Dopamine D3 receptor deletion increases tissue plasminogen activator (tPA) activity in prefrontal cortex and hippocampus.

Considerable evidence indicates that dopamine (DA) influences tissue plasminogen activator (tPA)-mediated proteolytic processing of the precursor of brain-derived neurotrophic factor (proBDNF) into mature BDNF (mBDNF). However, specific roles in this process for the dopamine D3 receptor (D3R) and the underlying molecular mechanisms are yet to be fully characterized. In the present study, we hypothesized that D3R deletion could influence tPA activity in the prefrontal cortex and hippocampus. Using D3R knockout (D3(-/-)) mice, we show that receptor inactivation is associated with increased tPA expression/activity both in the prefrontal cortex and, to a greater extent, in the hippocampus. Augmented tPA expression in D3(-/-) mice correlated with increased BDNF mRNA levels, plasmin/plasminogen protein ratio and the conversion of proBDNF into mBDNF, as well as enhanced tPA and mBDNF immunoreactivity, as determined by quantitative real time polymerase chain reaction (qRT-PCR), immunoblot and immunohistochemistry. In addition, when compared to wild-type controls, D3(-/-) mice exhibited increased basal activation of the canonical cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-driven Akt/cAMP-response element-binding protein (CREB) signaling cascade, as determined by the increased Akt phosphorylation both at Thr304 and Ser473 residues, of DA and cAMP-regulated protein of 32kDa (DARPP-32) at Thr34 and a phosphorylation state-dependent inhibition of glycogen synthetase kinase-3ß (GSK-3ß) at Ser9, a substrate of Akt whose constitutive function impairs normal CREB transcriptional activity through phosphorylation at its Ser129 residue. Accordingly, CREB phosphorylation at Ser133 was significantly increased in D3(-/-) mice, whereas the GSK-3ß-dependent phosphorylation at Ser129 was diminished. Altogether, our finding reveals that mice lacking D3Rs show enhanced tPA proteolytic activity on BDNF which may involve, at least in part, a potentiated Akt/CREB signaling, possibly due to hindered GSK-3ß activity.

Epidermal growth factor receptor (EGFR) and neuregulin (Neu) activation in human airway epithelial cells exposed to nickel acetate.

Nickel compounds are potential carcinogenic agents that produce a range of biological effects, including inhibition of cell death. Because suppression of apoptosis is thought to contribute to the initiation of carcinogenesis, we investigated the effects of nickel acetate (Ni(2+)) treatment on apoptosis in two different airway epithelial cell lines (A549 and Beas-2B, respectively). Furthermore, since both the epidermal growth factor receptor (EGFR) and neuregulin (Neu) are involved in neoplastic development, mRNAs and expression levels of total and phosphorylated proteins (p-EGFR(Tyr1173) and p-Neu(Tyr1248), respectively) were also measured. We found that exposure of A549 cells to Ni(2+) resulted in significantly reduced cell viability, as well as increased apoptosis and DNA fragmentation at relatively low concentrations (0.1 and 0.5mM) after 24 and 48h. These changes were accompanied by reduced EGFR and Neu mRNAs and proteins, phosphorylated proteins as well as decreased Bcl-2 and increased BAX protein expression. Conversely, Beas-2B cells exposed to equivalent concentrations of Ni(2+) did not show evident signs of apoptosis and DNA damage, hence showing increased expression and phosphorylation of both EGFR and Neu, increased Bcl-2 and reduced BAX expression. Altogether, our finding indicate that Ni(2+) exposure differently affects apoptosis initiation either in non-tumorigenic (Beas-2B) and tumorigenic airway epithelial cells (A549), suggesting a potential involvement of EGFR/Neu receptors.

[Unusual location of peritoneal inclusion cysts]. / Inusuale localizzazione di cisti da inclusione peritoneale.

The peritoneal inclusion cyst is a rare, probably congenital, pathology of the mesothelium that develops on coelomatic residues. A case is reported of an unusual location of peritoneal cyst, in which the increase in volume, associated with the patient's concern and the presumed anatomic site of the lesion led to its removal by the laparoscopic route. The type of location and the relative inaccuracy of preoperative imaging are discussed.

[Complications of cytoreductive surgery associated with intraperitoneal chemohyperthermia: prevention and treatment]. / Complicanze della chirurgia citoriduttiva associata a chemioipertermia intraperitoneale (CIIP) prevenzione e trattamento.

New approach to peritoneal carcinomatosis combining cytoreductive surgery and hypertermic intraperitoneal chemotherapy suggest improved survival when it is possible to achieve a complete cytoreduction. In this study we consider the major complications related to this procedure and purpose our approach for their prevention and treatment.

[Cytoreduction and intraoperative peritoneal chemohyperthermia in carcinomatosis from colonic carcinoma and in peritoneal pseudomyxoma]. / Citoriduzione e chemioipertermia intraoperatoria peritoneale (CIIP) nella carcinosi da carcinoma del colon e nello pseudomixoma peritonei.

New approach in treatment of peritoneal carcinomatosis combining cytoreductive surgery and intraperitoneal chemotherapy suggests improved survival when it is possible to achieve a complete cytoreduction. In this study we consider the carcinomatosis from colorectal and appendiceal adenocarcinoma. In all cases, patients in whom cytoreductive surgery was complete had a median survival much longer compared with patients in whom was not possible and, as perfusion works on minimal residual disease, peritonectomy is the only surgical technique that aim at total removal of parietal and visceral peritoneal lesions.

[Treatment of peritoneal mesothelioma using cytoreduction and intraperitoneal hyperthermic chemotherapy]. / Trattamento del mesotelioma peritoneale mediante citoriduzione e chemioipertermia intraperitoneale (CIIP).

UNLABELLED: Malignant mesothelioma of the peritoneum is a rare tumor for which the therapeutic approach has not yet been standardized. Cytoreductive surgery and hyperthermic antiblastic peritoneal perfusion (HAPP) may be effective in the treatment of this neoplasm. From 1995 to March 2003, we operated 24 patients with malignant peritoneal mesothelioma. Nineteen times we were able to perform radical surgery and HAPP: 6 CC-0, 10 CC-1 and 3 CC-2 (nodules smaller than 1 cm). HAPP was performed by the original "semi-closed" technique, using MMC+ CDDP in 3 patients, CDDP + doxorubicin in 15 patients, only doxorubicin in 1 patient). RESULTS: Operating mortality was 11% and postoperative morbidity was 26%. 4 patients are DOD (40, 20, and 2 at 2 months); 5 patients are AWD (72, 34, 25, and 2 at 15 months); 8 patients are NED (81, 47, 2 at 20 months, 16, 13, 12 months, 1 patient recently operated). The median survival is 40 months. The high rate of morbidity and mortality is due to the presence of postoperative paraneoplastic syndromes, with alterations of coagulation and onset of ARDS. Therefore the good survival results make the methodic one of the best options in the treatment of the disease.

[Treatment of pseudomyxoma peritonei using cytoreduction and intraperitoneal hyperthermic chemotherapy]. / Il trattamento dello pseudomixoma peritonei (PMP) mediante citoriduzione e chemioipertermia intraperitoneale (CIIP).

Pseudomixoma peritonei (PMP) is a rare neoplasia with a low grade of clinical malignity. Generally, the main treatment of this tumor is the surgical debulking. Best results are obtained combining surgery and hyperthermic antiblastic peritoneal perfusion (HAPP) with CDDP and MMC. From April '97 to March 2003, we operated on 132 patients, 8 times with a palliative intent. In 27 times we achieved a complete cytoreduction (17 CC0 and 10 CC1) followed by HAPP. As regards results, no post-operative mortality was reported and 19% of major morbidity was observed. 26 patients are NED at maximum follow-up of 6 years and 1 patient had recurrence 6 months after primary resection. We believe that cytoreduction and HAPP is the golden standard of PMP therapy when it is possible to achieve a complete cytoreduction. Most of the times, the disease is not radically treated and therefore, after diagnosis, patients should be only referred to specialized centers.

[Use of pentaglobin in the treatment of sepsis in the patient undergoing intraperitoneal hyperthermic chemotherapy]. / Utilizzo del pentaglobin nel trattamento della sepsi nel paziente sottoposto a chemioipertermia intraperitoneale (CIIP).

In patients subjected to cytoreduction and hyperthermic antiblastic peritoneal perfusion (HAPP), their immunocompromized conditions claim a very aggressive therapeutic approach in case of periotonitis and sepsis. Therefore, we use an adjuvant therapy of severe bacterial infections additional to antibiotic therapy by using Pentaglobin. It contains human plasma proteins, of which immunoglobulin at least 95%, with high rate of IgG, IgM and IgA, infused intravenously at 12 mL/h for 3 days continuously. From November 2000 to March 2003, we combined this approach for the treatment of peritonitis/sepsis in 11 patients. In 10 patients we obtained a complete control of the infective status in 8 days, while 1 patient died for MOFF. So, even with the exiguity of our casuistry, we obtained a better and more rapid clinical control of the patients respect to the previous period when the Pentaglobin was not used.

Treatment of pseudomyxoma peritonei with two times--cytoreduction and hypertermic antiblastic peritoneal perfusion (HAPP).

Pseudomyxoma peritonei is a rare neoplasia with a low grade of clinical malignity in which neoplastic masses product large amount of mucinous material. Its treatment advocates an aggressive cytoreduction of all visceral and peritoneal lesions and Hyperthermic Antiblastic Peritoneal Perfusion (HAPP). In three cases we programmed a two stage surgical approach for the massive amount of peritoneal implants. Two times we achieved our aim, while one time, the wide progression of the disease during the two surgical procedures made useless our efforts to have a complete cytoreduction and the following HAPP. This last patient refused systemic chemotherapy between the two surgeries and we think that this should be one of the reasons of the failure.

An Italian Multicentric Phase II study on peritonectomy and intra peritoneal hyperthermic perfusion (IPHP) to treat patients with peritoneal mesothelioma.

Peritoneal mesothelioma (PM) is a rare disease, with a poor prognosis. We decided to prospectively evaluate the prognostic impact and the morbimortality of cytoreductive surgery combined with intraperitoneal hyperthermic perfusion in the treatment of this clinical entity. Sixty one patients with PM (31 males and 30 females) were enrolled onto a Phase II multicentric clinical trial. The mean age was 51 years (range: 24-72). CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C or cisplatin and doxorubicin for 60/90 minutes under hyperthermic conditions (42.5 degrees C). One patient was operated on twice because of disease recurrence. Mean follow-up was 20 months (range: 0.1-76). Forty six (74%) patients were optimally cytoreduced. Five-year overall and 5 yr progression-free survivals were 54% and 37%, respectively. Completeness of cytoreduction was significantly associated with outcome. Twenty Grade III complications occurred in 14 (23%) patients and the most frequent one was digestive fistula/perforation (11%). No treatment-related mortality was recorded. CRS + IPHP was proven to be acceptable in terms of morbidity and mortality in patients with PM and suggest a positive impact on outcome. Further prospective controlled studies are warranted to confirm these results.

[Cytoreductive surgery and intraperitoneal hyperthermic-antiblastic therapy (HAPP) in peritoneal carcinomatosis]. / Chirurgia citoriduttiva e chemioipertermia intraperitoneale (CIIP) nel trattamento delle carcinosi peritoneali.

Peritoneal carcinosis often occurs during the evolution of many neoplasias either abdominal or extra-abdominal. The free time survival of the patients affected by carcinosis is poor (about 6 months) as regards gastric and colorectal cancer. In the last ten-year period a combined surgical technique aiming at the total removal of parietal and visceral peritoneal lesions (peritonectomy) and at the perfusion of peritoneal cavity with chemo-drugs in hyper-thermia had developed. This method is based on the presence of the peritoneal-plasmatic barrier that holds back high molecular weight drugs, keeping from passing at the systemic circulation; in this way it is possible to use higher and more concentrate chemo-drug doses in a very limited area than in the systemic chemotherapy. The association between chemotherapy and hyperthermia produces a synergic effect: hyperthermia, infarct, makes chemo-drugs more effective and selective, improving their capability of penetration in tumoral masses; heat has furthermore an intrinsic anti-neoplastic action, being altered the reparation mechanisms of the tumoral cells. A WEB research on Medline site has been conducted choosing especially those articles referable at the 1999-2000 period. The selected articles have been briefly analysed in the "Clinical experience" section. Authors' experiences have been divided, as far as possible, on the basis of the tumors treatable with cytoreduction and HAPP: 1) Colon-rectal Cancer; 2) Pseudomyxoma peritonei/Appendicular Adenocarcinoma; 3) Gastric Cancer; 4) Ovarian Cancer; 5) Peritoneal Mesothelioma. The determinant variables in the analysis of the results are basically three: 1) Selection of the patients, 2) Characteristics of the surgical operation, 3) Characteristics of the HAPP. Colon-rectal carcinoma: the survival time of the recurrent disease, obtained by some authors like P.H. Sugarbaker, is surely remarkable (50% at 5 years in the patients where a complete cytoreduction was possible to perform), but the result obtained in patients affected by peritoneal carcinosis, subjected to this technique at the first clinical presentation (100% at 5 years) is much more interesting. For this type of neoplasia, it is important to underline that not all the authors report the same results, with a median survival time lower than that of the American author. Pseudomyxoma peritonei: about this rare neoplasia, the "golden standard" treatment consists on cytoreduction of all visceral and peritoneal macroscopical lesions, with a homogeneous distribution of the data obtained by most authors: median survival time included among 70% and 90% at 5 years. Gastric cancer: there is a considerable difference between the data of Japanese authors and others. In the treatment of peritoneal carcinosis the results are, on average, rather poor; better results have been obtained using this technique as an adjuvant presidium for the prevention of the onset of peritoneal carcinosis. Ovarian cancer: the results about the recurrent ovarian cancer are good; in the future, it will be useful to start a phase III study to render effective the use of this technique in the ovarian cancer at the beginning of its clinical story. Peritoneal mesothelioma: till now, a standardized alternative, approaching this neoplasia, does not exist; the results are encouraging, with good median and free time survival.

Composition of Ragusano cheese during aging.

Ragusano cheese is a brine-salted pasta filata cheese. Composition changes during 12 mo of aging were determined. Historically, Ragusano cheese has been aged in caves at 14 to 16 degrees C with about 80 to 90% relative humidity. Cheeses (n = 132) included in our study of block-to-block variation were produced by 20 farmhouse cheese makers in the Hyblean plain region of the Province of Ragusa in Sicily. Mean initial cheese block weight was about 14 kg. The freshly formed blocks of cheese before brine salting contained about 45.35% moisture, 25.3% protein, and 25.4% fat, with a pH of 5.25. As result of the brining and aging process, a natural rind forms. After 12 mo of aging, the cheese contained about 33.6% moisture, 29.2% protein, 30.0% fat, and 4.4% salt with a pH of 5.54, but block-to-block variation was large. Both soluble nitrogen content and free fatty acid (FFA) content increased with age. The pH 4.6 acetate buffer and 12% TCA-soluble nitrogen as a percentage of total nitrogen were 16 and 10.7%, respectively, whereas the FFA content was about 643 mg/100 g of cheese at 180 d. Five blocks of cheese were selected at 180 d for a study of variation within block. Composition variation within block was large; the center had higher moisture and lower salt in moisture content than did the outside. Composition variation within blocks favored more proteolysis and softer texture in the center.

Assessment of the dairy production needs of cattle owners in southeastern Sicily.

This study was undertaken to investigate research and outreach priorities for Progetto Ibleo (Project Ibleo), a center created in 1990 with tripartite government funding to serve dairy producers in the Hyblean region of Sicily. Data comprised values for production and composition of milk from 1984 to 1989 from 35 herds of Modicana cows on a system based on pasture and that from 69 input-intensive herds of Holstein cows, associated lactation and reproduction measures, and yield and composition of forages from 4 of these farms in 1988. Season had a large effect on the neutral detergent fiber and crude protein composition of forages, production and composition of milk, and predicted yield of fresh Ragusano cheese manufactured from the milk of these cows. The poorest forage quality and the poorest cow performance were observed in summer and fall months (May to October). Lactation curves that were flat, without a discernible peak, or convex were observed for both systems, especially for cows calving in spring and in the dry summer seasons (March to July). These abnormalities, signifying substantial sacrifices in production potential, probably had a complex etiology that stemmed from low nutrient intake and high neutral detergent fiber and low crude protein composition of the grazed and preserved forages. Research and outreach priorities to support the Hyblean dairy industry should include chemical evaluation of forages and other feedstuffs, low moisture ensiling of high quality winter forages, better formulation of diets that are dense with nutrients, and the shifting of calving patterns to better exploit high quality winter forages.

Thiothixene induced edema.

The case described is of a woman who developed marked leg edema during thiothixene administration, and other cases of neuroleptic induced edema are reviewed. Possible mechanisms for the edema formation and clinical implications are discussed.