Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: A phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy

Background  

In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3–4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established.     

Primary diagnosis of syphilis by the ophthalmologist

BACKGROUND: Throughout the developed world the reported incidence of sexually transmitted diseases is rising with previously unreported cases at rates of 40 - 70 %. According to German sources, recent epidemiological data show a considerable increase of syphilis especially among homosexual men in larger cities. PATIENTS: We report on 4 patients (age 38 - 54) who were referred to our outpatient department because of vision loss of unknown origin. All were subsequently tested positive for syphilis. None of the patients (3 men, 1 woman) belonged to a risk group, only one described systemic symptoms (urethritis and arthritis). The ocular manifestations of syphilis were broad: granulomatous and non-granulomatous anterior uveitis, papillitis, and chorioretinitis. Two patients also tested positive for HIV. After systemic antibiotic therapy, the ocular diseases stabilized. CONCLUSION: Diagnosis and therapy of syphilis is cost-effective. The rise of syphilis especially in urban areas necessitates a high level of suspicion dealing with patients with intraocular inflammation of unknown origin. Lues serology should be incorporated into routine lab diagnostics to aid in the detection of such cases.     

Lifestyle factors as risk factors for fatigue and psychological distress in the working population: prospective results from the Maastricht Cohort Study

We examined potentially modifiable lifestyle factors as possible risk factors for the onset of fatigue and psychological distress after 1-year follow-up among 8833 employees who participated in the prospective Maastricht Cohort Study of "Fatigue at Work." Results showed, even after adjustment for demographics, presence of disease, other lifestyle factors, psychosocial work characteristics, and psychological distress, that overweight (body mass index, 25 to 29.9) and being physically inactive during leisure time were strongly related to onset of fatigue in men, whereas underweight (body mass index, < 18.5) in women increased the risk for future fatigue. In addition, the study suggests some differential effects of lifestyle factors in the onset of psychological distress. Certainly, these modifiable factors can be targeted in interventions, either on an individual or group level, to prevent or at least reduce the risk of developing fatigue and psychological distress in the working population.     

Single-channel pharmacology of mibefradil in human native T-type and recombinant Ca(v)3.2 calcium channels

To study the molecular pharmacology of low-voltage-activated calcium channels in biophysical detail, human medullary thyroid carcinoma (hMTC) cells were investigated using the single-channel technique. These cells had been reported to express T-type whole-cell currents and a Ca(v)3.2 (or alpha 1H) channel subunit. We observed two types of single-channel activity that were easily distinguished based on single-channel conductance, voltage dependence of activation, time course of inactivation, rapid gating kinetics, and the response to the calcium agonist (S)-Bay K 8644. Type II channels had biophysical properties (activation, inactivation, conductance) typical for high-voltage-activated calcium channels. They were markedly stimulated by 1 microM (S)-Bay K 8644, allowing to identify them as L-type channels. The channel termed type I is a low-voltage-activated, small-conductance (7.2 pS) channel that inactivates rapidly and is not modulated by (S)-Bay K 8644. Type I channels are therefore classified as T-type channels. They were strongly inhibited by 10 microM mibefradil. Mibefradil block was caused by changes in two gating parameters: a pronounced reduction in fraction of active sweeps and a slight shortening of the open-state duration. Single recombinant low-voltage-activated T-type calcium channels were studied in comparison, using human embryonic kidney 293 cells overexpressing the pore-forming Ca(v)3.2 subunit. Along all criteria examined (mechanisms of block, extent of block), recombinant Ca(v)3.2 interact with mibefradil in the same way as their native counterparts expressed in hMTC cells. In conclusion, the pharmacologic phenotype of these native human T-type channels--as probed by mibefradil--is similar to recombinant human Ca(v)3.2.     

Mechanism-based inactivation of cytochromes P450 2E1 and 2E1 T303A by tert-butyl acetylenes: characterization of reactive intermediate adducts to the heme and apoprotein

The kinetics for the inactivation of cytochrome P450 2E1 and the mutant P450 2E1 T303A by tert-butyl acetylene (tBA) and tert-butyl 1-methyl-2-propynyl ether (tBMP) were investigated. The two acetylenes inactivated the 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) O-deethylation activity of purified rabbit P450s 2E1 and 2E1 T303A in a reconstituted system in a time-, concentration-, and NADPH-dependent manner. The K(I) values for the inactivation of P450s 2E1 and 2E1 T303A by tBA were 1.0 and 2.0 mM, the k(inact) values were 0.20 and 0.38 min(-)(1), and the t(1/2) values were 3.5 and 1.8 min, respectively. The K(I) values for the tBMP-inactivated P450s were 0.1 and 1.0 mM, the k(inact) values were 0.12 and 0.07 min(-)(1), and the t(1/)(2) values were 5.9 and 10.2 min, respectively. Losses in enzyme activity occurred with concurrent losses in the P450 CO spectrum and P450 heme, which were accompanied by the appearance of two different tBA- or tBMP-modified heme products in each inactivated sample. LC-MS analysis of the adducts showed masses of 661 or 705 Da, consistent with the mass of an iron-depleted heme plus the masses of a tBA or tBMP reactive intermediate and one oxygen atom, respectively. Only the tBA-inactivated P450 2E1 revealed a tBA-adducted apoprotein with an increase in mass of 99 Da, corresponding to the mass of tBA plus one oxygen atom. Surprisingly, the inactivation, CO spectral and heme loss, and heme adduct formation of the tBA-inactivated T303A mutant were completely reversible after dialysis. In addition, metabolism of para-nitrophenol was not compromised by the tBA-inactivated T303A mutant. Therefore, our studies on the inactivation of P450s 2E1 and 2E1 T303A by tBA and tBMP suggest the existence of three distinct mechanisms for inactivation, among which includes a novel, reversible heme alkylation that has not been previously described with P450 enzymes.