Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system.

In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), has potent anti-proliferative/immunomodulatory effects on various tissues. Consistently, the enzyme that catalyzes the synthesis of 1,25(OH)(2)D(3), 1alpha-hydroxylase (1alpha-OHase) and the vitamin D receptor have a widespread tissue distribution. Among site-specific functions, the hormone has been suggested to be involved in uterine physiology. However, molecular analysis of the vitamin D system in normal endometrium throughout the menstrual cycle as well as its regulation in the context of endometrial physiological and pathological events have received very limited attention. Thus, we have studied expression, localization and regulation of 1alpha-OHase in human cycling and early pregnant endometrium. The capacity for 1alpha-hydroxylation and the presence of vitamin D receptor in endometrial cells have also been evaluated. The functional significance of these findings has been tested by evaluating gene expression of the catabolic enzyme, vitamin D 24-hydroxylase, and of the adhesion protein, osteopontin. Finally, to verify any potential dysfunction of the vitamin D system in endometriosis, a reproductive disease characterized by immune-mediated anomalies, we have analyzed expression of 1alpha-OHase in both eutopic and ectopic endometrium of affected patients. Results obtained showed that the active form of the 1alpha-OHase gene was expressed in human endometrial stromal cells independent of the cycle phase but with a significant increase in early pregnant decidua. A similar profile was observed for the protein, which was abundantly expressed in the cytoplasm of both endometrial stroma and epithelial glands. Both cycling and early pregnant endometrial cells also expressed the vitamin D receptor. In the same cells, 1alpha-OHase mRNA levels were significantly stimulated by the pro-inflammatory cytokine interleukin (IL)-1beta (50 and 500 pg/ml) while addition of the active form of the hormone could modulate both CYP24 and osteopontin gene expression. The 1alpha-OHase gene was also expressed in ectopic endometrium and its levels were increased in proliferative phase cultures derived from patients with endometriosis. Human cycling endometrium may be included among the extrarenal sites able to synthesize vitamin D. The IL-1beta-mediated induction of 1alpha-OHase gene and the hormonal modulation of osteopontin support a role for the hormone in the immunological mechanisms underlying uterine function. Abnormalities of this system are present in endometriosis.

Human decidual natural killer cells as a source and target of macrophage migration inhibitory factor.

The human uterine mucosa of early pregnancy is largely populated by CD56(bright) natural killer (NK) cells (uterine (u) NK cells). The specific functions of these cells are still unknown, but their interaction and response to foetal trophoblasts are thought to be important for the establishment of a successful pregnancy. The study reported herein shows that uNK cells respond to, and produce, macrophage migration inhibitory factor (MIF), a cytokine highly expressed in the human placenta and in the cyclic and pregnant endometrium. Recombinant human MIF reduced in a dose-dependent manner the cytolytic activity of purified uNK cells against K562 cells. RT-PCR, Western blot analysis and ELISA demonstrated the synthesis and secretion of the cytokine by uNK cells. Double immunofluorescence staining showed the presence of MIF in uterine CD56 + cells. Finally, neutralization of the endogenous cytokine by a polyclonal antibody resulted in a sharp increase in the cytolytic activity of uNK cells. These findings indicate the existence of a previously unrevealed paracrine and autocrine action of MIF on uNK cells and support its contribution to the immune privilege at the maternal-foetal interface.

Gastrointestinal surgical emergencies in patients treated for hemathological malignancies.

BACKGROUND: Upper and lower gastrointestinal symptoms are major and serious complications in patients who undergo chemotherapy for hematological malignancies. Their most frequent causes are acute intestinal graft-versus-host disease (GVHD) after bone marrow transplant, infections, toxicity or preexisting gastrointestinal diseases. Mortality can reach 30-60% of cases. PATIENTS AND METHODS: We report 15 cases operated on for abdominal emergencies: 3 severe gastrointestinal bleeding and 12 acute abdomen. RESULTS: We performed 10 bowel resections, one cholecystectomy, one splenectomy, two laparotomy with pancreatic debridement and peritoneal lavage, and one suture of perforated peptic ulcer. Operative mortality was 33.3% (5/15). Deaths have been reported only in the group of patients with acute abdomen. In all cases death was correlated to generalized sepsis related to immunosuppression. CONCLUSIONS: We believe that an aggressive approach, consisting of close monitoring and early laparotomy combined with vigorous supportive therapy, should be used when dealing with suspected gastrointestinal complications in patients with hematological malignancies.

Results of emergency surgery in patients with Moschowitz's disease refractory to hematological treatment: is splenectomy always advisable?

BACKGROUND: Patients with thrombotic thrombocytopenic purpura (TTP), Moschowitz's disease, run a high risk of perioperative bleeding and need intensive hematologic support. In some patients, TTP is associated with cancer but the surgical role in these patients is still unclear. To illustrate the surgical problems and outcome we present the case histories of three patients with TTP observed in our emergency department. MATERIALS AND METHODS: Two patients had TTP secondary to cancer and one patient with primary TTP (no evidence of neoplasia) had emergency operation for gastric hemorrhage, occlusion and TTP unresponsive to plasmapheresis. RESULTS: The first two patients who had not radical resection of cancer and no splenectomy, died for TTP complications. The third patient who underwent emergency splenectomy, had an uneventful postoperative course and TTP completely regressed. CONCLUSIONS: These case reports suggest that patients with TTP should be screened to rule out cancer. In patients with acute cancer-related complications emergency surgery should aim to resect the cancer. An associated splenectomy may increase the effectiveness of postoperative hematologic therapy.

[Surgical management of pancreatic endocrine tumors in patients with MEN 1 syndrome. Considerations on one case observed]. / Problematiche chirurgiche nel trattamento delle neoplasie pancreatiche nel paziente affetto da MEN 1. Considerazioni su un caso osservato.

INTRODUCTION: Particular problems in MEN 1 syndrome come from the morphological identification of pancreatic tumors because of their are often small [<1 cm] and multiple [89% of the cases]. However intraoperatively it could be difficult to identify with palpation the tumors described by preoperative investigations and to decide the most suitable surgical treatment. The authors describe one case recently observed to underline and update the correct management. CASE REPORT: A 34 year old woman was admitted for the surgical treatment of an insulinoma. Polimenorrea, hypercalcemia and familiarity for MEN 1 syndrome were also present. A CT scan showed the tumors in the body and tail of the pancreas [diameter 0.5-1 cm]. MRI described only a small mass in pancreatic head. A calcium angiography was positive for insulin secretion after calcium infusion in hepatic and gastroduodenal artery, and for glucagon secretion after infusion in splenic artery. An intraoperative ultrasonography discovered three nodules that were enucleated. They were one insulinoma and two glucagonomas respectively. After enucleation glycemia became immediately normal. CONCLUSION: To avoid wide surgical resections [es. left pancreatectomy] we suggest a conservative treatment [multiple enucletion with or without a pancreatic-jejunum side-to-side anastomosis] with a meticulous preoperative and intraoperative evaluation of all pancreatic nodules.

Stochastic resonance between dissipative structures in a bistable noise-sustained dynamics.

We study an extended system that without noise shows a monostable dynamics, but when submitted to an adequate multiplicative noise, an effective bistable dynamics arises. The stochastic resonance between the attractors of the noise-sustained dynamics is investigated theoretically in terms of a two-state approximation. The knowledge of the exact nonequilibrium potential allows us to obtain the output signal-to-noise ratio. Its maximum is predicted in the symmetric case for which both attractors have the same nonequilibrium potential value.

Systematic radical gastrectomy and D2 lymphadenectomy in primary gastric B cell lymphoma: impact on diagnosis, classification and long term results. A prospective study.

The role of surgery in the treatment of primary gastric lymphoma has been recently re-evaluated. We report the results of a series of 37 operated patients for primary gastric lymphoma (PGL). All patients underwent gastrectomy with D2 lymphadenectony and bilateral liver biopsies. Postoperative histopathological classification was compared to preoperative staging data. No mortality and low morbidity were observed in this series of patients. We found a high incidence of mixed grading of tumors and a relatively high incidence of lymph node metastases in low grade lymphoma. Relying on preoperative biopsies and imaging techniques could lead to preoperative staging inaccuracy and therefore to inappropriate treatment planning. For these reasons we advocate systematic primary surgery in PGL. Surgery could be useful for staging purposes and seems to be curative in stage IE.

Maternal-conceptus cross talk--a review.

The implantation process requires a functionally normal conceptus and a receptive endometrium, but also a communication link between them. This paracrine dialogue involves not only gonadal steroids but also a variety of other biologic molecules secreted by the conceptus and the reproductive tissues themselves in a communicative, interconnected network. The factors facilitating this dialogue includes chemokines, cytokines, adhesion molecules, growth factors. Recently, the soluble form of HLA-G and the vitamin D system have also been proposed as components of this cross-talk. Inherent among the factors involved is the fact that their effects are redundant and pleiotropic. Normal implantation and placentation are critical for a successful pregnancy. Therefore, a better understanding of the molecular mechanisms responsible for these processes will lead to the development of new regulating agents with novel diagnostic, biological and therapeutic potential for both facilitating and hindering a normal reproductive function.

Limit cycle induced by multiplicative noise in a system of coupled Brownian motors.

We study a model consisting of N nonlinear oscillators with global periodic coupling, and local multiplicative and additive noises. The model was shown to undergo a nonequilibrium phase transition towards a broken-symmetry phase exhibiting noise-induced "ratchet" behavior. A previous study [H. S. Wio, S. Mangioni, and R. Deza, Physica D 168-169, 184 (2002)] focused on the relationship between the character of the hysteresis loop, the number of "homogeneous" mean-field solutions, and the shape of the stationary mean-field probability distribution function. Here, we show-as suggested by the absence of stable solutions when the load force is beyond a critical value-the existence of a limit cycle induced by both multiplicative noise and global periodic coupling.

Different basic fibroblast growth factor and fibroblast growth factor-antisense expression in eutopic endometrial stromal cells derived from women with and without endometriosis.

In all species studied, the basic fibroblast growth factor (bFGF) gene is transcribed into multiple mRNAs, one of which is an antisense RNA (1B FGF-AS) probably involved in regulating the stability of the sense transcript. In this study we investigated whether the regulatory mechanisms of bFGF expression might be altered in endometrial stromal cells derived from women with endometriosis. bFGF and 1B FGF-AS mRNA levels were quantified in primary cultures of eutopic endometrial stromal cells derived from 29 women without endometriosis and 24 patients affected by the disease. When the data were analyzed according to the phase of the menstrual cycle, endometrial stromal cells derived from patients in the late proliferative phase showed significantly higher bFGF mRNA values and significantly lower 1B FGF-AS mRNA levels compared with control samples. Furthermore, the mean bFGF/1B FGF-AS mRNA ratio was significantly higher in endometrial stromal cells derived from patients compared with that in controls (mean +/- SEM, 2.31 +/- 0,55 and 0.77 +/- 0.14, respectively; P = 0.009). Moreover, for bFGF expression the differences existing at the mRNA level were maintained at the protein level. These findings support the hypothesis that 1B FGF-AS mRNA could regulate the expression of the sense transcript and suggest that in endometrial cells derived from patients, the presence of higher bFGF levels could improve their ability to proliferate at the ectopic site.

Functional results of a personal technique of reconstruction after pancreaticoduodenectomy.

The aim of the study is to propose a new technique of reconstruction after pancreaticoduodenectomy with more attention to the functional aspects. From 1995 and 2003, 25 patients underwent pancreaticoduodenectomy for pancreatic or periampullary cancer. The reconstruction was carried out by: end-to-end gastro-jejunal anastomosis (first jejunal loop); a Roux-en-Y T-T pancreatico-jejunal anastomosis leaving a silastic catheter in the Wirsung; hepatico-jejunostomy and jejuno-jejunostomy below the biliary anastomosis; superselective vagotomy. Mortality was 8%. Regarding the complications, we observed 3 biliary fistulas, mean duration 5 days, with spontaneous healing; 8 pleural effusions and 7 wound infections. Postoperative 3 months reevaluation showed weight gain in 14 patients with no other digestive symptoms (vomiting, fullness, dumping). With a scintigraphic meal we observed a good rythmic and regular gastric emptying. No jejunal peptic ulcers were noted in all patients after the gastric protonic pump inhibitors were discontinued. Fecal fats were evaluated in all cases for malabsorption 3 months after operation with low fat fecal levels. The preliminary results of our recent experience seem to be encouraging. This technique may have a useful application in the clinical setting as far as radicality and quality of life of the patients with pancreaticoduodenectomy.

Coupling-reentrant phase transition, complex hysteretic behavior, and efficiency optimization in coupled phase oscillators submitted to colored flashing potentials.

A recent mean-field analysis of a model consisting of N nonlinear phase oscillators-under the joint influence of global periodic coupling with strength K0 and of local multiplicative and additive noises-has shown a nonequilibrium phase transition towards a broken-symmetry phase exhibiting noise-induced transport, or "ratchet" behavior. In a previous paper we focused on the relationship between the character of the (mean velocity vs load force F) hysteresis loop, the number of "homogeneous" mean-field solutions, and the shape of the stationary mean-field probability distribution function (PDF). Here we assume that the multiplicative noises of the model are Ornstein-Uhlenbeck with common strength Q and self-correlation time tau. By resorting to an effective Markovian approximation, we study the tau dependence of the phase boundary, and that of the line signaling the transition from the "interaction-driven regime" to the "noise-driven regime." We also study-for selected representative points of the K0 vs Q phase diagram-the tau dependence of the transport properties induced by coupling and colored multiplicative noise (including the efficiency epsilon of the mechanical rectification process) and that of the above-mentioned PDF.

Transition from anomalous to normal hysteresis in a system of coupled Brownian motors: a mean-field approach.

We address a recently introduced model describing a system of periodically coupled nonlinear phase oscillators submitted to multiplicative white noises, wherein a ratchetlike transport mechanism arises through a symmetry-breaking noise-induced nonequilibrium phase transition. Numerical simulations of this system reveal amazing novel features such as negative zero-bias conductance and anomalous hysteresis, explained by performing a strong-coupling analysis in the thermodynamic limit. Using an explicit mean-field approximation, we explore the whole ordered phase finding a transition from anomalous to normal hysteresis inside this phase, estimating its locus, and identifying (within this scheme) a mechanism whereby it takes place.

Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Study Group.

The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9;22) and t(4;11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12;21)(p13;q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12;21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12;21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre-B immunophenotype. Among the B-lineage subgroup, the t(12;21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (> or = 1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index > or = 1.16 < 1.6). Our findings reinforce the need to include the molecular screening of the t(12;21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

Long-term persistence of hemopoietic chimerism following sex-mismatched bone marrow transplantation.

Fifty-eight samples of bone marrow (31), whole peripheral blood (8) and separated fractions of circulating mononuclear (11) and polymorphonuclear (8) cells from 18 male patients, transplanted for hematological diseases from related (14) or unrelated (4) female donors were analyzed for chimerism at subsequent intervals (range, 1-72 months) following bone marrow transplantation, by means of PCR amplification of the Y-chromosome-specific DYS14 sequence, revealed by a radiolabelled hybridization probe (dot blot technique, 0.01% sensitivity). Detection of male cells was positive in all but two of 52 samples collected within the third year after transplantation and negative in six samples collected from three patients after the third year. In the first year after transplantation, mixed chimerism was found in all patients, apparently with no correlation with graft-versus-host disease. Comparable results were found in fractions of mononuclear and polymorphonuclear cells, when analyzed separately. The persistence of very low levels of recipient cells in patients in continuous complete remission until the third year after transplantation, suggests the persistence of normal host hemopoiesis for a long period of time after the so-called myeloablative regimen. The progressive negativization, occurring in our patients between the second and the fourth year after transplantation, could signify the disappearance of residual host hemopoiesis or its decrease to below the detection level of this highly sensitive method.