Case of Stricture of the Urethra Cured by Division.

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The Hypothesis of Locality and its Limitations

The hypothesis of locality, its origin and consequences are discussed. This supposition is necessary for establishing the local spacetime frame of accelerated observers; in this connection, the measurement of length in a rotating system is considered in detail. Various limitations of the hypothesis of locality are examined.Comment: LaTeX file, no figures, 14 pages, to appear in: "Relativity in Rotating Frames", edited by G. Rizzi and M.L. Ruggiero (Kluwer Academic Publishers, Dordrecht, 2003

Two sword lengths apart: Credible commitment problems and physical violence in democratic national legislatures

Ideally, national legislatures in democracies should be venues for peacefully resolving conflicts between opposing groups. However, they can become places of physical violence. Such violence can be an indication that countries’ legislative institutions are functioning far from the democratic ideal of being venues for peaceful conflict reconciliation. In some cases, such as Ukraine prior to the 2014 outbreak of armed conflict in the country’s east and south, violence can indicate and possibly fuel deeper political divisions. In this first global study of legislative violence, I show that brawls are more likely when legislators find it difficult to credibly commit to follow peaceful bargains. Credible commitment problems are more acute in countries with new democracies and disproportionate electoral outcomes – that is, when electoral votes for parties do not closely correspond to the legislative seats they are given. I find robust support for this argument by first examining a case study of legislative violence in the antebellum United States Senate. Pro- and anti-slavery senators became increasingly unable to maintain credible commitments in the lead-up to the 1856 caning of Senator Charles Sumner as the allocation of seats in the legislative body became more disproportional. Second, I find further support for my argument in a new global dataset of contemporary instances of violence in national legislatures. In addition, I find strong evidence that violence is more likely in legislatures with small minority governments. Despite reasonable expectations, civil wars are not associated with more legislative violence

A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m−2 and capecitabine 1250 mg m−2 BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m−2) in combination with capecitabine (1250 mg m−2 BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction

Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer

Purpose: Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and Methods: In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. Results: There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination: anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P =.03);for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. Conclusion: Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer