Survival and reproductive costs of repeated acute glucocorticoid elevations in a captive, wild animal.

Organisms are continuously encountering both predictable and unpredictable ecological stressors within their environment. The activation of the hypothalamic-pituitaryadrenal (stress) axis is a fundamental process allowing animals to cope with and respond to such encounters. A main consequence of HPA axis activation is the release of glucocorticoid hormones. Although short-term glucocorticoid elevations lead to changes in physiological and behavioral processes that are often adaptive, our understanding of fitness consequences of repeated acute elevations in glucocorticoid hormones over a longer time period is largely lacking. This is of particular current importance as animals are facing a significant increase in exposure to stressors including those associated with human-induced rapid environmental change. Here, we test fitness-relevant consequences of repeated exposure to glucocorticoids in the absence of natural challenges, by treating wild-caught gravid female eastern fence lizards (Sceloporus undulatus) with a daily transdermal dose of a glucocorticoid hormone until laying. This treatment causes an increase in plasma glucocorticoids that mimics the natural response lizards have when they encounter a stressor in the wild, without confounding effects associated with the encounter itself. This treatment reduced females' reproductive success (hatching success) and survival. Further, glucocorticoid-induced reductions in reproductive success were greater when females had experienced higher temperatures the previous winter. This demonstrates the potential significant consequences of repeated exposure to acute elevations in glucocorticoid hormones. Additionally, the costs of repeated glucocorticoid elevation may be further exaggerated by an individual's previous experience, such as the potential compounding effects of winter warming increasing animals' vulnerability to increased glucocorticoid levels during spring breeding.

Sex-dependent effects of maternal stress: Stressed moms invest less in sons than daughters.

Multigenerational effects can have important and sex-dependent effects on offspring. Sex allocation theory predicts that females should differentially invest in sons and daughters depending on sex-specific fitness returns and costs of investment. Maternal stress-relevant (glucocorticoid) hormones may be one mechanism driving this effect. We investigated how maternal stress hormones differentially affected sons and daughters by manipulating levels of the glucocorticoid, corticosterone (CORT), in gravid female eastern fence lizards (Sceloporus undulatus) and quantifying reproductive investment and sex ratio of resulting clutches, and the mass, snout-vent length, and body condition of sons versus daughters at hatching. We found no effect of maternal CORT-treatment on the number or size of eggs laid or on the sex ratio of resulting offspring, but sons of CORT-treated mothers were shorter, lighter, and of poorer body condition at hatching than were sons of control mothers. We found no difference in size or condition of daughters with maternal treatment. Our results suggest that maternal stress, mediated by elevations in maternal CORT concentrations, can have sex-specific effects on offspring manifesting as lower investment in sons.

Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma.

BACKGROUND: The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects. METHODS: Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients. RESULTS: Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, K(trans) values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1alpha, IL-8, ICAM-1, and VCAM-1. CONCLUSION: Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.

Gastric carcinoma after surgical treatment of peptic ulcer: an analysis of morphologic features and a comparison with cancer in the nonoperated stomach.

BACKGROUND: Surgery for peptic ulcer is associated with an increased risk of later development of gastric carcinoma. This risk applies to cancer occurring in the distal stomach, not at the cardia. Mucosal alterations occurring in the nonneoplastic mucosa, adjacent to postgastrectomy carcinomas, are currently poorly defined. METHODS: Between 1975 and 1995, the authors collected records of 76 patients with gastric carcinoma developing after previous ulcer surgery. Thirty-three gastrectomy specimens were available for study and were compared with a control series of gastric carcinomas occurring in the intact stomach. Morphologic features studied were macroscopic findings, tumor type, extent of inflammation, atrophy, intestinal metaplasia, reactive gastropathy, and presence of Helicobacter pylori. When possible, a semiquantitative grading system (Sydney system) was used. RESULTS: The 33 patients with resected carcinoma after ulcer surgery were representative of the total 76 patients. There were no differences between the seven postulcer surgery cardia carcinomas and the control cardia carcinomas. The 18 distal carcinomas occurring after prior gastrectomy had significantly less intestinal metaplasia and Helicobacter pylori in the nonneoplastic mucosa than did the controls. Eight distal carcinomas occurring after a vagotomy and pyloroplasty had adjacent mucosa with findings intermediate between the gastrectomy carcinomas and the controls. CONCLUSIONS: The differences shown suggest that for distally located postgastrectomy carcinomas Helicobacter pylori infection with extensive intestinal metaplasia may be relatively less important in pathogenesis and that intestinal reflux with reactive gastropathy more important. There was no evidence to support a different mechanism of pathogenesis for postsurgical carcinomas occurring at the cardia from that of control cardia carcinomas.

Arylsulphonyl hydroxamic acids: potent and selective matrix metalloproteinase inhibitors.

A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.

Granular cell tumor of the thyroid.

A case of granular cell tumor of the thyroid gland occurring in a 23-year-old woman is reported. The patient presented with a painless mass in the neck, but was otherwise in good health and had no associated disorders. Fine-needle aspiration biopsy was performed prior to surgery and yielded thyroid epithelial cells with possible oncocytic-type change. To our knowledge, the English language literature contains only one other report of a granular cell tumor of the thyroid. Our case supports the recent suggestion of a neural crest origin for some types of thyroid neoplasia.

Mesohepatectomy.

BACKGROUND: Formal anatomic (lobar) or extended hepatectomies are recommended for liver malignancies located centrally within the liver (Couinaud's segments IVA, IVB, V, and VIII). Mesohepatectomy, resection of central hepatic segments and leaving the right and left segments in situ, removes large central tumors preserving more functioning liver tissue than either extended left or right hepatectomy. Mesohepatectomy is a seldom used, technically demanding procedure, and its application is yet to be defined. METHODS: Medical charts of 244 consecutive liver resection patients were reviewed retrospectively. Eighteen patients were treated with mesohepatectomy. Six patients had metastatic liver tumor (MLT), 11 had hepatocellular carcinoma (HCC), and 1 had gallbladder adenocarcinoma. The operative results were compared with groups of patients treated by lobar hepatectomy (n = 71) and extended left or right hepatectomy (n = 43). RESULTS: The mean mesohepatectomy operative time was 238 versus 304 minutes in the extended group. Inflow occlusion mean time was longer in the mesohepatectomy group than in extended procedures, 45 versus 39 minutes (P = not significant). Comparing the extended hepatectomy group, the mesohepatectomy group had a mean operative estimated blood loss 914 cc versus 1628 cc (P <0.01), postoperative hospital stay 9 versus 16 days (P = 0.054) and volume of resected liver 560cc versus 1500cc (P <0.01) respectively. The late complication rate was lower in the mesohepatectomy group than in the extended group and was comparable to the lobar hepatectomy group (P = 0.05). CONCLUSIONS: Despite its technical demands, mesohepatectomy should be considered as an alternative to extended hepatectomy for selected patients with primary and secondary hepatic tumors localized in middle liver segments, as its complication rate, postoperative recovery, and preserved liver tissue compare favorably with extended hepatic resection.

Solid-phase synthesis and biological screening of N-alpha-mercaptoamide template-based matrix metalloprotease inhibitors.

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.

Occurrence of butyltin residues in sediment and mussel tissues from the lower-most Tennessee River and Kentucky Lake, U.S.A.

Surface sediments and mussel samples were collected at six selected locations in the lower-most Tennessee River and Kentucky Lake, U.S.A. and analyzed for butyltin (BT) derivatives. In sediments, total BT concentrations ranged from 6.8 to 356 ng g-1 dry wt. A wide range of concentrations in sediments suggested the presence of localized area of contamination. In mussel tissues, total BT concentrations varied between 26-107 ng g-1 dry wt. BT levels were comparable to the levels reported in mussels from some coastal sites as well as a few freshwater ecosystems. Leaching of tributyltin-containing anti-fouling paints in the ocean-going ships is a source of tributyltin, and discharge of municipal sewage and industrial waste waters in to this watershed may account for the presence of the monobutyltin and dibutyltin derivatives detected in the samples. To our knowledge, this is the first report on the butyltin concentrations in sediment and mussel tissues from the lower-most Tennessee River and Kentucky Lake.

Radiofrequency ablation followed by resection of malignant liver tumors.

BACKGROUND: Radiofrequency ablation (RFA) has recently been used to treat liver tumors, but few clinical reports have described the pathological characteristics of radiofrequency ablation in human specimens. This study delineates the gross pathologic and histochemical changes induced by RFA in benign and malignant human liver tissue and confirms the tumor necrosis described in early clinical reports. METHODS: Ten patients with metastatic tumors of the liver received a single treatment of ultrasound-guided percutaneous RFA to 12 tumors. Hepatic resection was carried out within 6 weeks of RFA. Specimens were stained with standard hematoxylin and eosin stain followed by oxidative stain to determine if there was evidence of viable tumor within the zone of ablation. RESULTS: Nine of the 12 ablations were resected. Microscopic examination within the zone of ablation showed successful ablation in 8 of the 9 resected ablations. CONCLUSIONS: Percutaneous RFA creates well-circumscribed areas of tumor necrosis with apparent cell death using an oxidative stain. Further investigation is encouraged to determine the clinical effectiveness of radiofrequency ablation in the complete destruction of liver tumors for palliative or curative intent.

Electronic imaging and clinical implementation: work group approach at Mayo Clinic, Rochester.

Electronic imaging clinical implementation strategies and principles need to be developed as we move toward replacement of film-based radiology practices. During an 8-month period (1998 to 1999), an Electronic Imaging Clinical Implementation Work Group (EICIWG) was formed from sections of our department: Informatics Lab, Finance Committee, Management Section, Regional Practice Group, as well as several organ and image modality sections of the Department of Diagnostic Radiology. This group was formed to study and implement policies and strategies regarding implementation of electronic imaging into our practice. The following clinical practice issues were identified as key focus areas: (1) optimal electronic worklist organization; (2) how and when to link images with reports; (3) how to redistribute technical and professional relative value units (RVU); (4) how to facilitate future practice changes within our department regarding physical location and work redistribution; and (5) how to integrate off-campus imaging into on-campus workflow. The EICIWG divided their efforts into two phases. Phase I consisted of Fact finding and review of current practice patterns and current economic models, as well as radiology consulting needs. Phase II involved the development of recommendations, policies, and strategies for reengineering the radiology department to maintain current practice goals and use electronic imaging to improve practice patterns. The EICIWG concluded that electronic images should only be released with a formal report, except in emergent situations. Electronic worklists should support and maintain the physical presence of radiologists in critical areas and direct imaging to targeted subspecialists when possible. Case tools should be developed and used in radiology and hospital information systems (RIS/HIS) to monitor a number of parameters, including professional and technical RVU data. As communication standards improve, proper staffing models must be developed to facilitate electronic on-campus and off-campus consultation.

Coexisting carcinoid tumors in familial adenomatous polyposis-associated upper intestinal adenomas.

Upper gastrointestinal polyps and extraintestinal tumors are well recognized in association with familial adenomatous polyposis (FAP). Although carcinoid tumors have been reported in association with sporadic colonic neoplasms and ulcerative colitis, to date, carcinoids have not been reported in association with FAP. We report a patient with FAP who has recurrent carcinoid tumors located at the bases of duodenal adenomas. The genetic basis of carcinoid neoplasms is still uncertain. This report may represent the clinical effect of the APC gene mutation on the enterochromaffin cell line manifesting as recurrent carcinoid tumors in physical association with intestinal adenomas. Future genetic analysis and epidemiological studies may be of value in determining whether a true association exists.

Inverted Meckel's diverticulum: an entity simulating an ileal polyp.

A case of inverted Meckel's diverticulum is described. This presented as an ileal polyp in an individual with chronic unexplained iron deficiency anemia. Most prolapsed Meckel's diverticula occur acutely as intussusceptions with bowel obstruction and characteristically develop in childhood. This case therefore represents an unusual surgical problem in an older individual in which the diagnosis was clinically unexpected.

A comparative study between the gastric mucosa of west Canadians and other dwellers of the Pacific Basin.

The presence of non-neoplastic changes in the gastric mucosa--such as intramucosal glandular cysts, pyloric cells with ciliated metaplasia, with large or small mucus negative vacuoles, and with glassy cytoplasm, as well as extensive intestinal metaplasia (IM)--was investigated in 241 consecutive gastrectomy specimens from the archival files of the Vancouver Hospital situated on the Pacific coast of Canada. A total of 2,938 sections were reviewed (mean number of sections per gastrectomy: 12.24 (range 5-56 sections). Of the specimens with intestinal type carcinoma (known to be promoted by environmental factors), 68.9% contained intramucosal cysts, 35.6% pyloric cells with ciliated metaplasia, 35.6% pyloric cells with large vacuoles, 20.0% pyloric cells with small vacuoles, 4.4% pyloric cells with glassy cytoplasm and 40.0% high IM values. Those percentages were significantly higher than for specimens having diffuse type carcinomas, peptic ulcers, benign gastric tumors or non-neoplastic gastric diseases. The present findings substantiate early results obtained in other populations dwelling along the Pacific Basin. In contrast, dwellers of the Atlantic Basin with gastric carcinoma of intestinal type or other gastric diseases, seldom have similar gastric non-neoplastic changes. It is suggested that the gastric mucosa of Pacific coast Canadians may develop, similarly with inhabitants of other regions of the Pacific Basin, non-neoplastic changes, most notably when harbouring an adenocarcinoma of intestinal type. Environmental factors acting in that basin may account for the results obtained.

Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size.

OBJECTIVE: To determine, in vivo, the effect of radiofrequency ablation (RFA) treatment time and tissue blood flow on the size and shape of the resulting necrotic lesion in porcine liver. SUMMARY BACKGROUND DATA: Radiofrequency ablation is an electrosurgical technique that uses a high frequency alternating current to heat tissues to the point of desiccation (thermal coagulation). Radiofrequency ablation is well established as the treatment of choice for many symptomatic cardiac arrhythmias because of its ability to create localized necrotic lesions in the cardiac conducting system. Until recently, a major limitation of RFA was the small lesion size created by this technique. Development of bipolar and multiple-electrode RFA probes has enabled the creation of larger lesions and therefore has expanded the potential clinical applications of RFA, which includes the treatment of liver tumors. A basic understanding of factors that influence RFA lesion size in vivo is critical to the success of this treatment modality. The optimal RFA technique, which maximizes liver lesion size, has yet to be determined. Theoretically, lesion size varies directly with time of application of the RF current, and inversely with blood flow, but these relationships have not been previously studied in the liver. METHODS: Six animals underwent hepatic RFA (460 kHz), for 5, 7.5, 10, 12.5, 15, and 20 minutes. Identical, predetermined anatomic areas of the liver were ablated in each animal. Two additional animals underwent 12 RFA treatments -- 6 with vascular inflow occlusion (Pringle maneuver) and 6 with uninterrupted hepatic blood flow. Animals were euthanized and the livers were removed for gross pathologic examination. All lesions were measured in three dimensions and photographed. Tissues were examined by routine histology and by histochemistry to determine viability. RESULTS: Increasing duration of RFA application from 5 through 20 minutes did not create lesions of larger diameter, but this time increase did predict deeper lesion production (beta = 0.34, p = 0.04). A range of lesion shapes were created from four separate ovals (corresponding to each electrode), to larger ovals intersecting to form a cross, to spheroid lesions. The number of blood vessels in close proximity to the probe tip (within a 1-cm radius from the center of the lesion) strongly predicted minimum lesion diameter (beta = -0.61, p = 0.0001) and lesion volume (beta = -0.56, p = 0.0004). This negative effect of blood flow on lesion size was confirmed experimentally. Radiofrequency ablation lesions created during a Pringle maneuver were significantly larger in all three dimensions than lesions created without a Pringle maneuver: minimum diameter was 3.0 cm (with Pringle) versus 1.2 cm (p = 0.002), maximum diameter was 4.5 cm (with Pringle) versus 3.1 cm (p = 0.002), depth was 4.8 cm (with Pringle) versus 3.1 cm (p < 0.001), and lesion volume was 35.0 cm3 (with Pringle) versus 6.5 cm3 (p < 0.001). CONCLUSIONS: Blood flow is a strong predictor of all RFA lesion dimensions in porcine liver in vivo, whereas a change of treatment time from 5 to 20 minutes is predictive only of lesion depth, but not diameter or volume.

A novel Alcian yellow-toluidine blue (Leung) stain for Helicobacter species: comparison with standard stains, a cost-effectiveness analysis, and supplemental utilities.

Helicobacter pylori (Hp) gastritis is a worldwide problem significantly associated with duodenal and gastric peptic ulcer disease, gastric carcinomas, and MALT-type lymphomas. A simple, rapid, reproducible, reliable, and inexpensive stain to detect the organism in gastric biopsy specimens is thus of great value. To assess the reliability and cost-effectiveness of a novel Alcian yellow-toluidine blue (Leung) stain for Hp, we stained 60 endoscopic mucosal biopsy specimens from patients with Hp gastritis and measured time to detection of organism, Hp numbers (scale, 1-5), and technical costs. We also stained serial 5-microm step sections of 17 of these cases with the Giemsa and modified Steiner (MS) methods, and similar measurements were made. Also, specimens from various normal gastrointestinal sites and metaplastic lesions, as well as four cases each of giardiasis and cryptosporidiosis, were stained with the Leung method. In the subset of 17 cases, the Leung stain enhanced detection time and compared favorably with the Giemsa method, though the MS method was somewhat superior. Hp scores were similar among all groups. Mean time to detection and Hp scores were similar in the larger (n = 60) group stained with hematoxylin and eosin and the Leung stain. Material costs and technologist's time for Giemsa stains, however, were greater than for the Leung stain, and technologist's time for MS was nearly fourfold that of the Leung stain. With the Leung method, mucus from all gastrointestinal sites and metaplastic lesions stained yellow, and this stain provided excellent contrast and morphologic definition in giardiasis and cryptosporidiosis. We suggest that the newly developed Alcian yellow-toluidine blue (Leung) histochemical stain is a good choice as the standard for routine Hp staining because it is the cheapest and easiest to prepare and because pathologists' detection with this stain compares favorably with detection times achieved with more traditional and established methods.