lymphocyte and intragraft cytokine mRNA expression with rejection in orthotopic liver transplantation.

BACKGROUND: Regulation of allograft rejection mediated by CD4+ T lymphocytes is dependent on the pattern of cytokines produced by these cells. The purpose of this study was to examine liver transplant recipients to determine whether peripheral blood lymphocyte (PBL), intragraft cytokine production, or both correlated with histologic assessment of graft rejection. METHODS: PBL and liver biopsy specimens from transplant recipients were examined at varying times after transplantation. Biopsy samples were examined histologically. Messenger RNA was extracted from PBL and liver biopsy specimens and was then amplified by polymerase chain reaction with oligo-specific primer pairs for interleukin (IL)-2, IL-4, IL-6, transforming growth factor-beta, interferon-gamma, and beta-actin. RESULTS: PBL transcription of IL-2, IL-6, and interferon-gamma was significantly increased in transplant recipients with rejection compared with that in recipients without rejection or healthy individuals who did not undergo transplantation (p < 0.05). Equivalent transcription of IL-4 and transforming growth factor-beta was observed in all patients regardless of rejection status. Graft specimens exhibited quantitative increases in IL-2 and interferon-gamma transcription during rejection with increased IL-4 transcription in the absence of rejection. CONCLUSIONS: Our data show that specific patterns of peripheral and intragraft cytokine production play a role in the regulation of rejection in liver transplantation.

CD4+ T cells mediate preexposure-induced increases in murine intraabdominal abscess formation.

We have previously shown that an increased number of Escherichia coli/Bacteroides fragilis intraabdominal abscesses are produced in mice after preexposure to small numbers of live E. coli or B. fragilis. Splenic lymphocyte subset changes and the importance of different elements of the immune response in this system were studied. Preexposure to bacteria induced a significant increase in the percentage of splenic T cells without altering the CD4/CD8 ratio. The passive transfer of either 10(7) mixed splenic lymphocytes, 5 x 10(6) mixed T cells, or 2.5 x 10(6) CD4+ T cells from preexposed animals to naive siblings 24 hr prior to abscess induction resulted in increased abscess formation. Transfer of serum, B cells, < 10(7) lymphocytes, CD8+ T cells, or any cell type from naive animals did not change abscess number. The bacterial composition of abscesses changed only in animals receiving either serum or B cells from donors preexposed to B. fragilis, where an increased number of B. fragilis per abscess was found. The CD4+ T cell response can be altered by transient infections and is critical to subsequent abscess formation, and a concurrent humoral response may play a role in determining an abscess' ultimate bacterial composition.

The role of Candida albicans in the pathogenesis of experimental fungal/bacterial peritonitis and abscess formation.

The recovery of Candida albicans along with bacteria from the abdomen in the setting of peritonitis is becoming increasingly common. It is not known whether the interactions between the fungal and bacterial elements of these infections are synergistic, competitive, or neutral. To study this question, we have examined the effects of both the addition of C. albicans to a solely bacterial infection caused by Escherichia coli and Bacteroides fragilis, and the deletion of various components of this system using directed antimicrobial therapy. In a mixed infection, both C. albicans and bacteria contributed to mortality, since only the combination of cefoxitin and amphotericin B improved survival (from 50% to 90%). The addition of C. albicans to the bacterial inoculum increased the recovery of abscesses, but only to the number seen with fungal infection alone, implying two fairly independent processes. Although the number of bacteria recovered from abscesses at 10 days postinfection was unchanged with the addition of fungi, the deletion of the bacterial component of mixed infections led to the overgrowth of C. albicans. We conclude that this model of mixed C. albicans/E. coli/B. fragilis peritonitis is best characterized as two nonsynergistic, parallel infections with incomplete competition, allowing the survival of all three organisms to eventual abscess formation.

Effectiveness of fluconazole in murine Candida albicans and bacterial C. albicans peritonitis and abscess formation.

The role of fluconazole in the treatment of many forms of focal mycoses remains unclear. We studied the effectiveness of three different oral doses of fluconazole in three murine models of Candida albicans peritonitis leading to intra-abdominal abscess formation. During monomicrobial Candida infection, fluconazole decreased mortality and the number of C. albicans cultured per abscess; prolonged treatment also eliminated Escherichia coli translocation. In mixed C. albicans/E. coli/Bacteroides fragilis infection, prolonged treatment with higher doses of fluconazole decreased mortality, the number of abscesses formed, and the number C. albicans per abscess. In animals with a similar polymicrobial infection but with concurrent cefoxitin treatment, fluconazole decreased mortality and the number of C. albicans per abscess; in addition, prolonged treatment reduced the number of abscesses. Amphotericin B gave similar results in all three models. These data indicate that the clinical use of fluconazole in peritonitis should be investigated.

Development of Candida albicans and C. albicans/Escherichia coli/Bacteroides fragilis intraperitoneal abscess models with demonstration of fungus-induced bacterial translocation.

The development of models of both Candida albicans and mixed C. albicans/Escherichia coli/Bacillus fragilis peritonitis in immunologically normal mice are described, each with significant mortality and intra-abdominal abscess formation. C. albicans inoculated alone induced bacterial translocation into abscesses, and the addition of bacteria reduced the number of, but did not eliminate. C. albicans in abscesses. There was no synergy seen between fungi and bacteria in terms of either morbidity or mortality.

Aztreonam vs. gentamicin in experimental peritonitis and intra-abdominal abscess formation.

The activity of gentamicin is known to be decreased in acidic environments, and both the peritoneum during peritonitis and the interior of abscesses have been shown to be acidic and hypoxic. The activity of beta-lactam antibiotics is felt to be relatively less diminished under the same circumstances. We determined that the minimum inhibitory concentration of gentamicin against one pathogenic strain of Escherichia coli increased eight-fold, to 8 mugm/mL, when testing conditions were changed from normoxic and neutral to hypoxic and acidic, whereas the MIC of aztreonam doubled under the same conditions, to 0.25 mugm/mL. In further experiments in a murine model of mixed Escherichia coli/Bacteroides fragilis intra-abdominal abscesses, we demonstrated that a combination of aztreonam and clindamycin was superior to a combination of gentamicin and clindamycin in terms of completely preventing abscess formation (33% vs. 0%) and eliminating Escherichia coli from abscesses that did form (100% vs. 61%).