Analysis of CDKN1A polymorphisms: markers of cancer susceptibility?

The CDKN1A (TP21) gene encodes a 21-kD protein that is a critical downstream mediator of wild-type TP53 and an important regulator of the cell cycle. Failure in the function of this gene would be expected to result in abnormal cell proliferation and transformation. Tumor-associated mutations of the coding region of the TP21 are rare. On the other hand, some TP21 polymorphisms have been identified and characterized by single base substitutions. In the present study, we investigated the potential role of TP21 gene polymorphisms in skin, head, and neck tumorigenesis. A total of 261 samples were examined by polymerase chain reaction single-strand conformational analysis, and one mutation at codon 31 and four polymorphisms in exons 2 (codon 55) and 3 [nucleotide (nt)590] and in promoter region (nt2298) were identified. In conclusion, this investigation confirmed the rarity of mutations in this gene, arguing against a role for TP21 mutations in skin, head, and neck cancers. Also, our results show significant differences in nt2298 allele frequencies between normal individuals and skin malignant tumors (P < 0.05). The results suggest that this polymorphism affects TP21 transactivator binding and may be important during the pathogenesis of skin cancer.     

Segmental jejunal lipomatosis--a rare cause of intestinal obstruction

A rare case of a segmental small intestinal (jejunal) lipomatosis is described. A 33-year-old male was admitted with a clinical diagnosis of an acute intestinal obstruction. A plain erect abdominal x-ray showed multiple air-fluid levels. On an exploratory laparotomy, a jejunojejunal intussusception was found secondary to a segmental submucosal lipomatosis. This was treated by a segmental resection and anastomosis, which resulted in a complete cure. Here we present this case with a review of the relevant literature.     

Structural and functional analysis of a new desmin variant causing desmin‐related myopathy

Desmin‐related myopathy is a familial or sporadic disease characterized by skeletal muscle weakness and cardiomyopathy as well as the presence of intracytoplasmic aggregates of desmin‐reactive material in the muscle cells. Previously, two kinds of deletions and eight missense mutations have been identified in the desmin gene and proven to be responsible for the disorder. The present study was conducted to determine structural and functional defects in a pathogenic desmin variant that caused a disabling disorder in an isolated case presenting with distal and proximal limb muscle weakness and cardiomyopathy. We identified a novel heterozygous Q389P desmin mutation located at the C‐terminal part of the rod domain as the causative mutation in this case. Transfection of desmin cDNA containing the patient’s mutation into C2.7, MCF7, and SW13 cells demonstrated that the Q389P mutant is incapable of constructing a functional intermediate filament network and has a dominant negative effect on filament formation. We conclude that Q389P mutation is the molecular event leading to the development of desmin‐related myopathy. Hum Mutat 18:388–396, 2001. © 2001 Wiley‐Liss, Inc.     

NMR studies on energy metabolism of immobilized primary neurons and astrocytes during hypoxia, ischemia and hypoglycemia

Changes in high-energy phosphate metabolites (ATP and phosphocreatine) were monitored, in real time, by 31P-nuclear magnetic resonance in primary cell cultures of neurons and astrocytes during periods of hypoxia, ischemia and hypoglycemia, and also during the recovery periods following the re-establishment of standard conditions. Cells were immobilized in basement membrane gel threads and perfused with oxygen-depleted medium (oxygen concentration below 30 microM), to create hypoxic conditions, or with aerobic medium (oxygen concentration approximately 460 microM) containing different concentrations of glucose (hypoglycemia). Ischemic conditions were imposed by stopping perfusion for different periods of time (15 min to 2 h). The experimental set-up enabled the acquisition of 31P-spectra with high signal-to-noise ratio within 10-20 min for both cell types. The effect of hypoxia on glucose metabolism was assessed by 13C-NMR using [1-13C]glucose as substrate. The levels of ATP and PCr in astrocytes were unaffected during hypoxia (up to 2 h), but decreased notably under ischemia. In neurons, hypoxic periods caused a sharp drop of the ATP and PCr levels, and considerable damage to the capacity of neurons to replenish the ATP and PCr pools upon returning to normoxic conditions. However, neurons were remarkably less sensitive to ischemic conditions, the ATP and PCr pools being restored quickly, even after 2 h under challenging conditions. The data show that neurons were more resistant to ischemia than astrocytes, and suggest that the capacity to sustain the pools of ATP and PCr was part of the neuronal protective strategy.     

Anatomy of spontaneous splenorenal and gastrorenal venous anastomoses: Review of the literature

Summary Portal hypertension is characterised by the development of a collateral portocaval circulation. Among these venous reroutings, some are situated posteriorly in the left subphrenic compartment. These are the spontaneous splenorenal and gastrorenal anastomoses. Their incidence is estimated at around 16%. On the one hand, there are the direct shunts, which anastomose the spelling v. to the left renal v., of an anecdotal nature, and on the other the spontaneous indirect splenorenal shunts, characterised by the presence of a complete neurovascular pedicle traversing the gastrophrenic ligament. This relates to the gastric collateral v., which is connected to the left renal v. via the inferior v. of the left crus of the diaphragm and the middle capsular v., hence the name gastro-phreno-capsulorenal shunt. At an advanced stage of portal hypertension these splenorenal shunts may acquire a major caliber and behave like actual surgical shunts.

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Anatomie des anastomoses veineuses spléno-rénale et gastro-rénales spontanées: revue de la littérature

Résumé L'hypertension portale se caractérise par le développement d'une circulation collatérale porto-cave. Parmi ces dérivations veineuses, certaines ont une topographie postérieure, localisée dans la loge sous-phrénique gauche. Ce sont les anastomoses spontanées splénorénales et gastro-rénales. Leur prévalence est estimée aux alentours de 16%. On distingue, d'une part, les shunts directs, qui anastomosent la v. splénique à la v. rénale gauche, de constatation anecdotique, non systématisés sur le plan anatomique ; d'autre part, les shunts splénorénaux spontanés indirects caractérisés par l'existence d'un pédicule complet vasculo-nerveux, cheminant dans le ligament gastro-phrénique. Il s'agit de la v. collatérale gastrique qui est reliée à la v. rénale gauche par l'intermédiaire de la v. inférieure du pilier gauche du diaphragme et de la v. capsulaire moyenne, d'où le nom de shunt gastro-phrénocapsulo-rénal. A un stade avancé de l'hypertension portale, ces shunts splénorénaux peuvent acquérir un calibre important et se comporter alors comme de véritables shunts chirurgicaux.

     

Lipoperoxidation products and thiol antioxidants in chromium exposed workers

Hexavalent chromium is an established carcinogenic agent, which is not directly reactive with DNA. Its genotoxicity involves a reduction step, producing reactive oxygen species and radicals, and also lower valence forms which form stable complexes with intracellular macromolecules. The trivalent form of chromium may directly react with the genetic material and has also been shown to generate oxidative damage in vitro. To further evaluate the importance of in vivo oxidative DNA damage in the toxicity of each valence form, we conducted a comparative study on hexavalent and trivalent chromium-exposed workers (manual metal arc stainless steel welders and leather tanning workers), focusing on the total oxidative status by quantifying the level of lipoperoxidation products in urine. Thiol antioxidants are important in response to oxidative stress, and therefore, the concentration of glutathione and cysteine in peripheral blood lymphocytes was also determined. Chromium exposure was evaluated by quantifying total chromium in plasma and urine. Both groups had a significant increase in lipid peroxidation products expressed as malondialdehyde (MDA) in urine (tanners 1.42 +/- 0.61 micromol/g creatinine, welders 1.67 +/- 1.13 micromol/g creatinine versus controls 0.81 +/- 0.26 micromol/g creatinine, P < 0.005 in both cases) but only welders had a significant decrease in glutathione concentration in lymphocytes. There was a positive correlation between chromium in plasma and urinary MDA in welders, but not in tanners. This work is part of a larger study of which major results have been published previously including cytogenetics and DNA-protein cross-links in workers exposed to the two different forms of chromium. These results are compared with the results of oxidative damage from this study.     

Pulmonary and mediastinal "sarcoidosis" following surgical resection of cancer

Previous reports indicate that enlarged hilar and mediastinal lymph nodes caused by sarcoid-like reactions may develop after curative resection of cancer, and their presence does not necessarily denote neoplastic recurrence. Reports further suggest that coexisting pulmonary infiltrates in this setting may be related to sarcoidosis. In this study, we describe two patients who had resected lung and gastric cancer and who later developed pulmonary interstitial infiltrate, concurrent with progressive mediastinal lymphadenopathy initially thought to be caused by intrathoracic dissemination of their cancer. These changes were shown by open lung biopsy to be a benign, granulomatous reaction interpreted as sarcoidosis. Thus, it is important to recognize this clinical pattern when pulmonary infiltrates develop after complete treatment of cancer in an otherwise relapse-free patient and to encourage lung or lymph node biopsy in these particular settings in order to confirm a sarcoid-like reaction, thereby avoiding unnecessary chemotherapy for presumed tumor recurrence.     

Seasonal malaria transmission and variation of anopheline density in two distinct endemic areas in Brazilian Amazonia

Studies on seasonal anopheline fauna variation were performed in two distinct settlements in the State of Rond?nia, Brazil: one at the Madeira River banks (Portuchuelo) with stable native Amazonian population; the other at an inland lumber-extracting farm (Urupá) in dry land, in which adults are mostly migrants. During a 6-yr period (1994-2000), 8,638 adult anophelines were collected: 2,684 in Urupá and 5,954 in Portuchuelo. Anopheles darlingi represented >95% of total mosquitoes caught. Dissection of 4,424 A. darlingi females yielded a very low sporozoite infection index below 0.1%. Oocysts were found in both localities in approximately 0.1% of dissected mosquitoes. Determination of the hour biting rates disclosed seasonal variations in both localities. However, in Portuchuelo, mosquito density peaked at the acme of the rainy season, whereas at Urupá it peaked in the dry season. The increase in mosquito density and incidence of malaria cases were coincident. The high mosquito densities observed in the riverine settlement of Portochuelo sector B, which permits evaluation in > 10,000 mosquitoes' bites/person/year, could explain, in spite of the low mosquito's infection index, the previously described development of natural immunity in the local population that is not observed in the dry land agroindustrial settlement of Urupá.     

Induction of an adaptive response to quercetin, mitomycin C and hydrogen peroxide by low doses of quercetin in V79 Chinese hamster cells

The adaptive response is a phenomenon by which cells exposedto low, non-cytotoxic doses of a genotoxicant become significantlyresistant to a subsequent higher dose of the same or anothergenotoxic agent. Induction of the adaptive response has beenmainly studied using ionizing radiation and alkylating agentsas genotoxic agents. However, other mutagenic agents may warrantfurther study, since the adaptive response as a whole may bean important general biological mechanism to maintain geneticintegrity and thus could prevent carcinogenic initiation ofcells. The exposure to mutagenic agents present, or formed,in the diet is considered an important factor in the etiologyof human tumors and a considerable number of these agents havenot yet been identified or characterized. Flavonoids are a largegroup of polyphenolic quinoids found in a wide variety of ediblefruits and vegetables and a few, such as quercetin, presentgenotoxic activity in vitro. The mechanisms of mutagenicityof quercetin involve the production of oxygen radicals throughan autoxidation process dependent on pH value and the presenceof oxygen. Although there are few doubts regarding the mutagenicityof quercetin invitro, carcinogenicity of this flavonoid is stillcontroversial. In view of these conflicting results and theradiomimetic nature of the mutagenicity of flavonoids, we addressedthe question of cell exposure to quercetin at the low levelspresent in the diet leading to adaptation to further exposureto mutagens or carcinogens. The work reported here concernsinduction of an adaptive response by low doses of quercetinto challenging doses of quercetin and other compounds, namelyhydrogen peroxide and mitomycin C, using induction of chromosomalaberrations in V79 cells as the end point. ⁴To whom correspondence should be addressed: Tel: +351 1 3610290; Fax: +351 1 3622018; Email: jose.rueff{at}gene.unl.mailpac.pt