Low lymphatic vessel density associates with chronic rhinosinusitis with nasal polyps.

OBJECTIVES: Chronic rhinosinusitis with and without nasal polyps (CRSwNP and CRSsNP) and antrochoanal polyps (ACP) are different upper airway inflammation phenotypes with different pathomechanisms. In order to understand the development of tissue edema, the present study aimed to evaluate lymphatic vessel density in CRSsNP, CRSwNP and ACP. MATERIALS AND METHODS: 120 retrospective nasal and maxillary sinus specimens were stained immunohistochemically with a von Willebrand factor polyclonal antibody recognizing vascular and lymphatic endothelium, and with a podoplanin monoclonal antibody recognizing lymphatic endothelium. Vessels were studied by microscopy in a blinded fashion, and the vessel density and the relative density of lymphatic vessels were calculated. Patient characteristic factors and follow-up data of in average 9 years were collected from patient records. RESULTS AND CONCLUSION: In the nasal cavity, the low absolute and relative density of vessels and of lymphatic vessels was associated with CRSwNP and ACP tissues compared to control inferior turbinate. This was observed also in the inflammatory hotspot area. In the maxillary sinus, lower absolute and relative density of lymphatic vessels associated with the CRSwNP phenotype. High lymphatic vessel density in polyp tissue associated with the need for revision CRS-surgery. As a conclusion, low density of lymphatic vessels distinguished patients with CRSwNP not only in the hotspot area of polyp tissue, but also in maxillary sinus mucosa. Yet, higher lymphatic vessel density seems to associate with polyp recurrence. Further studies are still needed to explore if formation of nasal polyps could be diminished by intranasal therapeutics affecting lymphangiogenesis.

Proliferative and anti-apoptotic activity of esophageal mucosa in gastroesophageal reflux disease is not affected by fundoplication: a 4-year follow-up study.

BACKGROUND: The role of fundoplication in the prevention of esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist regarding their response to fundoplication. METHODS: Ki-67 and Bcl-2 expression was assessed in the esophagogastric junction (EGJ) and the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication and in 7 controls. Endoscopy was performed preoperatively and 6 (20 patients) and 48 months (16 patients) postoperatively. RESULTS: There were positive correlations between Ki-67 and Bcl-2 levels in the EGJ (p > 0.001) and in the distal (p = 0.001) and proximal esophagus (p = 0.013). Compared to the preoperative level, Ki-67 expression was elevated in the distal (p = 0.012) and proximal (p = 0.007) esophagus at 48 months. In addition, compared to control values, Ki-67 expression was lower at the 6-month follow-up in the EGJ (p = 0.037) and the proximal esophagus (p = 0.003), and higher at the 48-month follow-up in the distal esophagus (p = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (p = 0.038). CONCLUSIONS: Proliferative activity after fundoplication increased in the long term in the distal esophagus despite a normal fundic wrap and healing of GERD.

Indoleamine 2,3-dioxygenase expression is associated with chronic rhinosinusitis with nasal polyps and antrochoanal polyps.

Chronic rhinosinusitis without and with nasal polyps (CRSwNP and CRSsNP), and antrochoanal polyps are different phenotypes with different pathomechanisms. Indoleamine 2,3-dioxygenase (IDO) is an enzyme expressed in many cells involved in the catabolism of the essential amino acid tryptophan to kynurenine. IDO might have a role in allergic airway inflammation. The aim was to evaluate if IDO expression is associated with CRSsNP, CRSwNP, or ACP. One hundred fifty specimens from the nasal cavity and sinus mucosa were immunohistochemically stained with mAb anti-IDO. The expression of epithelial and leukocyte IDO was associated with CRSwNP and ACP. The presence of ASA intolerance, asthma, atopy, smoking and use of medication did not significantly change the results. The different expression of IDO could putatively indicate the differences in the pathomechanisms of CRSsNP, CRSwNP and ACP. Further studies on the role of IDO in upper airways pathologies are required.

Sex hormone regulation of in vitro immune response. Estradiol enhances human B cell maturation via inhibition of suppressor T cells in pokeweed mitogen-stimulated cultures.

The effects of the main male and female sex hormones, testosterones and estradiol, in pokeweed mitogen (PWM)-stimulated cultures of human blood lymphocytes were studied. We found that the addition of physiological concentrations of estradiol (780-2,600 pmol/liter) to PWM cultures significantly increased the accumulation of immunoglobulin M-containing and -secreting cells detected by immunofluorescence and/or by the reversed protein-A plaque assay. The dose range of estradiol that induced enhanced B cell maturation did not affect the proliferative response. Estradiol displayed the same effect in vitro on lymphocytes from both men and women. Fractionation of lymphocyte subpopulations before culturing revealed that estradiol does not display a direct mitogenic or stimulatory effect of B cells. Instead, estradiol inhibits the suppressive activity of a radio-sensitive (1,000 rad) subset of T lymphocytes bearing Fc-receptors for immunoglobulin G. Nontoxic concentrations fo testosterone did not influence the in vitro B cell maturation. These observations provide a cellular basis for the differences in the immunoreactivities of males and females. The estradiol-induced inhibiton of suppressor T cells might be important for the pathogenesis of various autoimmune disorders.

De novo expression of endothelial sialyl Lewis(a) and sialyl Lewis(x) during cardiac transplant rejection: superior capacity of a tetravalent sialyl Lewis(x) oligosaccharide in inhibiting L-selectin-dependent lymphocyte adhesion.

Acute organ transplant rejection is characterized by a heavy lymphocyte infiltration. We have previously shown that alterations in the graft endothelium lead to increased lymphocyte traffic into the graft. Here, we demonstrate that lymphocytes adhere to the endothelium of rejecting cardiac transplants, but not to the endothelium of syngeneic grafts or normal hearts analyzed with the in vitro Stamper-Woodruff binding assay. Concomitant with the enhanced lymphocyte adhesion, the cardiac endothelium begins to de novo express sialyl Lewis(a) and sialyl Lewis(x) (sLea and sLex) epitopes, which have been shown to be sequences of L-selectin counterreceptors. The endothelium of allografts, but not that of syngeneic grafts or normal controls, also reacted with the L-selectin-immunoglobulin G fusion protein, giving further proof of inducible L-selectin counterreceptors. The lymphocyte adhesion to endothelium could be significantly decreased either by treating the lymphocytes with anti-L-selectin antibody HRL-1, or by treating the tissue sections with sialidase or anti-sLea or anti-sLex monoclonal antibodies. Finally, we synthetized enzymatically several members of the sLex family oligosaccharides and analyzed their ability to block lymphocyte adhesion to cardiac endothelium. The monovalent sLex (a tetramer), divalent sLex (a decamer), and tetravalent sLex (a 22-mer) could all significantly reduce lymphocyte binding, but the inhibition by the tetravalent sLex-construct was clearly superior to other members of the sLex family. The crucial control oligosaccharides, sialyl lactosamines lacking fucose but being otherwise similar to the members of sLex family, had no effect on lymphocyte binding.

Birch pollen allergen Bet v 1 binds to and is transported through conjunctival epithelium in allergic patients.

BACKGROUND: Previous work in type-I pollen allergies has mainly focused on lymphocytes and immune responses. Here, we begin to analyse with a systems biology view the differences in conjunctival epithelium obtained from healthy and allergic subjects. METHODS: Transcriptomics analysis combined with light and electron microscopic analysis of birch pollen allergen Bet v 1 located within conjunctival epithelial cells and tissues from birch allergic subjects and healthy controls was carried out. RESULTS: Bet v 1 pollen allergen bound to conjunctival epithelial cells within minutes after the exposure even during the nonsymptomatic winter season only in allergic, but not in healthy individuals. Light- and electron microscopy showed that Bet v 1 was transported through the epithelium within lipid rafts/caveolae and reached mast cells only in allergic patients, but not in healthy individuals. Transcriptomics yielded 22 putative receptors expressed at higher levels in allergic epithelium compared with healthy specimens. A literature search indicated that out of these receptors, eight (i.e. 37%) were associated with lipid rafts/caveolae, which suggested again that Bet v 1 transport is lipid raft/caveola-dependent. CONCLUSIONS: We show a clear difference in the binding and uptake of Bet v 1 allergen by conjunctival epithelial cells in allergic vs healthy subjects and several putative lipid raft/caveolar receptors were identified, which could mediate or be co-transported with this entry. The application of discovery driven methodologies on human conjunctival epithelial cells and tissues can provide new hypotheses worth a further analysis to the molecular mechanisms of a complex multifactorial disease such as type-I birch pollen allergy.

Ischemic intestinal injury during cardiopulmonary bypass does not show an association with neutrophil activation: a porcine study.

BACKGROUND: Neutrophil activation and tissue sequestration are crucial events in intestinal ischemia-reperfusion injury, but their role in the gut wall after clinical cardiopulmonary bypass (CPB) remains unclear. We tested whether local post-CPB inflammatory response in the gut wall would be associated with intestinal mucosal perfusion. METHODS: Twenty pigs underwent 60 min of aortic clamping and 75 min of normothermic perfusion. Intestinal biopsies were taken after 120 min of reperfusion. Based on ileal myeloperoxidase activity (MPO), the animals were divided into 2 groups, CPB-induced increase in MPO (MPO+) versus no such increase (MPO-), for comparison of the parameters that measure gut mucosal perfusion. Ileal p(CO)((2)) and intramucosal pH were determined, and arterial gases were analyzed. Additionally, several hemodynamic parameters and blood thrombin-antithrombin complexes (TAT) were measured. RESULTS: Myocyte degeneration, endothelial activation and vasculitis were more pronounced in the MPO+ group (p < 0.05), while the MPO- group showed significantly increased pi(CO)((2)) and lower mucosal pH values during reperfusion. Hemodynamics and TAT levels did not differ between the groups. CONCLUSION: Tissue sequestration of neutrophils was poorly associated with perturbed mucosal perfusion after CPB. Mechanisms of gut wall injury after a low-flow/reperfusion setting can differ from those in reperfusion injury after total ischemia.

Is Cystatin C more sensitive than creatinine in detecting early chronic allograft nephropathy?

BACKGROUND: Cystatin C (CyC) has been suggested as a more accurate indicator of renal function than creatinine (Crea). CyC performance against graft histopathology has not been investigated. AIM: To compare CyC and Crea-based methods as predictors of chronic allograft damage index (CADI). MATERIAL AND METHODS: 105 protocol biopsies obtained at 6 months post-transplantation were classified with Banff'97 and CADI. CyC and Crea were measured concomitantly. Histology was correlated to CyC, Crea, their reciprocals, CyC-estimated GFR (Larsson), Cockroft and Gault (C&G) and abbreviated MDRD using Kendall's Tau. The area under ROC curve (ROC-auc),sensitivity/specificity, positive and negative predictive values were calculated at CADI cut-off of 2. RESULTS: Mild histological changes were best revealed by Crea, although with modest sensitivity/ specificity. A Crea threshold of 111 micromol/l distinguished 74% of the patients with CADI > 2 and excluded this condition in 66%. For Crea, ROC-auc was 0.72 (p < 0.001). Crea and 1/Crea correlated best to CADI, chronic allograft nephropathy, chronic inflammation, tubular atrophy, vascular changes and glomerulopathy. Neither C&G nor MDRD improved Crea performance alone. CyC and Larsson formula performed the same (ROC-auc 0.67). A CyC threshold of 1.12 mg/l distinguished 69% of the patients with CADI > 2 and excluded it in 60%. Significant Tau correlation was found between CyC, 1/CyC and Larsson with CADI, chronic inflammation, tubular atrophy and chronic vascular changes. CONCLUSIONS: CyC, 1/CyC and Larsson-estimated GFR did not offer significant advantages over Crea in predicting mild histological allograft changes. Protocol biopsy provides information that cannot be sensitively predicted by biochemical measurements used in clinical practice.

Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.

OBJECTIVES: The purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder. BACKGROUND: An inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families. METHODS: Two unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus. RESULTS: Of the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood. CONCLUSIONS: A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.

Chronic rejection of rat renal allografts. II. The impact of prolonged ischemia time on transplant histology.

The effect of prolonged ischemia time on the generation of chronic rejection was investigated in long-surviving rat renal allografts. Three groups of rats were compared: allografts with a 30-min ischemia time, allografts with a 60-min ischemia time, and syngeneic grafts with a 60-min ischemia time. All transplants were initially immunosuppressed with 5 mg/kg/day of cyclosporine i.m. for 3 weeks postoperatively. The CsA trough levels were similar in the three rat groups. All groups demonstrated an initial rise and fall in serum creatinine; a simultaneous biopsy confirmed acute CsA toxicity. Thereafter the serum creatinine level remained on the normal control level both in the 30-min ischemia allografts and in the 60-min ischemia syngeneic grafts. After the initial decline, the serum creatinine level steadily increased in the 60-min ischemia allograft group and was 181 +/- 64 mumol/L at the end of the observation period, 12 weeks postoperatively, compared with 85 +/- 21 mumol/L in the 30-min ischemia allografts and 89 +/- 25 mumol/L in the 60-min ischemia syngeneic grafts. Quantitative histology that was performed upon autopsy demonstrated that the 60-min ischemia allografts showed persistent inflammation, inflammatory cell pyroninophilia, vascular arteriosclerosis and obliteration, and glomerular sclerosis, which were significantly stronger than in similarly immunosuppressed syngeneic transplants. Reduction of the ischemia time from 60 to 30 min significantly ameliorated the vascular and glomerular changes in the allografts but not the inflammatory alterations. This experimental study confirms previous clinical observations and demonstrates that prolonged ischemia contributes to chronic rejection in renal allografts. The results suggest that the effect of prolonged ischemia on chronic rejection is directed primarily to the parenchymal components of the graft, possibly to the graft vascular endothelium. As prolonged ischemia did not significantly affect the inflammation in the transplants, we conclude that the effect is not directed to the intensity of the host antigraft immune response.

Chronic rejection in the rat aortic allograft. V. Mechanism of the angiopeptin (BIM23014C) effect on the generation of allograft arteriosclerosis.

Synthetic cyclic octapeptide analogues of somatostatin, such as angiopeptin (BIM23014C; AP) inhibit myointimal proliferation in chronically rejecting rabbit and rat allografts and following angioplasty in rabbits. We have investigated the mechanism of angiopeptin inhibition of allograft arteriosclerosis. DA (RT1a) aortic allografts were transplanted to WF (RT1v) recipients, which either received 80 micrograms/kg/day of AP (Alzet mini-pumps, s.c., 0-180 days) or were left untreated. AP administration did not affect the intensity of adventitial inflammation, nor reduced the disappearance of smooth-muscle cell nuclei from the media (media necrosis); however, it reduced their appearance in the intima and intimal thickening. The effect disappeared, however, from the 3rd month onward. In vivo labeling with tritiated thymidine and autoradiograms demonstrated that AP reduced slightly the proliferation of the inflammatory cells in adventitia and of smooth-muscle cells in the media, and reduced strongly and significantly (P < 0.01) the proliferation of smooth-muscle cells in the intima. Analysis of the major chronic-rejection associated eicosanoids from the vascular wall showed that AP had no effect on the release of the pro-inflammatory thromboxane B2 from the allograft. As AP did not reduce the intensity of perivascular inflammation, reduced only slightly the proliferation of inflammatory cells, and did not affect the release of thromboxane B2 from the inflammatory macrophages, it is likely that the AP effect is not directed to the inflammatory cells. As previous in vitro studies have demonstrated that vascular smooth-muscle cells proliferate in response to several growth factors, and as somatostatin analogues are inhibitory to their action, our data suggest that the action of AP on allograft arteriosclerosis is due to a direct effect on smooth-muscle-cell proliferation.

Acute rejection of porcine small bowel allograft. An extended histological scoring system.

Using nonimmunosuppressed piglet small bowel grafts, we performed a detailed histological study on acute rejection and analyzed altogether 45 different histological parameters throughout the bowel wall, in 10 allografts and 6 autografts. Heterotopic grafts were followed by full-thickness biopsies every other day beginning on the 3rd day after transplantation. The parameters were scored from 0 to 3 according to the severity of the change and the values of every variable were compared statistically between the 2 groups. The earliest significant changes, beginning on days 3-5, were infiltration of inflammatory cells and pyroninophilia among these cells in lamina propria; edema, fibrosis, and inflammation in submucosa and muscularis; vacuolar degeneration of myocytes; and endothelial and intimal changes in vessels. Villous blunting and cuboidal epithelium were the other early markers. On day 7, the epithelial and vascular changes became most significant. We want to emphasize especially the vascular parameters: endothelial swelling and proliferation, intimal thickening, intramural inflammation, and obliteration of the lumen. The dilatation of lymph vessels and changes of Peyer's patches had no value in the estimation of rejection. All allografts became necrotic by day 11 after transplantation.

CD5 and immunoglobulin VH gene expression in B-cell lines from patients with autoimmune diseases.

We studied the CD5 mRNA expression and VH gene family usage in Epstein-Barr virus (EBV)-immortalized B-cell lines derived from the blood of patients with type 1 diabetes (IDDM) of recent onset and of patients with polyneuritis cranialis multiplex (cranial neuritis; CN). After immortalization with EBV, at least 10 cell lines from each subject were tested for surface CD5 and CD20. mRNA expression was studied using cDNA probes for the six VH families as well as for CD5. The EBV lines from the IDDM patients used the VHIV family more frequently and VHI and VHII families less frequently than lines from controls. EBV lines from CN patients expressed the VHI and VHII families more often than those of the controls. When the IDDM and CN lines were compared, the lines derived from IDDM patients were found to use VH families I and II less frequently and VH families IV and V more frequently than lines from CN patients. There were no significant differences in the mean numbers of CD5+ B cells in the cell lines tested. More than half of the lines from each patient expressed CD5 at the mRNA level. No correlation was seen between the expression of surface CD5 and the level of CD5 mRNA expression. There was, however, a positive correlation between the usage of VH families III, V and VI, and the CD5 mRNA expression. In conclusion, the usage of VH families I to VI seemed to differ in patients with IDDM and CN. No differences were seen in the surface CD5 expression, but the lines expressing CD5 mRNA preferentially used the VH families III, V and VI.

Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes.

A number of physiological and synthetic progestins were tested for their ability to compete with [3H]dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid-like effects on the same cells. As compared to the reference compound dexamethasone (relative receptor binding affinity defined as 100%), two potent synthetic progestins with a pregnane-type structure, megestrol acetate and medroxyprogesterone acetate, were found to display a considerable binding affinity towards the receptor (46 and 42%, respectively). The relative binding affinity of the naturally occurring ligand, cortisol, to the receptor was clearly lower (25%). The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid. No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor-specific ligand [3H]Org 2058 was used. Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid-like effects on the lymphocyte functions. These included inhibition of the proliferative responses to the T-cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen-stimulated cultures. The progestin effect appears to be mediated through a radiosensitive (suppressor) subpopulation of T lymphocytes. In contrast, the synthetic progestins related structurally to 19-nortestosterone, norethisterone and d-norgestrel, were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions. These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character (e.g. suppression of the pituitary-adrenal axis) might be expected when these compounds are used in pharmacological doses.

Endothelial and epithelial expression of sialyl Lewis(x) in squamous carcinoma of the tongue.

In this retrospective study we describe the immunohistochemical expression pattern of sLe(x) epitopes in endothelial and epithelial cells of 59 squamous carcinomas of the tongue, and relate this to the relative survival rates of the patients. Endothelial sLe(x) expression was significantly elevated in malignant lesions compared to normal tissues, but did not have any prognostic value for the relative survival rate. In contrast, epithelial sLe(x) expression was decreased in carcinomas compared to normal tongue. The patients whose carcinoma showed only moderate epithelial HECA-452 reactivity had a significantly better relative survival rate than the patients with tumor specimens with neglible or very high HECA-452 reactivity. The epithelial staining with the two other anti-sLe(x) antibodies (CSLEX-1 and 2F3) did not correlate with the survival rates of tongue carcinoma patients.

Carcinoembryonic antigen is expressed on endothelial cells. A putative mediator of tumor cell extravasation and metastasis.

Carcinoembryonic antigen (CEA) is a highly glycosylated cell surface protein. It is produced in large amounts in essentially all colon and several other adenocarcinomas. It has therefore been widely used as a clinical tumor marker. CEA is also a member of the immunoglobulin superfamily. Members of this family, such as ICAM-1, ICAM-2, VCAM-1 and NCAM, are known to participate in cell-cell adhesion. Similarly, the intercellular adhesion properties of CEA have been documented: it has been shown to mediate homotypic adhesion of cultured human colon adenocarcinoma cell lines. In this study we show for the first time that CEA is expressed on cultured human umbilical vein endothelial cells and on the endothelial cell line Ea.hy926. The expression of CEA on cultured endothelial cells can be enhanced by TNF-alpha or IFN-gamma, and decreased by IL-4. We demonstrate using immunohistochemistry that anti-CEA monoclonal antibody reacted with FVIII-positive endothelium in tissue sections prepared from lymph nodes. Finally, we were able to show that CEA-positive breast carcinoma cells bind to purified CEA protein, whereas CEA-negative breast carcinoma cells do not. These results reveal for the first time that endothelial cells express CEA on the cell surface and suggest that CEA-expressing adenocarcinomas could adhere to endothelial cells via CEA-CEA interaction, thus facilitating tumor cell extravasation and hematogenic metastasis.

The effects of anti-estrogen therapy on lymphocyte functions in breast cancer patients.

The effects of anti-estrogen therapy (tamoxifen or toremifene) on in vitro lymphocyte functions were investigated in breast cancer patients. We found that the amount of DNA synthesis, with or without PWM stimulation, was decreased in all cancer patient groups compared to normal controls. The number of Ig-secreting cells was enhanced in unstimulated peripheral blood lymphocyte cultures but decreased in PWM-stimulated cultures. This occurred in all cancer patient groups investigated, with or without anti-estrogen therapy, as compared to healthy controls. On the other hand, subsequent samples with two-month intervals showed that anti-estrogens can increase PFC responses and inhibit DNA synthesis of peripheral blood lymphocytes in more than half of the patients. Interestingly, the enhancing dexamethasone effect, which usually causes an increase in the number of Ig-secreting cells in PWM-stimulated cultures, was also seen more often in anti-estrogen-treated patients. These results suggest that anti-estrogens may have immunoregulatory effects in vivo.

The effect of toremifene therapy on serum immunoglobulin levels in breast cancer.

Estrogens and anti-estrogens enhance the number of immunoglobulin (Ig)-secreting cells in pokeweed mitogen (PWM)-stimulated lymphocyte cultures. Lymphocytes from patients who have received anti-estrogen therapy show similar enhancement of Ig-secreting cells after PWM stimulation. In this study the effect of anti-estrogen (toremifene) therapy on serum immunoglobulin (IgA, IgM, IgG) levels in breast cancer patients was investigated. Serum Ig levels were followed up to two years after or during the therapy. An unexpected finding was that the Ig levels decreased during the follow-up period. This decrease was seen in patients who responded to the therapy as well as in those who did not.

MRI enhancement and microvascular density in gliomas. Correlation with tumor cell proliferation.

RATIONALE AND OBJECTIVES: Angiogenesis and proliferation activity are important indicators of tumor behavior in human gliomas. The authors studied how tumor enhancement in MR imaging and intratumoral vascular density were correlated with cell proliferation in cerebral gliomas. METHODS: The authors studied retrospectively 62 cerebral gliomas. Patients were examined before surgery with contrast-enhanced MR imaging. Microvessel density and the cell proliferation rate of tumor specimens were measured immunohistochemically using factor VIII and MIB-1 antibodies. Contrast enhancement of the tumors was evaluated by two radiologists. RESULTS: Contrast enhancement was observed in 45 tumors and was correlated with histologic cell proliferation (P = 0.0007) and microvessel density (P = 0.01). There was also a correlation between tumor vascular density and the cell proliferation rate (r = 0.51, P < 0.0001). Histologic tumor grade was associated with vascular density (P = 0.001). CONCLUSIONS: Lesion enhancement on preoperative contrast-enhanced MR imaging correlates with vascularity and proliferation activity of gliomas. The additional correlation between tumor vascularity and proliferation suggests that intratumoral microvessel density could be useful in estimating tumor proliferation.

Endothelialitis and accelerated arteriosclerosis in human heart transplant coronaries.

We have analyzed the autopsy material of 11 cardiac allograft recipients, whose grafts became nonfunctional less than 1 year after transplantation. All patients had received routine triple-drug immunosuppression. Two of these patients showed accelerated transplant arteriosclerosis; the graft loss was associated with strong intimal proliferative response affecting the first-order and second-order intramuscular branches of the major coronary vessels. Histologic evidence showed only a slight inflammatory reaction in the vascular adventitia. The media was mostly intact, and the internal elastic lamina showed occasional breaks. A very prominent inflammatory reaction was noted in the subendothelial space in the intima. Immunohistochemistry with monoclonal antibodies revealed that the luminal part of the intima was invaded by anti-leukocyte common antigen and anti-UCHL1 positive T lymphocytes, whereas the abluminal part consisted mostly of anti-smooth muscle alpha-actin-positive smooth muscle cells. We call this subendothelial accumulation of lymphocytes endothelialitis. The suggestion has been made that accelerated arteriosclerosis may be associated with cyclosporine treatment. Correlation with the recipient's cytomegalovirus status in this study suggests that cytomegalovirus infection may contribute to the development of endothelialitis and accelerated arteriosclerosis in heart transplant recipients.