Accuracy of cytologic interpretation of pancreatic neoplasms by fine needle aspiration and pancreatic duct brushings

OBJECTIVE: To investigate the accuracy of fine needle aspiration (FNA) specimens and pancreatic duct brushings in the detection of pancreatic lesions and to compare the results with follow-up biopsy and/or surgical interpretation. STUDY DESIGN: We reviewed a total of 57 specimens (37/20), 37 FNA specimens and 20 pancreatic duct brushings, from 45 patients treated at Froedtert Memorial Lutheran Hospital, affiliated with the Medical College of Wisconsin, Milwaukee, over a 4-year period. The FNA and brushing samples were categorized as follows: positive for malignancy (21/3 = 24), suspicious for malignancy (8/7 = 15) and atypical (8/10 = 18). The results were then correlated with the tissue diagnosis. RESULTS: The 24 cytologic samples positive for malignancy included 23 (20/3) pancreatic ductal carcinoma (CA) and 1 (1/0) neuroendocrine CA; in the suspicious category, 11 (6/5) were pancreatic ductal CA; 2 (0/2) mucinous neoplasms and (2/0) neuroendocrine neoplasms; in the atypical category; 2 (2/0) suggestive of mucinous neoplasia, 1 (1/0) suggestive of serous neoplasia and 9 (2/7) favor reactive; and 6 (3/3) without further categorization. Tissue diagnoses were available in 26 cases: 12 (10/2) cases positive for malignancy, 8 (5/3) suspicious for malignancy and 6 (5/1) atypical. The 12 cytologically positive cases confirmed by histology showed 10 ductal CA, 1 neuroendocrine CA and 1 negative. All 8 cases (100%) suspicious for malignancy revealed positive results, including 5 ductal CA, 1 neuroendocrine neoplasm, 1 mucinous cystic neoplasm and 1 lymphoma. Of the 6 atypical lesions, 1 showed ductal CA, 2 mucinous cystic neoplasm and 3 chronic pancreatitis. CONCLUSION: Pancreatic FNA and duct brushings [table: see text] are accurate methods in identifying pancreatic lesions, particularly ductal CA. Accuracy can be improved in the case of mucinous and other lesions with adequate cellularity of the smear and recognizing the limitations of brush samples in the case of mucinous cystic lesions. False negative results may occur in cases of poor representation of malignant cells or poor sampling.     

Cellular redistribution of inducible Hsp70 protein in the human and rabbit heart in response to the stress of chronic hypoxia: role of protein kinases,

Many infants who undergo cardiac surgery have a congenital cyanotic defect where the heart is chronically perfused with hypoxemic blood. Infant hearts adapt to chronic hypoxemia by activation of intracellular protein kinase signal transduction pathways. However, the involvement of heat shock protein 70 in adaptation to chronic hypoxemia and its role in protein kinase signaling pathways is unknown. We determined expression of message and subcellular protein distribution for inducible (Hsp70i) and constitutive heat shock protein 70 (Hsc70) in chronically hypoxic and normoxic infant human and rabbit hearts and their relationship to protein kinases. In chronically hypoxic human and rabbit hearts message levels for Hsp70i were elevated 4- to 5-fold compared with normoxic hearts, Hsp70i protein was redistributed from the particulate to the cytosolic fraction. In normoxic infants Hsp70i protein was distributed almost equally between the cytosolic and particulate fractions. Hsc70 message and subcellular distribution of Hsc70 protein were unaffected by chronic hypoxia. We then determined if protein kinases influence Hsp70i protein subcellular distribution. In rabbit hearts SB203580 and chelerythrine reduced Hsp70i message levels, whereas SB203580, chelerythrine, and curcumin reversed the subcellular redistribution of Hsp70i protein caused by chronic hypoxia, with no effect in normoxic hearts, indicating regulation of Hsp70i message and subcellular distribution of Hsp70i protein in chronically hypoxic rabbit hearts is influenced by protein kinase C and mitogen-activated protein kinases, specifically p38 MAPK and JNK. We conclude the Hsp70 signal transduction pathway plays an important role in adaptation of infant human and rabbit hearts to chronic hypoxemia.     

Role of the passive apoptotic pathway in graft-versus-host disease

Donor T cells have been shown to undergo apoptosis during graft-vs-host disease (GVHD). Although active apoptosis mediated through Fas/Fas ligand interactions has been implicated in GVHD, little is known about the role of the passive apoptotic pathway. To examine this question, we compared the ability of normal donor T cells and T cells overexpressing the antiapoptotic protein, Bcl-x(L), to mediate alloreactive responses in vitro and lethal GVHD in vivo. In standard MLCs, T cells that overexpressed Bcl-x(L) had significantly higher proliferative responses but no difference in cytokine phenotype. Overexpression of Bcl-x(L) prolonged survival of both resting and alloactivated CD4(+) and CD8(+) T cells as assessed by quantitative flow cytometry, accounting for the higher proliferative responses. Analysis of engraftment in murine transplantation experiments demonstrated an increase in donor T cell chimerism in animals transplanted with Bcl-x(L) T cells, suggesting that overexpression of Bcl-x(L) prolonged T cell survival in vivo as well. Notably, transplantation of Bcl-x(L) T cells into nonirradiated F(1) recipients also significantly exacerbated GVHD as assessed by mortality and pathological damage in the gastrointestinal tract. However, when mice were irradiated no difference in GVHD mortality was observed between animals transplanted with wild-type and Bcl-x(L) T cells. These data demonstrate that the passive apoptotic pathway plays a role in the homeostatic survival of transplanted donor T cells. Moreover, the susceptibility of donor T cells to undergo passive apoptosis is a significant factor in determining GVHD severity under noninflammatory but not inflammatory conditions.     

The archaeal respiratory supercomplex SoxM from S. acidocaldarius combines features of quinole and cytochrome c oxidases

The hyperthermoacidophilic archaeon Sulfolobus acidocaldarius has a unique respiratory system with at least two terminal oxidases. Genetic and preliminary biochemical studies suggested the existence of a unique respiratory supercomplex, SoxM. Here we show (i) that all respective genes are translated into polypeptides, and (ii) that the supercomplex can be separated from the alternative oxidase SoxABCD and in that way characterized in a catalytically competent form for the first time. It acts as a quinol oxidase and contains a total of seven metal redox centers. One of it--the blue copper protein sulfocyanin--functionally links two subcomplexes. One is a bb3-type terminal oxidase moiety containing CuA and CuB, whereas the other consists of a Rieske FeS-protein and a homolog to cytochrome b--in this case hosting two hemes As. Based on a 1:1 stoichiometry, 1 mol complex contains 6 mol Fe and 4 mol Cu. Its activity is completely inhibited by cyanide and strongly by aurachin-C and -D derivatives as inhibitors of the quinol binding site. These data suggest that the complex provides two proton pumping sites. Interestingly, subunit-II reveals an unusual pH dependence and is proposed to act as a pH sensor as well as a regulator of catalytic activity via a reversible transition between two states of the CuA ligation. This is a novel hint at how S. acidocaldarius can adapt to and survive in its extreme natural environment.     

Silicone gel infiltration of a peripheral nerve and constrictive neuropathy following rupture of a breast prosthesis.

Following rupture of a subpectoral breast prosthesis, massive amounts of silicone gel migrated into the arm of a patient. The patient developed painful paresthesias and decreased sensation in the cutaneous distribution of the superficial radial nerve. Nerve conduction studies showed both an increase in distal latency and decreased amplitude in this nerve compared with the normal opposite side. Subsequent neurolysis confirmed dense fibrosis surrounding the nerve. Silicone droplets also were observed within the thickened epineurium of the median nerve, but no electrophysiologic evidence of neuropathy occurred. Multiple debridements of the subcutaneous tissue of the arm were necessary. In one of these specimens, histologic sections demonstrated silicone gel infiltration of a subcutaneous nerve. This is the first reported case of silicone gel infiltration of a nerve and constrictive neuropathy associated with a prosthesis rupture.     

Short-term effect of silicone gel on peripheral nerves: a histologic study.

The effect of silicone gel on the peripheral nerve was studied in Sprague-Dawley rats. Silicone gel was placed either extraneurally (N = 36) adjacent to or injected directly in the sciatic nerve (N = 20). Nerve histology was studied every 2 weeks over a 20-week period. Extraneural silicone gel elicited an intense inflammatory response characterized initially by predominantly histiocytes with a few eosinophils, lymphocytes, and foreign-body giant cells. The cellular response peaked at 4 weeks, after which time collagen deposition increased and the thickness of the cellular infiltrate surrounding the gel decreased. The gel was temporarily contained by the inflammatory response, but throughout the time course of the study, gel migration and breakup into smaller droplets occurred. Each droplet appeared to initiate the inflammation-fibrosis cycle anew. Perineural fibrosis was marked by 20 weeks, but there was no penetration of the epineurium by the gel. Intraneurally injected silicone gel also caused a delayed, but similar inflammatory response, eventually followed by fibrosis surrounding the gel. Intraneural gel tended to remain in larger droplets and did not migrate over the duration of this study. No direct evidence of gel toxicity to peripheral nerves was observed in either the extraneural or intraneural gel groups despite the initial intense inflammatory response and subsequent fibrosis.     

Evaluation of the effect of GHRH(1-44)NH2 on the secretion of interleukin-2 (IL-2) and soluble IL-2 receptor alpha (sIL-2Ralpha) from human peripheral blood mononuclear cells in vitro

OBJECTIVE: The bidirectional communication between the neuroendocrine and the immune systems is now a subject of an intensive investigation. Somatoliberin (GHRH) is a hypothalamic hormone that enhances the synthesis and the release of growth hormone (GH) from the anterior pituitary cells. Few recent reports demonstrate also role of the neuropeptide in the regulation of the immune system function. AIM: The aim of the study was to examine the influence of GHRH on IL -2 as well as sIL -2Ralpha secretion from mitogen-stimulated peripheral blood mononuclear cells. MATERIAL AND METHOD: Mononuclear cells (PBMC) were isolated from the peripheral blood of healthy adults according to the technique described by B?yum. Cells, cultured 24 hours at 37 degrees C in humidified atmosphere of 95% air and 5% CO2, were stimulated with phytohemaglutinin (PHA; 10 microg/ml), and then GHRH(1-44)NH2 at the final concentrations 10(-12), 10(-10), 10(-8) and 10(-6) M was added to appropriate wells. ELISA kits were used to measure IL-2 and sIL-2Ralpha concentrations in the supernatants of cultured cells. Comparisons between tested groups were made by U Mann-Whitney test. The differences were considered significant if p < 0.05. RESULTS: GHRH stimulated the secretion of IL -2 into the supernatants acting significantly at the concentration of 10(-12) M (p < 0.001). Moreover, GHRH at concentrations 10(-10) M and 10(-8) M significantly increased the secretion of sIL-2Ralpha as well (p < 0.001). Strong positive correlation between tested GHRH concentrations and sIL-2Ralpha levels in the supernatants was demonstrated (r = 0.8664; p <0.001). CONCLUSIONS: The results demonstrate the potential involvement of GHRH in the regulation of T lymphocytes secretory function.     

Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha

Amyloid deposition within the brains of Alzheimer's Disease patients results in the activation of microglial cells and the induction of a local inflammatory response. The interaction of microglia or monocytes with beta-amyloid (A beta) fibrils elicits the activation a complex tyrosine kinase-based signal transduction cascade leading to stimulation of multiple independent signaling pathways and ultimately to changes in proinflammatory gene expression. The A beta-stimulated expression of proinflammatory genes in myeloid lineage cells is antagonized by the action of a family of ligand-activated nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs). We report that THP-1 monocytes express predominantly PPAR gamma isoform and lower levels of PPAR alpha and PPAR delta isoforms. PPAR mRNA levels are not affected by differentiation of the cells into a macrophage phenotype, nor are they altered following exposure to the classical immune stimulus, lipopolysaccharide. Previous studies have found that PPAR gamma agonists act broadly to inhibit inflammatory responses. The present study explored the action of the PPAR alpha isoform and found that PPAR alpha agonists inhibited the A beta-stimulated expression of TNFalpha and IL-6 reporter genes in a dose-dependent manner. Moreover, the PPAR alpha agonist WY14643 inhibited macrophage differentiation and COX-2 gene expression. However, the PPAR alpha agonists failed to inhibit A beta-stimulated elaboration of neurotoxic factors by THP-1 cells. These findings demonstrate that PPAR alpha acts to suppress a diverse array of inflammatory responses in monocytes.