Human pancreatic adenocarcinomas express parathyroid hormone-related protein.

PTH-related protein (PTHrP) is expressed in many common malignancies such as breast and prostate cancer and can regulate their growth. Little is known, however, about the role of PTHrP in pancreatic adenocarcinoma. To study PTHrP in pancreatic exocrine cancer, we studied its expression in pancreatic cancer cell lines and surgical specimens. Eight human pancreatic adenocarcinoma cell lines were evaluated: AsPC-1, BxPC-3, Capan-1, CFPAC-1, MIA PaCa-2, PANC-1, PANC-28, and PANC-48. Murine monoclonal antibodies to the amino-terminal (1-34), mid-region (38-64), and carboxyl-terminal peptides (109-141) of PTHrP were used to identify cellular PTHrP and secreted PTHrP, including Western blotting and immunocytochemical staining for PTHrP from each cell line. Cellular PTHrP was detected in all cell line extracts by both Western blotting and immunoassay. CFPAC-1, derived from a pancreatic liver metastasis, had the highest concentration of PTHrP, and MIA PaCa-2, derived from primary pancreatic adenocarcinoma, had the lowest. PTHrP was localized by immunocytochemical staining in the cytoplasm in all but one cell line, and both nuclear and cytoplasmic immunostaining were observed in the MIA PaCa-2 and PANC-1 cells. Secretion of PTHrP into cell medium was also observed for each cell line and paralleled intracellular PTHrP levels. Evidence for differential processing of PTHrP expression was provided by studies demonstrating different patterns of PTHrP among the cell lines when assessed by PTHrP immunoassays directed against different PTHrP peptides. In specific, PTHrP secretion measured by a PTHrP-(38-64) assay was highest for BxPC-3, whereas the highest levels of secreted PTHrP-(109-141) occurred in CFPAC-1 and PANC-1. Growth of AsPC-1 cells was stimulated in a dose-dependent manner by PTHrP-(1-34). Immunostaining from archival tissue of patients with pancreatic adenocarcinoma revealed strong PTHrP expression in all 14 specimens. All patients were eucalcemic preoperatively. These results demonstrate that PTHrP is commonly expressed in pancreatic cancer. Our data suggest that PTHrP may have growth-regulating properties in pancreatic adenocarcinoma cells, but further studies are required.

Increased expression of tissue cytokines in graft-versus-host disease after small bowel transplantation in the rat.

BACKGROUND: Graft-versus-host disease (GVHD) occurs in the recipient after small bowel transplantation (SBT). Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin 6 (IL-6), may be important mediators of GVHD. Increased expression of these cytokines might precede the clinical manifestations of GVHD induced by SBT. METHODS: Heterotopic SBT was performed using Lewis donors into Lewis x Brown Norway F1 (LBN-F1) recipients. The isograft control was performed from LBN-F1 into LBN-F1. Animals were killed on the 5th and 11th postoperative day (POD). mRNA was isolated from recipient native small bowel, colon, spleen, liver, and mesenteric lymph nodes and from nonsurgical controls as baseline. Semiquantitative reverse transcriptase polymerase chain reaction was performed to amplify mRNA transcripts for TNF-alpha, IFN-gamma, and IL-6 using alpha32P-dATP incorporation. Clinical signs, histologic assessment, and cytokine expression were correlated. RESULTS: On POD 5, there were neither clinical signs nor histologic features of GVHD, but mRNA expression of TNF-alpha and IL-6 in small bowel, IL-6 in spleen, and IFN-gamma in mesenteric lymph nodes were significantly increased in allograft animals when compared with normal and isograft tissues. On POD 11, both the clinical signs and histologic features of GVHD were seen, and TNF-alpha and IL-6 in native small bowel, TNF-alpha in colon, IFN-gamma in spleen, and IL-6 in mesenteric lymph nodes were significantly increased in allograft animals when compared with that in normal and isograft tissues. CONCLUSIONS: In conclusion, TNF-alpha, IFN-gamma, and IL-6 expression precede clinical onset and histologic evidence of GVHD in specific tissues. Therefore, increased expression of these cytokines is correlated with the development of GVHD in this model of SBT.

AIDS and malignant mesothelioma--is there a connection?

A 35-year-old male homosexual, a former intravenous drug abuser, was found to be human immunodeficiency virus (HIV) positive in 1984. He developed AIDS in 1987 and began treatment with zidovudine in 1989. One year later he developed left apical pleural blebs, a pneumothorax and an exudative pleural effusion. A malignant mesothelioma developed at the pleural blebs in the left apex. He was treated with adriamycin but rapid progression of the malignancy occurred and he died three months later. At autopsy, a malignant mesothelioma, causing respiratory failure and death, was found. The patient had no exposure to asbestos and asbestosis was not present at autopsy. We postulate that the development of malignant mesothelioma was probably related to HIV immune suppression or HIV and/or cytomegalovirus or zidovudine and is a complication of AIDS similar to the development of other malignant neoplasms in patients with AIDS.

Percutaneous pulmonary endoarterial biopsy in an experimental model of pulmonary hypertension.

STUDY OBJECTIVES: The aims of this study were: to evaluate the performance of a novel arterial biopsy catheter in obtaining pulmonary endovascular samples in hypertensive dogs; to compare the results of pulmonary endoarterial biopsy in hypertensive vs normotensive dogs; and to assess the histologic changes in the hypertensive model. DESIGN AND INTERVENTIONS: Thirty-four dogs (27 with normal pulmonary arterial pressures and seven with pulmonary hypertension) were catheterized through an external jugular vein to obtain endovascular biopsy samples from distal pulmonary arteries 2 to 3 mm in luminal diameter. To induce pulmonary hypertension, seven dogs were given repeated infusions of 0.6- to 0.9-mm ceramic microspheres into the superior vena cava. Endoarterial samples were obtained at pulmonary systolic arterial pressures ranging from 10 to 110 mm Hg. MEASUREMENTS AND RESULTS: Sixty-two biopsy catheterization procedures were performed in the 34 dogs. After 12 initial procedures of technique refinement, endoarterial samples were obtained in each of the last 50 procedures (21 in normotensive dogs and 29 in hypertensive dogs). The average number of endovascular biopsy samples retrieved was 7.1 (range, 2 to 12) from a mean of 8.6 (range, 2 to 15) biopsy attempts per catheterization (success rate=83%). The average biopsy piece measured 1.13 mm in length, 0.33 mm in depth, and up to 1.0 mm in width. The biopsy success rates and endoarterial sample sizes were similar in normotensive and hypertensive dogs. Smooth muscle cells and endothelial cells were grown from the biopsy samples. There were no significant procedural complications, except for one self-limited hemorrhage. Histologically, samples obtained from dogs with pulmonary hypertension showed characteristic changes when compared with biopsies from normotensive dogs. CONCLUSION: This new endoarterial biopsy catheter was safe and effective when used to obtain pulmonary endoarterial samples in dogs with normal and experimentally elevated pulmonary arterial pressures. The quality and quantity of the biopsy samples allowed identification of pathologic changes.

Features of cancer in nonagenarians and centenarians.

OBJECTIVE: To describe the incidence rates and sites of cancer, the causes of death, and gender and ethnic variations in patients with cancer in a population of people 90 years of age and older. DESIGN: Analysis of the 14,088 cases of cancer in this age group, accessioned by the California Cancer Registry from 1988 through 1993, and comparison with those less than age 90. MEASUREMENTS: Incidence rates and numbers and percents of cases with various features (gender, ethnicity, site of tumor, stage, causes of death). RESULTS: The peak age-specific incidence (ASI) of cancer is in the group 80 to 84 years of age. Those 90 to 94 years of age had a higher ASI than any group except those ages 75 to 89. There are ethnic variations in the sites of cancer in people aged 90 or older. Colorectal cancer accounts for more than one-fifth of the new cases of cancer in people 90 or older. In women aged 90 or older, the most common sites of cancers are colorectal, breast, and lymphoma/leukemia. In men of the same age, prostate, colorectal, and lung/bronchus are the most common sites. As age increases, fewer people have their cancers staged, and for lung/bronchus, prostate, and breast, more cancers are first diagnosed in the distant stage in people aged 90 and older. Of the people with cancer who die, the proportion dying of cancer decreases as age increases. CONCLUSION: Cancer is a common disease in nonagenarians and centenarians and will be an increasing healthcare problem. Knowledge of its features is essential to those planning, delivering, and financing health care.

The humoral hypercalcemia of benignancy. A newly appreciated syndrome.

It has become recently appreciated that the hypercalcemia of malignancy is commonly caused by the increased production of parathyroid hormone-related protein (PTHrP) by the cancer. In fact, the demonstration of increased PTHrP production in a patient with hypercalcemia is regarded as pathognomonic of malignancy. The authors describe a patient with a benign ovarian lesion that produced PTHrP and caused hypercalcemia. They identify other reports of hypercalcemia associated with hypercalcemia and benign tumors, and refer to this syndrome as the humoral hypercalcemia of benignancy. Although apparently rare, a benign PTHrP-producing tumor should be considered in the differential diagnosis of hypercalcemia.

High vegetable and fruit diet intervention in premenopausal women with cervical intraepithelial neoplasia.

OBJECTIVE: To examine whether diet intervention can promote increased vegetable and fruit intake, as reflected in increased plasma carotenoid and decreased plasma total homocysteine concentrations, in premenopausal women with cervical intraepithelial neoplasia, a precancerous condition. DESIGN: Randomized controlled diet intervention study. SUBJECTS: Fifty-three free-living premenopausal women who had been diagnosed with cervical intraepithelial neoplasia, were randomly assigned to an intervention (n = 27) or a control (n = 26) group. INTERVENTION: Individualized dietary counseling to increase vegetable and fruit intake. MAIN OUTCOME MEASURES: Diet was assessed by food frequency questionnaire. Plasma carotenoids and total homocysteine were measured at enrollment and at 6 months follow up. ANALYSIS: Associations between baseline plasma concentrations of carotenoids and homocysteine and influencing factors were examined with multiple regression analysis. Repeated measures analysis of variance was used to test for group by time effects in these plasma concentrations. Plasma carotenoids at baseline and 6 months in the study groups, and differences in homocysteine concentrations from baseline to 6 months, were compared with independent sample t tests. RESULTS: Repeated measures analysis of variance showed significant group by time effects (P<.01) in plasma carotenoid and homocysteine concentrations. In the intervention group, total plasma carotenoids increased by an average of 91%, from 2.04+/-0.13 (mean+/-standard error of the mean) to 3.90+/-0.56 micromol/L and plasma total homocysteine was reduced by 11%, from 9.01+/-0.40 to 8.10+/-0.44 micromol/L (P<.003). Neither changed significantly in the control group. APPLICATIONS: Individualized dietary counseling can effectively promote increased vegetable and fruit intake in premenopausal women. This dietary pattern may reduce risk for cancer and other chronic diseases and also promote an improvement in folate status.

Comparison of the toxicities of two iron formulations in a swine model.

OBJECTIVE: To describe the histopathologic and pharmacokinetic differences of acute iron poisoning between chewable multivitamins with iron and solid iron tablets in a swine model. METHODS: This was a prospective, randomized, unblinded toxicity study of iron poisoning of two iron formulations in male Yorkshire pigs. Eight swine were randomized to receive 60 mg/kg of iron in either solid iron tablets or chewable multivitamins with iron. Serum iron, arterial blood gases, and episodes of vomiting were recorded over a ten-hour period. Routine histologic evaluations of the esophagus, stomach, small intestine, large intestine, and liver were performed immediately after the study period. Pharmacokinetic analyses of area under the concentration-time curve (AUC), time to peak concentration, and peak serum iron concentration were performed. RESULTS: There was no significant difference between the serum iron levels except at three and four hours. There was a significant higher AUC in the chewable group compared with the solid group. Pathologic evaluation identified severe esophageal inflammation and focal erosion in the solid iron tablet group in two of the four animals, compared with no focal erosions and minimal esophageal inflammation in the chewable group. No significant change was identified in the liver, small intestine, or large intestine in either group. CONCLUSIONS: These results demonstrate increased local gastrointestinal toxicity following a large ingestion of solid iron tablets in a swine model, compared with chewable multivitamins with iron. Higher serum iron levels were identified in the animals that received chewable multivitamins with iron.

Induction of pulmonary granulomas, macrophage procoagulant activity, and tumor necrosis factor-alpha by trehalose glycolipids.

Trehalose 6,6' dimycolate (TDM), a mycobacterial glycolipid, induces granulomas and hemorrhagic toxic reactions when administered in oil but not as a suspension in saline. It was previously demonstrated by us that TDM forms highly structured layers at oil-water interfaces and then postulated that its toxicity derives from the adhesive properties of these layers. To test this hypothesis, an evaluation was made of the ability of TDM and two analogs, trehalose 6-monomycolate (TMM) and galactose-galactose 6, 6' dimycolate (GDM), to induce pulmonary granulomas and stimulate expression of procoagulant activity (PCA) and tumor necrosis factor-alpha (TNF-alpha). Intravenous injection in mice of oil-in-water emulsions of TDM produced more and larger pulmonary granulomas than injection of TMM or GDM. Similarly, TDM on the surface of beads induced higher levels of PCA and TNF-alpha in human mononuclear cells than the analogs. The correlation of these results with the structure of surface layers of the glycolipids strengthens the hypothesis that the particular surface structure formed by TDM is necessary for its biologic activity.

Fast three-step method for shear moduli calculation from quartz crystal resonator measurements.

Quartz crystal resonator measurements can be used for polymer material characterization. The non-gravimetric regime of these resonators is exploited: the electrical response of polymer-coated quartz resonators depends on the polymer shear modulus. Previously reported methods employ an electrical admittance analysis together with difficult and time-consuming data fitting procedures to calculate the film shear modulus. This contribution presents a fast and accurate three-step method for the calculation of complex shear moduli of polymer films from quartz crystal resonator measurements. In the first step, the acoustic load impedance is calculated from the electrical admittance of the quartz crystal. The key point of this method is the application of a family of approximations for the calculation of the shear modulus from the acoustic load impedance in the second step. In the third step, the best approximation is improved further in an iterative procedure.

Signal amplification with multilayer arrangements on chemical quartz-crystal-resonator sensors.

Viscoelastic properties of chemically sensitive coatings can enhance the mass sensitivity of quartz-crystal-microbalance (QCM) sensors. If analyte sorption is accompanied by a change of the viscoelastic properties of the coating material, the accumulated mass cannot be calculated from the frequency shift without further information. We developed a sensor concept, which is based on a double-layer arrangement, permitting acoustic amplification and chemical sensitivity to be separated. With a proper selection of materials, the first layer realizes a constant acoustic amplification of the mass effect; the chemically sensitive layer acts purely gravimetrically. Major sensor design parameters are the shear modulus and the thickness of the first layer. From the acoustic point of view, the thickness of the chemically active layer and its material properties are less critical; a glasslike, rigid coating is preferred for a stable sensor transfer function. Simultaneous measurement of the resonant frequency of the quartz crystal and its motional resistance can be exploited to check the acoustic amplification.

Symptoms and quality of life in obese children and adolescents with non-alcoholic fatty liver disease.

BACKGROUND: Data on the quality of life (QOL) of children with non-alcoholic fatty liver disease (NAFLD) are needed to estimate the true burden of illness in children with NAFLD. AIM: To characterize QOL and symptoms of children with NAFLD and to compare QOL in children with NAFLD with that in a sample of healthy children. METHODS: Quality of life and symptoms were assessed in children with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network. PedsQL scores were compared with scores from healthy children. For children with NAFLD, between-group comparisons were made to test associations of demography, histological severity, symptoms and QOL. RESULTS: A total of 239 children (mean age 12.6 years) were studied. Children with NAFLD had worse total (72.8 vs. 83.8, P < 0.01), physical (77.2 vs. 87.5, P < 0.01) and psychosocial health (70.4 vs. 81.9, P < 0.01) scores compared with healthy children. QOL scores did not significantly differ by histological severity of NAFLD. Fatigue, trouble sleeping and sadness accounted for almost half of the variance in QOL scores. Impaired QOL was present in 39% of children with NAFLD. CONCLUSIONS: Children with NAFLD have a decrement in QOL. Symptoms were a major determinant of this impairment. Interventions are needed to restore and optimize QOL in children with NAFLD.

Quantitative characterization of cells at the interface of long-term implants of selected polymers.

Comprehensive understanding of the relationship between biologic response and biomaterial characteristic requires quantitative evaluation of the cells at the interface of the material and descriptions of ultrastructural features of these cells. The purpose of this study was to qualitatively and quantitatively characterize the long term in vivo tissue and cellular response to two polymeric materials presently employed in the fabrication of surgical implants. Ultrahigh molecular weight polyethylene (PE) and polysulfone (PSF) particles were implanted subcutaneously into rats for 100-118 weeks. Specimens were embedded in paraffin and ERL embedding medium in preparation for light and transmission electron microscopy. Percentage of the particle surface covered by various cell types was determined using a computer interactive image analysis system. PE and PSF particles were sequestered within a subcutaneous fibrous capsule. Cell types present included macrophages, fibroblasts and giant cells characteristic of a foreign body granuloma. Statistical comparison of the percent particle surface covered by each cell type revealed no significant difference between PSF and PE. However, surface texture appeared to influence the tissue response. TEM confirmed the identity of the cells at the interface and consistently revealed a layer of amorphous extracellular substance including cell debris on the material surface. Results evidence the tissue compatibility of PE and PSF and indicate no significant difference in the tissue response to these polymers.

Role of mass accumulation and viscoelastic film properties for the response of acoustic-wave-based chemical sensors.

The sensitivity of acoustic-wave microsensors coated with a viscoelastic film to mass changes and film modulus (changes) is examined. The study analyzes the acoustic load at the interface between the acoustic device and the coating. The acoustic load carries information about surface mass and film modulus; its determination has no restrictions in film thickness. Two regimes of film behavior can be distinguished: the gravimetric regime, where the sensor response is mainly mass sensitive, and the nongravimetric regime, where viscoelasticity gains influence on the sensor response. We develop a method, which allows the assignment of the sensor signal to a gravimetric or a nongravimetric response. The critical value can be determined from oscillator measurements. The related limits for the coating thickness are not the same for the coating procedure and mass accumulation during chemical sensing. As an example, we present results from a 10 MHz quartz crystal resonator.

Morbidity, mortality, and placental pathology in excessively long umbilical cords: retrospective study.

The purpose of this study was to compare specific fetal, maternal, and placental factors, including neonatal morbidity and mortality, in infants with umbilical cords (UCs) of normal length to the same factors in infants with excessively long umbilical cords (ELUCs). We performed an 18-year retrospective chart review of the medical records of mothers and infants with ELUCs (926 cases) and normal-length UCs (200 cases) and recorded maternal factors, fetal factors, and neonatal outcomes. Corresponding placental pathologic reports and slides were reviewed. Statistical analysis comparing the two groups included univariate and multivariate analyses. ELUCs were significantly associated with certain maternal factors (systemic diseases, delivery complications, increased maternal age), fetal factors (non-reassuring fetal status, respiratory distress, vertex presentation, cord entanglement, fetal anomalies, male sex, increased birth weight), gross placental features (increased placental weight, right-twisted cords, markedly twisted cords, true knots, congestion), and microscopic placental features (nucleated red blood cells, chorangiosis, vascular thrombi, vascular cushions, meconium, increased syncytial knots, single umbilical artery). Some of these histopathologic features have previously been associated with fetal hypoxia and/or altered blood flow in the placenta. Infants with ELUCs were found to be at a significantly increased risk of brain imaging abnormalities and/or abnormal neurological follow-up. In addition, mothers with a history of an ELUC are at increased risk of a second long cord.

Sclerosing mesenteritis: an unusual cause of abdominal pain in an HIV-positive patient.

Sclerosing mesenteritis is a rare, idiopathic, and benign mesenteric lesion that is characterized by fat necrosis, fibrosis, and chronic inflammation. We report a case of sclerosing mesenteritis presenting as recurrent abdominal pain in an HIV-positive patient. Because of the wider differential diagnosis in such cases, the patient underwent an extensive workup culminating in a laparoscopy with biopsy. Tamoxifen has been shown to be useful in the treatment of desmoid tumors and idiopathic retroperitoneal fibrosis. We present the first case of sclerosing mesenteritis to respond to tamoxifen therapy. Because this drug is relatively safe and simple to dose, its utility as therapy for patients with this benign but debilitating disease should be considered.

Liver biopsies in adult hemophiliacs with hepatitis C: a United States center's experience.

We report a case series of 13 adult hemophiliacs with serological evidence of hepatitis C who underwent percutaneous liver biopsies without major complications. We also briefly review the recent literature on safety of liver biopsies in this population, and conclude that these patients may be safely biopsied using appropriate precautions regardless of the severity of hemophilia.

Development of a trehalose 6,6'-dimycolate model which explains cord formation by Mycobacterium tuberculosis.

Trehalose 6,6'-dimycolate (TDM) is a glycolipid of mycobacteria that displays an unusual toxicity and has been reported to be a virulence factor for Mycobacterium tuberculosis. Lack of understanding of the toxicity has impeded acceptance of TDM as a virulence factor. We previously reported that the toxicity of TDM depends on its presentation as a surface monolayer consisting of 30% trehalose and 70% exposed mycolic acid moieties. This paper further investigates the structure of the TDM monolayer. It began with the observation that beads coated with TDM, but not with closely related analogs, aggregate to form organized structures resembling the cords of virulent mycobacteria. This implied that the TDM molecules in the monolayer were arranged in an organized structure. This structure was investigated by real-time kinetic microscopy, scanning electron microscopy, and gross observations of the adhesion patterns of TDM-coated beads. In each of these models, the structures induced by TDM differed from those of analogs or other amphiphiles studied. These observations were used to construct a model of the structure of TDM monolayer which envisions linear arrays of TDM molecules arranged in a circumferential pattern on beads with discontinuities only at the two poles.

Enhancement of antibiotic susceptibility and suppression of Mycobacterium avium complex growth by poloxamer 331.

The resistance of Mycobacterium avium complex (MAC) to antibiotics is thought to be enhanced by its outer glycolipid layer, which protects the organisms from antibiotics and host defense mechanisms. We hypothesized that surfactants which disrupt the lipid barrier might be of therapeutic value. We evaluated the ability of 10 poloxamer surfactants to inhibit the growth of MAC organisms and to potentiate antimycobacterial drug activity in broth culture using a radiometric assay. Very large, small, or hydrophilic poloxamers had little or no effect. However, certain hydrophobic poloxamers, especially P331, retarded the growth of most isolates of MAC and produced a synergistic effect with rifampin. The MIC of rifampin required to inhibit the growth of MAC was reduced from a mean of 14.6 micrograms/ml (range, 4 to > 32 micrograms/ml) to 1.4 micrograms/ml (range, < 1.125 to 4 micrograms/ml) by 1.0 mg of P331 per ml (P < 0.01). Enhancement of antibiotic susceptibility was observed with concentrations of poloxamer as low as 10 micrograms/ml. These studies suggest that P331 might be useful in increasing the effectiveness of antibiotic therapy of MAC infections.

Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens.

During a 6-and-a-half month period, we identified 10 human immunodeficiency virus (HIV)-infected men who were receiving antiretroviral regimens, including nucleoside analogues, and who developed unexplained reproducible hyperlactatemia in association with either abdominal symptoms or an unaccounted-for elevated alanine aminotransferase level, or both. After careful consideration of the possible etiologies, antiretrovirals were discontinued; lactate levels normalized in all patients. The estimated incidence of this phenomenon in our clinic was 20.9 cases per 1000 person-years of nucleoside analogue treatment. These observations extend the spectrum of the nucleoside analogue-induced lactic acidosis/hepatic steatosis syndrome by the identification of a subtle and perhaps earlier form, which has characteristic symptoms and laboratory abnormalities, and a favorable prognosis on discontinuation of antiretroviral therapy.