Adipose progenitor cells increase fibronectin matrix strain and unfolding in breast tumors.

Increased stiffness represents a hallmark of breast cancer that has been attributed to the altered physicochemical properties of the extracellular matrix (ECM). However, the role of fibronectin (Fn) in modulating the composition and mechanical properties of the tumor-associated ECM remains unclear. We have utilized a combination of biochemical and physical science tools to evaluate whether paracrine signaling between breast cancer cells and adipose progenitor cells regulates Fn matrix assembly and stiffness enhancement in the tumor stroma. In particular, we utilized fluorescence resonance energy transfer imaging to map the molecular conformation and stiffness of Fn that has been assembled by 3T3-L1 preadipocytes in response to conditioned media from MDA-MB231 breast cancer cells. Our results reveal that soluble factors secreted by tumor cells promote Fn expression, unfolding, and stiffening by adipose progenitor cells and that transforming growth factor-ß serves as a soluble cue underlying these changes. In vivo experiments using orthotopic co-transplantation of primary human adipose-derived stem cells and MDA-MB231 into SCID mice support the pathological relevance of our results. Insights gained by these studies advance our understanding of the role of Fn in mammary tumorigenesis and may ultimately lead to improved anti-cancer therapies.

Atovaquone as long-term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance. Atovaquone Expanded Access Group.

OBJECTIVE: To evaluate the efficacy and tolerance of atovaquone used as long-term maintenance therapy in patients with toxoplasmic encephalitis and intolerant of conventional anti-Toxoplasma therapies. DESIGN: Uncontrolled open-label study of atovaquone given through an expanded access programme; statistical analysis was performed on an intent-to-treat basis. PATIENTS: Sixty-five patients intolerant of conventional toxoplasmic encephalitis therapies-pyrimethamine, sulphadiazine or clindamycin-received atovaquone as maintenance therapy after resolution of an acute episode of toxoplasmic encephalitis. Patients were clinically and neurologically evaluated monthly. Toxoplasmic encephalitis relapse was defined as the occurrence of neurological abnormalities, except in the case of a proven alternative diagnosis. RESULTS: Sixty-five patients were treated with atovaquone 750 mg four times daily and followed up for a mean period of 1 year. Mean CD4 lymphocytes count was 29 x 10(6)/l. Prior to starting atovaquone, patients had experienced a total of 129 episodes of intolerance to conventional anti-Toxoplasma drugs. Atovaquone was used as a single anti-toxoplasmic agent in 75% of the cases. Seventeen patients (26%) experienced a toxoplasmic encephalitis relapse. Sixty-three patients (97%) were able to tolerate and continued taking atovaquone. Two patients had to discontinue therapy because of side-effects. In a multivariate analysis, only the duration of pyrimethamine-sulphadiazine therapy during the acute therapy phase of toxoplasmic encephalitis was significantly associated with a decreased risk of toxoplasmic encephalitis relapse during maintenance therapy [relative risk, 0.64 for each week of pyrimethamine-sulphadiazine; 95% confidence interval (CI), 0.42-0.96; P = 0.03]. The survival probability was 70% at 1 year after the episode of toxoplasmic encephalitis (95% CI, 57-83). CONCLUSION: These results suggest that atovaquone is a well-tolerated alternative anti-Toxoplasma treatment for maintenance therapy in patients who are intolerant to conventional anti-Toxoplasma drugs.

A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the efficacy and tolerability of two recombinant human FSH (r-hFSH) preparations, follitropin-alpha (Gonal-F; Ares Serono, Geneva, Switzerland) and follitropin-beta (Puregon; Organon, Oss, the Netherlands), for superovulation in patients undergoing IVF-ET. DESIGN: Randomized, parallel-group, assessor-blind, single-center trial. SETTING: Outpatient tertiary referral center for assisted reproductive techniques. PATIENT(S): Forty-four infertile women undergoing IVF-ET. INTERVENTION(S): After down-regulation with buserelin acetate, patients were randomized to receive follitropin-alpha or follitropin-beta, 150 IU/d for 6 days; after that, dosages were adjusted according to the ovarian response. MAIN OUTCOME MEASURE(S): Cumulative dose of r-hFSH; duration of r-hFSH treatment; number of follicles of > or =11 mm and of 14 mm on day 7 of r-hFSH treatment and on the day of hCG administration; number of oocytes retrieved; number of viable embryos; and number of pregnancies (biochemical, ectopic, miscarried) and clinical pregnancies. RESULT(S): There were no statistically significant differences in any efficacy measures between the two preparations. The incidence of systemic adverse events was comparable in the two groups. Local reactions at the injection site were significantly more common and more severe with follitropin-beta than with follitropin-alpha CONCLUSION(S): Follitropin-alpha and follitropin-beta have comparable efficacy in patients undergoing IVF-ET.

[Influence of changes in climate and the calendar on the onset of a migraine crisis]. / Influence des variations climatiques et du calendrier sur le déclenchement des crises de migraine.

Several factors have been demonstrated to play a role in triggering acute episode of migraine headache. On the basis of observation, others have been suggested but not confirmed. Variations in climate are among the latter. Over a one-year period, we observed a population of 304 patients with migraine residing in a precise climatic zone. The frequency of acute episodes could be analyzed for 148 among them. There were 4,421 acute episodes recorded during the year. The periodicity during the year was compared with climate parameters: temperature (maximal, minimal, average), wind (force and direction), atmospheric pressure, rain, sunshine, relative humidity, and icy, foggy and stormy weather. Moon cycles were also assessed. No correlations were found between climate parameters or variations there of and onset of migraine. Variations in climate would thus appear to have no effect on migraine. Inversely, the results of this study demonstrated a day effect with a higher number of episodes on Saturday and less on Monday and Tuesday. The triggering effect of catamenia on many acute episodes was also confirmed.

Friction anisotropy and asymmetry of a compliant monolayer induced by a small molecular tilt

Lateral force microscopy in the wearless regime was used to study the friction behavior of a lipid monolayer on mica. In the monolayer, condensed domains with long-range orientational order of the lipid molecules were present. The domains revealed unexpectedly strong friction anisotropies and non-negligible friction asymmetries. The angular dependency of these effects correlated well with the tilt direction of the alkyl chains of the monolayer, as determined by electron diffraction and Brewster angle microscopy. The molecular tilt causing these frictional effects was less than 15 degrees, demonstrating that even small molecular tilts can make a major contribution to friction.