Minimal Excitations in the Fractional Quantum Hall Regime.

We study the minimal excitations of fractional quantum Hall edges, extending the notion of levitons to interacting systems. Using both perturbative and exact calculations, we show that they arise in response to a Lorentzian potential with quantized flux. They carry an integer charge, thus involving several Laughlin quasiparticles, and leave a Poissonian signature in a Hanbury Brown-Twiss partition noise measurement at low transparency. This makes them readily accessible experimentally, ultimately offering the opportunity to study real-time transport of Abelian and non-Abelian excitations.

Hypothyroidism and hyponatremia: data from a series of patients with iatrogenic acute hypothyroidism undergoing radioactive iodine therapy after total thyroidectomy for thyroid cancer.

PURPOSE: The aim of the present study was to evaluate the role of hypothyroidism as a cause of hyponatremia in a clinical model of iatrogenic acute hypothyroidism due to thyroid hormone withdrawal prior to ablative radioactive iodine (RAI) therapy after total thyroidectomy. METHODS: The study group consisted of 101 differentiated thyroid cancer (DTC) patients (77 women and 24 men). Plasma concentration of thyroid-stimulating hormone ([TSH]) and sodium ([Na+]) was evaluated before total thyroidectomy (pre[TSH] and pre[Na+]) and on the day of RAI therapy (post[TSH] and post[Na+]). RESULTS: The frequency of hypothyroidism-associated hyponatremia was 4 % (4/101). Pre[Na+] was significantly higher than post[Na+] (140.7 ± 1.6 vs 138.7 ± 2.3 mEq/L, p = 0.012). Moreover, a linear correlation was identified between pre[Na+] and post[Na+]. CONCLUSIONS: Iatrogenic acute hypothyroidism-related hyponatremia is uncommon. However, because of the significant reduction of [Na+] in the transition from euthyroidism to iatrogenic hypothyroidism, the value of pre[Na+] should be viewed as a parameter to be considered. Since it acts as an independent risk factor for the development of hyponatremia, patients with a pre[Na+] close to the lower limit of normal range may deserve a closer monitoring of [Na+].

Collagen-induced arthritis: severity and immune response attenuation using multivalent N-acetyl glucosamine.

Rheumatoid arthritis is an autoimmunity leading to considerable impairment of quality of life. N-acetyl glucosamine (GlcNAc) has been described previously as a potent modulator of experimental arthritis in animal models and is used for osteoarthritis treatment in humans, praised for its lack of adverse effects. In this study we present a comprehensive immunological analysis of multivalent GlcNAc-terminated glycoconjugate (GC) application in the treatment of collagen-induced arthritis (CIA) and its clinical outcome. We used immunohistochemistry and FACS to describe conditions on the inflammation site. Systemic and clinical effects were evaluated by FACS, cytotoxicity assay, ELISA, cytometric bead array (CBA), RT-PCR and clinical scoring. We found reduced inflammatory infiltration, NKG2D expression on NK and suppression of T, B and antigen-presenting cells (APC) in the synovia. On the systemic level, GCs prevented the activation of monocyte- and B cell-derived APCs, the rise of TNF-α and IFN-γ levels, and subsequent type II collagen (CII)-specific IgG2a formation. Moreover, we detected an increase of anti-inflammatory IL-4 mRNA in the spleen. Similar to the synovia, the GCs caused a significant reduction of NKG2D-expressing NK cells in the spleen without influencing their lytic function. GCs effectively postponed the onset of arthritic symptoms, reduced their severity and in 18% (GN8P) and 31% (GN4C) of the cases completely prevented their appearance. Our data prove that GlcNAc glycoconjugates prevent the inflammatory response, involving proinflammatory cytokine rise, APC activation and NKG2D expression, leading to the attenuation of clinical symptoms. These results support the glycobiological approach to the treatment of collagen-induced arthritis/rheumatoid arthritis (CIA/RA) as a way of bringing new prospects for more effective therapeutic interventions.

Assessment of sleep apnea syndrome in treated acromegalic patients and correlation of its severity with clinical and laboratory parameters.

BACKGROUND: Sleep apnea syndrome (SAS) is a frequent disorder in acromegalic patients and its frequency ranges from 45 to 87.5% of patients. Obstructive SAS is the prevailing form in acromegaly and its pathogenesis is based on craniofacial deformations and thickening of soft tissues and mucosas of upper airways and bronchi. Central and mixed types are less frequent. Respiratory complications, and SAS in particular, may contribute to the increased mortality observed in acromegaly. AIM: Aim of the present study is to assess the presence of SAS in acromegalic patients, its features and to correlate the severity of SAS with factors such as disease duration, body mass index (BMI), smoking, GH/IGF-I serum levels, associated comorbidities. SUBJECTS AND METHODS: Polygraphy (SOMNOcheck Effort Weinmann V2.05) was performed in 25 consecutive acromegalic patients (9 men and 16 women). Statistical analysis was performed with Mann-Whitney's test and Spearman coefficient. RESULTS: Fourteen out of 25 patients (56%) were affected by SAS. The prevailing form was obstructive SAS (12/14 patients). Smoking, female gender, and presence of lung disease appear to lead to a more severe form. We also found that the prevalence of hypertension was significantly higher in the group of patients with SAS, whereas no correlation was proved among SAS and disease duration, GH/IGF-I serum levels, somatostatin analogs treatment, BMI, and associated comorbidities. CONCLUSIONS: SAS is a frequent complication of acromegaly. Severe forms seem to be correlated with smoking and lung disease. Therefore, all acromegalic patients should be subjected to a polygraphic study for an early diagnosis and treatment and smoking should be discouraged.

The effect of selected feed mixtures on the duodenal morphology: comparison study.

The objective of this work was to compare the effect of selected feed mixtures on the duodenal morphology. One-hundred-four rats of the Wistar strain were divided to thirteen groups per eight rats. The experiment started in 35-day-old rats after birth and lasted for 32 days. The groups (A-M) were fed by commercial diet, 85 % wheat and 15 % oat diet, 85 % wheat and 15 % triticale, 85 % wheat and 15 % barley, 85 % wheat and 15 % amaranth, 85 % wheat and 15 % lantern, 85 % wheat and 15 % buckwheat, 100 % wheat, 100 % white lupine, 100 % flock peas - variety Garden, 100 % native peas - variety Garden, 100 % native peas - variety Zekon or 100 % extruded peas - variety Zekon diet, respectively. Samples from the duodenum were taken. The height of the villi and the depth of the crypts were measured. The tallest villi were measured in group F (474.33+/-114.36 microm) and the shortest villi were observed in group B (294.08+/-88.52 microm). The deepest crypts were measured in group K (166.41+/-35.69 microm) and the shallowest crypts were observed in group E (77.85+/-17.61 microm). The work documents that gluten-free and classical cereals combination can be a better choice for people who want to limit the gluten content of the diet.

Multiplex analysis of cytokines involved in tumour growth and spontaneous regression in a rat sarcoma model.

The aim of our study was to examine in vivo and in vitro cytokines produced by Lewis ratderived R5-28 sarcoma cells. These cells produce rapidly growing tumours in approximately two weeks after subcutaneous inoculation. However, spontaneous tumour regression was noted in about 40% of animals. For an explanation of this phenomenon, we evaluated the profile of 19 cytokines during tumour growth and spontaneous regression by the use of "antibody array". To detect cytokines directly originated by the sarcoma, the R5-28 cells were cultivated in vitro and then both the supernatants and the cell lysates were analysed. Our experiments showed three cytokines (MCP-1, TIMP-1 and VEGF) to be produced by R5-28 cells in vitro. Moreover, in vivo, another three cytokines (TNF-alpha, beta-NGF and LIX) were detected both in blood sera and tumour lysates, probably produced by immune and stromal cells during tumour growth. Changes in their expression after spontaneous regression are discussed.

Anticoagulant drugs increase natural killer cell activity in lung cancer.

BACKGROUND: In preclinical studies in animal models and in initial clinical trials, anticoagulation drugs have been shown to be effective in the prevention and treatment of haematogenous metastasis, and in the prolongation of survival in animal models. However, only a few studies have been performed on the direct influence of anticoagulation drugs on the immune system. OBJECTIVE: The purpose of this study is to determine the effect of warfarin, unfractioned heparin, low molecular weight heparins (LMWHs), and acetylsalicylic acid anticoagulants on the functional activity of natural killer (NK) cells. PATIENTS AND METHOD: Cytotoxic activity in patients with early, operable stages of non-small-cell lung cancer was compared with healthy volunteers. Cytotoxic studies were also carried out in tumor-bearing animals. RESULTS: Lung-cancer patients were characterized by significantly lower NK cell cytotoxicity (7.07 +/- 3.15) than healthy donors (44.12 +/- 10.62, P < 0.001). NK cell activation was found in both in vitro experiments using peripheral blood mononuclear cells (PBMC) from healthy donors and ex vivo in lung carcinoma patients after treatment with unfractionated heparin and fraxiparine. Similarly, potentiation of NK cell activity in Lewis lung carcinoma-bearing mice was found after therapy with unfractionated heparin. NK cell activity is lower in lung cancer patients than in normal subjects. CONCLUSIONS: NK cell activation was increased by LMWHs. Other anticoagulants augment the effector function of NK cells in cancer patients and in an animal model of lung cancer. This is a novel effect of these compounds, which were thought previously to exert their effect only via their anticoagulant properties.

Stroma as an Active Player in the Development of the Tumor Microenvironment.

The stroma is a considerable part of the tumor microenvironment. Because of its complexity, it can influence both cancer and immune cells in their behavior and cross-talk. Aside from soluble products released by non-cancer and cancer cells, extracellular matrix components have been increasingly recognized as more than just minor players in the constitution, development and regulation of the tumor microenvironment. The variations in the connective scaffold architecture, induced by transforming growth factor beta, lysyl oxidase and metalloproteinase activity, create different conditions of ECM density and stiffness. They exert broad effects on immune cells (e.g. physical barriers, modulation by release of stored TGF-ß1), mesenchymal cells (transition to myofibroblasts), epithelial cells (epithelial-to-mesenchymal transition), cancer cells (progression to metastatic phenotype) and stem cells (activation of differentiation addressed by the microenvironment characteristics). Physiological mechanisms of the wound healing process, as well as mechanisms of fibrosis in some chronic pathologies, closely recall aspects of cancer deregulated biology. Their elucidation can provide a better understanding of tumor microenvironment immunobiology. In the following short review, we will focus on some aspects of the fibrous stroma to highlight its active participation in the tumor microenvironment constitution, tumor progression and the local immunological network.

Cancer immunomodulation by carbohydrate ligands for the lymphocyte receptor NKR-P1.

Natural killer (NK) and T cells express a superfamily of proteins with structural features of C-type lectins. Recombinantly prepared soluble form of rat NKR-P1 (CD161) recognized carbohydrate GalNac and GlcNac moieties. Ganglioside GM2 and heparin related-IS oligosaccharides representing the high affinity ligands for this receptor, increased the sensitivity of targets for killing by the rat effectors isolated from blood and spleen in vitro. Based on these results, we investigated in vivo the possible therapeutic effect of GM2 and IS carried by liposomes during induced rat colorectal carcinogenesis. The reduction of cancer incidence versus the controls (50% vs 88.88%), approached the 5-fluorouracil treatment (41.66%).

Local recurrence after curative resection of colorectal adenocarcinoma.

A total of 853 patients with 861 colorectal adenocarcinomas were operated on at our institution between 1965 and 1981. Complete follow-up information was obtained in all but six patients (99.4%), and all available histologic slides were reviewed to determine pathologic stage and characteristics. Six hundred fifty-one patients (76.3%) underwent a potentially curative procedure, and their operative mortality rate was 2.8%. Of the 627 patients available for analysis, 50 (8%) had a local recurrence. The median time to local recurrence was 18 months, and only 16% of local recurrences were diagnosed 5 years after the original resection. Median survival of patients with a local recurrence was 3 1/2 years from the original resection, and 16 patients (32%) survived 5 years or longer. A multivariate logistic regression analysis was conducted to examine the influence of several clinical and pathologic characteristics on local recurrence among Dukes' stages B and C adenocarcinomas (n = 539) after exclusion of patients with synchronous tumors (n = 8), postoperative deaths (n = 18), loss to follow-up (n = 6), or incomplete data (n = 11). This analysis revealed that the local recurrence rate was significantly related to depth of invasion (B1 + C1 = 0%; B2 + C1 = 10%; p less than 0.01), site of origin (right plus transverse colon = 6%; left plus rectosigmoid colon = 10%; rectum = 12%; p less than 0.05), and lymphatic or capillary microinvasion (absent, 6%; present, 14%; p less than 0.05). This analysis attempts to identify patients at high risk for development of local recurrent disease to select candidates for postoperative adjuvant therapy.

A new experimental model for colorectal carcinogenesis in the rat.

A total of 130 rats were used in various experiments to prepare a new model for colorectal carcinogenesis. The experiments resulted in the development of a surgical technique that creates a subcutaneous cecal hernia, which allows the direct injection of the promoting substance, human bile from percutaneous biliary drainage, into the bowel of the rat. The method permits a direct, complete, and very easy access of a specific amount of the substance to be tested onto the colonic mucosa. The results have proven to be uniformly effective and easily reproducible and to ensure safe management of the animal.

Importance of tumor morphology for the long term prognosis of rectal adenocarcinoma.

A retrospective review of 149 consecutive potentially curable rectal adenocarcinomas operated on at our institution between 1965 and 1981 was carried out to assess whether tumor morphology influences long term survival. Complete follow-up was available on all patients and extended to 20 years. Data on tumor morphology was extracted from pathology reports and was available in 147 cases (98.6%). Tumors were defined as exophytic (n = 76) when exhibiting a polypoid growth pattern protruding into the lumen at least 1 cm; when lacking such characteristic growth pattern, tumors were classified under the general term of nonexophytic (n = 71). The 5 year survival rate calculated with life table analysis was 80 per cent for exophytic carcinomas and 54.1 per cent for nonexophytic tumors. This difference was verified by logistic regression analysis and proportional hazard technique and is statistically highly significant (P = 0.001). The rate of distant metastases was 29.7 per cent for exophytic adenocarcinoma and 48.6 per cent for nonexophytic tumors (P = 0.02). Although the results did not reach statistical significance, local recurrence of tumor occurred about twice as often in nonexophytic tumors (15.7%) compared with exophytic tumors (8.1%). Thus, we conclude that tumor morphology is an important preoperative prognostic factor for survival and prediction of distant metastasis, and possibly for local recurrence.

Prognostic significance of ploidy determination in rectal cancer.

Between 1965 and 1981, 154 patients with potentially curable rectal adenocarcinoma underwent surgical treatment at the University of Chicago Medical Center. In 134 cases, enough histological material was available to perform determinations of DNA content by the cytophotometric method (n = 108), or by the flow cytometric technique (n = 109). In 83 cases, DNA content was analyzed in the same specimen with both techniques, and in 77 of these cases the sections obtained from the paraffin blocks were contiguous. When using flow cytometry, 62% of stage B and 74% of stage C lesions were classified as aneuploid on the basis of a DNA index greater than 1. This correlation was statistically significant (p = 0.002). Patients with diploid tumors had an actuarial five-year survival equal to 62% in comparison with a 46-51% five-year survival for patients with aneuploid tumors. This difference was not statistically significant and it was explained by the tendency for aneuploid tumors to be in an advanced histopathological stage.

Nuclear detecting systems at LNL and LNS: foreseen experiments to provide basic data for heavy-ion risk assessment.

The use of existing detecting systems developed for nuclear physics studies allows collecting data on particle and ion production cross-sections in reactions induced by Oxygen and Carbon beams, of interest for hadrontherapy and heavy-ion risk assessment. The MULTICS and GARFIELD apparatus, together with the foreseen experiments, are reviewed.

[Familial neoplasms: investigation of genealogic trees of patients surgically treated for colonic adenocarcinoma]. / Familiarità dei tumori: indagine sugli alberi genealogici di pazienti operati per adenocarcinoma del grosso intestino.

In order to study the familial aggregation of colorectal cancer we investigated the pedigrees of the patients with adenocarcinoma of the large bowel who underwent a surgical operation between november 1990 and october 1992 at the Istituto di Chirurgia Generale e Sperimentale Of Pisa University. For each proband, information was obtained on his/her four grandparents and all their second generation descendants. The final sample included 99 probands and 1455 relatives. Only two cases with diagnosis of familial adenomatous polyposis were excluded. As a control group, we applied the same methodology to the spouses of probands, collecting in the end a sample of 72 families including 1163 individuals. The frequency of both colorectal and extracolonic cancer was higher in the relatives of cases than in the control group, for all the relationships. Among the first degree relatives, the empirical risk of colorectal cancer was 1/30 among the case families and 1/139 among the control families, for a 4.6 fold increase in risk. For cancers at all sites (colorectal excluded), the corresponding risk were 1/8 and 1/12. We computed the posterior probability of dying from cancer for a random individual, given the known affection status of one or more of his/her relatives of specified relationship. For an individual with one first degree relative affected by colorectal cancer the posterior risk of the same tumor was 1/15, compared to a value of 1/70 for the entire control population. Considering all cancers, colorectal excluded, we obtained the result that for a person with at least three affected relatives, one of first, one of second and one of third degree, the probability of dying from colorectal cancer was 6%. The distribution of the number of affected individuals for kindred was highly skewed, with a few families responsible of a large part of the observed familial aggregation. This was true for both the cases of colorectal cancer and for all-site cancer. However, no family fulfilled the criterion of hereditary nonpolyposis colorectal cancer (Lynch syndromes I or II).

NK cell-mediated cytotoxicity modulation by A(2) adenosine receptor agonist in different mammalian species.

Adenosines, endogenous purine nucleosides, appear in the extracellular space under metabolically stressful conditions associated with ischemia, inflammation, and cell damage. Their activity on innate immunity is prevalently inhibitory and can develop both in infectious and neoplastic diseases. During cancer development, tumor cells that release high concentrations of adenosines can impair the function of tumor-infiltrating lymphocytes and assist tumor growth by neo-angiogenesis. We evaluated the influence of A(2) adenosine receptor (A(2)AR) agonist on cytotoxic-cell response comparing human with other mammalian species (rodents, pigs, goats), both in healthy and in cancer conditions. The A(2)AR agonist developed dose-dependent inhibition of the cytotoxic activity of immune effector cells in all studied species. However, variability of the response was observed in relation to the species and the target cells that were used. Altogether, our data indicate that the A(2)AR plays a central role in adenosine-mediated inhibition of immune response to tumors.

Ras oncogene expression as a prognostic indicator in rectal adenocarcinoma.

In order to investigate the value of ras oncogene expression as a prognostic indicator in rectal adenocarcinoma, we evaluated the level of ras gene protein product (p21) in the available material of 149 consecutive Dukes' B and C specimens resected at our institution between 1965 and 1981. Five year follow-up was available in all patients. Pathology slides and archival paraffin blocks were retrieved for confirmation of the original diagnosis, study of histopathological features, and measurement of p21 content. P21 titers were obtained using the RAP-5 monoclonal antibody in a semiquantitative immunohistochemical assay. Titer was expressed as the highest dilution of antibody giving definitive staining using the avidin-biotin peroxidase method. The analysis indicated that the group of tumors with high (greater than or equal to 1:40,000) p21 titers had a worse 5-year survival (43.9 versus 64.3%, P less than 0.02), higher incidence of distant metastases (51.8 versus 23.2%, P less than 0.001), and more advanced Dukes' stage (53.7 versus 35.7% incidence of Dukes' C stage, P less than 0.04) than tumors with low (less than 1:40,000) titers. Multivariate analysis also demonstrated that the influence of the level of ras gene protein product on survival was independent of Dukes' stage. We conclude that detection of high levels of ras oncogene protein product indicates a group of tumors with a more aggressive behavior, characterized by a higher percentage of distant recurrences and worse prognosis. These findings suggest that measurement of p21 may become clinically important in identifying patients at high risk of recurrent disease.

Sulphation of hydroxybiphenyls in human tissues.

1. Sulphotransferase is an important detoxication pathway of hydroxybiphenyls and the kinetics of sulphotransferase activity were studied in human liver, ileum and colon mucosae, lung, kidney, urinary bladder mucosa and brain using 0-, m- and p-hydroxybiphenyl as substrates. 2. Sulphotransferase activity was detectable in all tissues studied, although it showed marked tissue-dependence. The rate of sulphation ranged greater than 100-fold in different tissues and the highest and lowest activities of sulphotransferase were found in liver and brain, respectively. 3. The Km of sulphotransferase was not tissue-dependent but was dependent on the isomer of hydroxybiphenyl. The Km varied over a 500-fold range and the highest and lowest values of Km were found with p-hydroxybiphenyl and m-hydroxybiphenyl, respectively.

Nuclear morphometric measurements in rectal adenocarcinoma cells of patients of different races.

The reasons for the different long-term prognoses of black and white patients following curative resection of a rectal adenocarcinoma are unknown. In order to investigate whether rectal adenocarcinomas in blacks have clinical or pathologic characteristics that are different from rectal adenocarcinomas in whites, 149 patients with potentially curable rectal cancers resected at the University of Chicago Medical Center between 1965 and 1981 were retrospectively analyzed. Clinical records, pathology reports and pertinent slides were reviewed in each case. In 142 cases, enough histologic material was available to perform nuclear photometric measurements and determinations of DNA content by the slide-cytophotometric method. There was no difference between black and white patients in the stage, differentiation degree, morphology and ploidy of the tumors, or in the presence of microinvasion, metastases and mucin production. However, adenocarcinoma cells of black patients had smaller nuclei than did the corresponding nuclei of white patients (54.7 +/- 2.34 sq microns versus 58.9 +/- 1.84 sq microns; P less than .05), and the neoplastic nuclei of black patients were significantly rounder and more regular than the nuclei of white patients (mean roundness factors of 1.1 +/- 0.003 vs. 1.11 +/- 0.005; P less than .05). Although these findings will require confirmation from other large clinical series, they suggest that the different prognoses of black and white patients after curative resection of a rectal adenocarcinoma may be explained by a different tumor behavior intrinsically related to different karyotypic characteristics of the neoplastic cells.