Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene.

Recent studies show that 1) the p53 tumor suppressor protein is overexpressed by rheumatoid arthritis (RA) synovium and fibroblast-like synoviocytes (FLS) and 2) somatic mutations previously identified in human tumors are present in RA synovium and FLS. We have hypothesized that abnormalities in p53 can contribute to chronic destructive RA synovitis. To understand the functional consequences of p53 abnormalities in FLS, RA and normal FLS expressing wild-type p53 were transduced with a retroviral vector encoding the human papilloma virus 18 E6 gene, which inactivates endogenous p53 protein. Three RA and one normal FLS lines were infected with recombinant retrovirus encoding the neomycin resistance gene (neo) or E6+neo. FLS proliferation, apoptosis, and invasion was studied in E6, neo, and uninfected parental strains (PS). The growth rate for E6 was significantly increased with a sixfold increase in cell number after 7 days compared with a twofold to threefold increase in neo and PS. When FLS were treated with cytokines, proliferative response of E6, neo, and PS to interleukin-1 and transforming growth factor-beta were similar. However, response to platelet-derived growth factor was significantly greater in E6 FLS compared with neo or PS. Apoptosis was studied by incubating FLS with sodium nitroprusside as a source of nitric oxide or hydrogen peroxide for 8 hours and examining DNA fragmentation and E6 cells were significantly less susceptible to cell death. In addition, E6 FLS were more invasive into cartilage extracts than neo or PS using an in vitro cell invasion assay. These data suggest that p53 is a critical regulator of FLS proliferation, apoptosis, and invasiveness. Abnormalities of p53 function might contribute to synovial lining expansion and joint destruction in RA.     

Endothelium-independent Vasoconstricting and Vasodilating Actions of Halothane on Rat Mesenteric Resistance Blood Vessels

Background: Whether volatile anesthetics produce changes in vascular resistance and blood flow because of direct effects on vascular tissue is unclear. Direct vasoconstricting and vasodilating actions have been demonstrated in isolated conductance arteries in vitro, but there is little information regarding direct effects on the small vessels that mediate resistance and flow changes in vivo.

Methods: We investigated the actions of halothane on 50-200 micro Meter branches of the rat mesenteric artery that were cannulated and studied in vitro. The vessels were pressurized to 60 mmHg, and vascular dimensions were continuously monitored using a computer-based real-time image analysis system. The vessel bath was perfused with HCO3 -buffered saline (37 degrees Celsius) equilibrated with 95% Oxygen2 /5% CO2 (plus/minus halothane). The vascular endothelium was mechanically removed before cannulation in some vessels.

Results: In unstimulated vessels, halothane had a concentration-dependent vasoconstricting action (EC50 = 0.45 mM = 1.5 vol% at 37 degrees Celsius) that was largely transient and was similar to that produced by caffeine. Both halothane and caffeine constrictions were unaffected by bath [Calcium2+], nifedipine (1 micro Meter) or Cadmium2+ (100 micro Meter) and were abolished by ryanodine (10 micro Meter). In addition, caffeine responses were attenuated by halothane in a concentration-dependent manner (EC50 - 1.6 mM). In vessels preconstricted with KCl (40 mM) or phenylephrine (10 sup -6 M), halothane produced transient constriction followed by concentration-dependent vasodilation. Ryanodine, which abolished halothane constrictions, had little effect on the amplitude of KCl- or phenylephrine-induced constrictions or the vasodilating action of halothane. Removal of the endothelium likewise had little effect on the vasoconstricting or the vasodilating actions of halothane in unstimulated, KCl- or phenylephrine-constricted vessels. Halothane completely relaxed KCl and phenylephrine constrictions with EC50 values of 0.36 mM (1.2% at 37 degrees Celsius) and 0.75 mM (2.5%), respectively, in intact vessels before ryanodine; 0.25 mM (0.8%) and 0.59 mM (1.9%) in intact vessels after ryanodine; and 0.52 mM (1.7%) and 0.67 mM (2.2%) in endothelium-denuded vessels.     

Deep cerebral venous thrombosis presenting as an encephalitic illness.

Three cases of deep cerebral vein thrombosis presenting as encephalitic illnesses are described. Thyrotoxicosis was present in one case, ulcerative colitis in one case and an anticardiolipin antibody was detected in two cases. All three patients were on oestrogen and progesterone. Magnetic resonance imaging and angiography allowed rapid confirmation of the diagnosis and permitted non-invasive follow up of this condition. The first two patients made complete clinical recoveries despite having thalamic infarction, in one case bilaterally, demonstrable radiologically.     

Reproductive factors and breast cancer: An overview

Summary Despite extensive research, there is still uncertainty on the separate effects of parity and age at first birth on breast cancer risk. Thus, information on these variables from formal epidemiological articles published in English since 1970 is reviewed in the present article. Among 26 studies considered, one found no significant association with either variable, seven showed an association between age at first birth but not parity and breast cancer risk, six an association with parity but not age at first birth, and in twelve studies both variables appeared to be independently related with breast cancer risk. Various reasons for these apparent differences can be considered, including heterogeneity between various populations (for instance, the proportion of multiparous women in studies showing no association with parity tended to be higher than in studies finding an inverse relation with parity), criteria for selection of cases and controls, influence of age and other covariates (among which the interval between pregnancies is of particular interest) and, of course, the role of chance. The data reviewed suggest, from an aetiological viewpoint, that both parity and age at first birth have some independent effect on breast carcinogenesis. From a public health viewpoint, however, it appears that the importance of age at first birth is greater, since the trend is linear across subsequent age levels, while the protection of parity seems to be quantitatively relevant only for women with four or five births or more.

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Fortpflanzungsfaktoren und Brustkrebs: eine Übersicht

Zusammenfassung Trotz intensiver Forschung bestehen immer noch Zweifel über die einzelnen Auswirkungen von Parität und Alter bei der Erstgeburt auf das Brustkrebsrisiko. Deshalb werden in diesem Artikel die Arbeiten, welche seit 1970 in Englisch veröffentlicht worden sind, analysiert. Von den 26 berücksichtigten Studien fand eine keine eindeutige Beziehung zu diesen beiden Variablen. Sieben wiesen eine Beziehung mit dem Alter bei der Erstgeburt nach, jedoch nicht mit der Parität. Sechs fanden einen Zusammenhang mit der Parität, aber nicht mit Alter bei Erstgeburt und aus 12 Studien ging hervor, dass beide Faktoren unabhängig voneinander mit dem Brustkrebsrisiko verbunden sind. Es gibt verschiedene Hypothesen, diese Diskrepanzen zu erklären, darunter auch die Verschiedenartigkeit in den untersuchten Bevölkerungen (so lag z.B. die Proportion der Frauen mit mehreren Geburten in jenen Studien, die nicht mit Parität verbunden sind höher, als in jenen, welche eine Verbindung zur Parität fanden), die Auswahlkriterien für Fälle und Kontrollen, der Einfluss des Alters und von anderen Variablen (wobei der Zeitabstand zwischen den Schwangerschaften besonders interessant ist) und natürlich die Rolle des Zufalls. Die gesichteten Resultate deuten vom ätiologischen Sichtpunkt darauf hin, dass Parität und Alter bei der Erstgeburt unabhängig voneinander das Brustkrebsrisiko beeinflussen. Die Beziehung zwischen dem Alter bei der Erstgeburt und der Brustkrebshäufigkeit scheint, vom Standpunkt der Sozialmedizin aus, jedoch von grösserer Bedeutung zu sein, da das Risiko in jeder Altersklasse linear ansteigt. Der Schutzeffekt der Parität hingegen ist erst von der vierten oder fünften Geburt an nachzuweisen.

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Les facteurs reproductifs et le cancer du sein: un résumé

Résumé Malgré des recherches approfondies, des doutes subsistent quant aux effets de parité et d'âge à la première naissance sur le risque du cancer du sein. Différents travaux parus en anglais depuis 1970 sont analysés dans cet article. Des 26 études analysées, une seule ne démontrait pas d'association. Sept ont montré une association avec l'âge à la première naissance mais pas avec la parité. Six ont démontré une association avec la parité mais non avec l'âge à la première naissance et 12 études ont montré une influence indépendante de ces deux facteurs sur le risque de cancer du sein. Différentes hypothèses peuvent être considérées pour ces différences apparentes, y compris l'hétérogénéité entre les populations étudiées (par exemple la proportion de femmes multipares est plus élevée dans les études démontrant une association avec la parité que dans celles avec une relation inverse), la sélection des cas et des témoins, la structure de l'âge, ainsi que d'autres facteurs comme par exemple l'intervalle entre les grossesses et bien sûr le hasard. Ces données laissent apparaître que la parité, ainsi que l'âge à la première naissance, peuvent influencer d'une manière indépendante le risque du cancer du sein. La corrélation entre l'âge à la première naissance et le cancer du sein est très importante pour la santé publique, étant donné que le risque augmente avec chaque classe d'âge, tandis que la parité n'a un effet protecteur qu'à partir de la quatrième ou de la cinquième naissance.

     

Streptococcus pyogenes infection in mouse skin leads to a time-dependent up-regulation of protein H expression

Streptococcus pyogenes protein H (sph) is an immunoglobulin-binding protein present in the Mga regulon of certain M1 serotype isolates. Although sph is present in many strains, it is frequently not expressed. In this paper we show that protein H was highly expressed after bacteria were injected into the skin of mice and were recovered from the blood, kidney, or spleen at various times postinfection. The percentage of protein H-positive colonies increased with time, reaching 100% in the spleen and kidney within 24 to 72 h postinfection. The up-regulation of sph expression was also observed in a mga mutant.