A matter of choice: strategy and discretion in the shadow of World War Two

American policy-makers are predisposed towards the idea of a necessary war of survival, fought with little room for choice. This reflects a dominant memory of World War II that teaches Americans that they live in a dangerously small world that imposes conflict. Critics argue that the ‘choice versus necessity’ schema is ahistorical and mischievous. This article offers supporting fire to those critiques. America’s war against the Axis (1941–45) is a crucial case through which to test the ‘small world’ view. Arguments for war in 1941 pose overblown scenarios of the rise of a Eurasian super-threat. In 1941 conflict was discretionary and not strictly necessary in the interests of national security. The argument for intervention is a closer call that often assumed. This has implications for America’s choices today.

Survival at the frontier of Holy War: political expansion, crusading, commerce and the medieval colonizing settlement at Biała Gora, North Poland

Between the eleventh and thirteenth centuries AD, the Lower Vistula valley represented a permeable and shifting frontier between Pomerelia (eastern Pomerania), which had been incorporated into the Polish Christian state by the end of the tenth century, and the territories of western Prussian tribes, who had resisted attempts at Christianization. Pomeranian colonization eventually began to falter in the latter decades of the twelfth and early thirteenth centuries, most likely as a result of Prussian incursions, which saw the abandonment of sites across the borderland. Subsequently, the Teutonic Order and its allies led a protracted holy war against the Prussian tribes, which resulted in the conquest of the region and its incorporation into a theocratic state by the end of the thirteenth century. This was accompanied by a second wave of colonization, which resulted in the settlement pattern that is still visible in the landscape of north-central Poland today. However, not all colonies were destroyed or abandoned in between the two phases of colonization. The recently excavated site of Biała Góra, situated on the western side of the Forest of Sztum overlooking the River Nogat, represents a unique example of a transitional settlement that included both Pomeranian and Teutonic Order phases. The aim of this paper is to situate the site within its broader landscape context which can be characterized as a militarized frontier, where, from the later twelfth century and throughout much of the thirteenth century, political and economic expansion was combined with the ideology of Christian holy war and missionary activity. This paper considers how the colonists provisioned and sustained themselves in comparison to other sites within the region, and how Biała Góra may be tentatively linked to a documented but otherwise lost outpost in this volatile borderland.

Fighting Al-Qaeda in Yemen? Rethinking the nature of the Islamist threat and the effectiveness of US counterterrorism strategy

This paper evaluates the US’ perception of and response to al-Qaeda in the Arabian Peninsula (AQAP) operating in Yemen. It evaluates the empirical evidence on which the present understanding of the group is based, the implications of the socio-political context in which it operates, and the uneasy position of the Yemeni government in the war against terror as it has been affected by US policy from the early 1990s to the present. In the contested Yemeni state, AQAP is competing for political legitimacy and is increasingly dependent on public support. The US’ kill-or-capture response, the “on-off” nature of its support that has made Yemen vulnerable to the influence of al-Qaeda in the past, and the actions of the Yemeni government itself, which depends on the continued existence of the threat to secure financial support vital for political survival, means that none of the measures being taken has the potential to defeat AQAP.

The Bomb: Nuclear Weapons in their Historical, Strategic and Ethical Context

This book examines to what extent the invention and first use of nuclear weapons was a turning point in the history of warfare and strategy(to what extent was it a mere continuation or perfection of air power strategy? Were the casualty numbers really unprecedented?), the ethics of war (was this form of war against civilians unprecedented?), and it asks whether it was an expression of total war or did it create total war

The Spanish Guerrilla 1808-1814 as a model for people’s wars and resistance movements

Transforming the meaning of the term 'guerrilla' which had once meant feud or private warfare, and then irregular war conducted by special forces on behalf of a state or government, the Spanish Guerrilla (part of the Peninsular War) against Napoleon became the model to be emulated by insurgency movements across the world. Even though the term itself continued to be used, even in Spanish, for special operations, in henceforth became imbued with an ideological dimension, which is how it would be used especially in the 20th century.

Proliferative and anti-proliferative effects of titanium- and iron-based metallocene anti-cancer drugs

In previous work we have found that Cp2TiCl2 and its corresponding deriv. of tamoxifen, Titanocene tamoxifen, show an unexpected proliferative effect on hormone dependent breast cancer cells MCF-7. In order to check if this behavior is a general trend for titanocene derivs. we have tested two other titanocene derivs., Titanocene Y and Titanocene K, on this cell line. Interestingly, these two titanocene complexes behave in a totally different manner. Titanocene K is highly proliferative on MCF-7 cells even at low concns. (0.5 .mu.M), thus behave almost similarly to Cp2TiCl2. This proliferative effect is also obsd. in the presence of bovine serum albumin (BSA). In contrast, Titanocene Y alone has almost no effect on MCF-7 at a concn. of 10 .mu.M, but exhibits a significant dose dependent cytotoxic effect of up to 50% when incubated with BSA (20-50 .mu.g/mL). This confirms the crucial role played by the binding to serum proteins in the expression of the in vivo, cytotoxicity of the titanocene complexes. From the hydridolithiation reaction of 6-p-anisylfulvene with LiBEt3H followed by transmetallation with iron dichloride [bis-[(p-methoxy-benzyl)cyclopentadienyl]iron(II)] (Ferrocene Y) was synthesized. This complex, which was characterized by single crystal X-ray diffraction, contains the robust ferrocenyl unit instead of Ti assocd. with easily leaving groups such as chlorine and shows only a modest cytotoxicity against MCF-7 or MDA-MB-231 cells.

Bioorganometallic fulvene-derived titanocene anti-cancer drugs

A review. 6-Substituted fulvenes are interesting and easily accessible starting materials for the synthesis of novel substituted titanocenes via reductive dimerization, carbolithiation or hydridolithiation reactions, which are followed by a transmetallation reaction with titanium tetrachloride in the latter two cases. Depending on the substitution pattern, these titanocenes prove to be bioorganometallic anticancer drugs, which have significant potential against advanced or metastatic renal-cell cancer. Patients bearing these stages of kidney cancer have a poor prognosis so far and therefore real progress in the area of metal-based anticancer drugs may come from this simple and effective synthetic approach. This tutorial review provides an insight into the synthesis of fulvene-derived titanocenes and their activity in preclin. expts.

Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID50 of 25 mu mol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 mu M). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G*) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1: 1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

Heteroaryl substituted titanocenes as potential anti-cancer drugs

From the reaction of Super Hydride (LiBEt3H) with 6-(furyl)fulvene (1a), 6-(thiophenyl)fulvene (1b) or 6-(N-methyl-pyrrole)fulvene (1c) the corresponding lithium cyclopentadienide intermediates (2a-c) were obtained. These intermediates were reacted with titanium tetrachloride and bis-[(furyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3a) and bis-[(thiophenyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3b) and bis-[(N-methylpyrrole-2-cyclopentadienylmethane)] titanium(IV) dichloride (3c) were obtained and subsequently characterised by X-ray crystallography. When titanocenes 3a-c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC50) of 1.6 x 10(-4) M, 1.5 x 10(-4) M and 9.1 x 10(-5) M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared to their corresponding ansa substituted analogues and also in comparison to unsubstituted titanocene dichloride. (c) 2006 Elsevier Inc. All rights reserved.

Proliferative and antiproliferative effects in substituted titanocene anticancer drugs

Substituted titanocenes like ansa-titanocenes, diarylmethyl-substituted and benzyl-substituted titanocenes, are known for their cytotoxic potential and they can be synthesised using 6-arylfulvenes. Nevertheless, in the case of using 6-(4-morpholin-4yl-phenyl) fulvene (5a) or 6-{[bis-(2-methoxyethyl)amino]phenyl} fulvene (5b) the synthetic possibilities seem to be limited, but the morpholino and the bis-(2-methoxyethyl)amino substituent are in terms of an improved water solubility and drug availability in the cell very interesting groups. The corresponding benzaldehydes, which are the starting material for the synthesis of these fulvenes, were not commercially available and therefore, a modified synthetic approach had to be introduced. Nevertheless, the reactivity of the obtained fulvenes was unexpected and only the ansa-titanocene bis-[{[bis-(2-methoxyethyl)amino]phenyl}cyclopentadienyl] titanium(IV) dichloride (6b) and the benzyl-substituted titanocene [1,2-di(cyclopentadienyl)-1,2-di(4-morpholin-4yl-phenyl)-ethanediyl] titanium dichloride (8a) could be obtained and characterised. When the benzyl-substituted titanocene (8a) was tested against pig kidney cells (LLC-PK) an anti-proliferative effect, resulting in an IC50 value of 25 mu M, was observed. This IC50 value is in the lower range of the cytotoxicities evaluated for titanocenes up to now. The ansa-titanocene (6b) showed surprisingly, when tested on the same cell line, a proliferative effect.

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and hetero aryl-substituted titanocene anti-cancer drugs

From the carbolithiation of N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 240, and 28 mu M for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC50 value of 5.5 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself. (c) 2007 Elsevier B.V. All rights reserved.

Diheteroarylmethyl substituted titanocenes: a novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC50) of 32 mu M, 140 mu M, and 240 mu M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues. (c) 2006 Elsevier B.V. All rights reserved.

Diarylmethyl substituted titanocenes: promising anti-cancer drugs

From the reaction of tert-butyl lithium with p-bromo-N,N-dimethylaniline (1a), p-bromoanisole (1b) or 1-bromo-3,5-dimethoxybenzene (1c), p-N,N-dimethylanityl lithium (2a), p-anisyl lithium (2b) or (3,5-dimethoxyphenyl) lithium (2c), respectively, were obtained. When reacted with 6-(p-N,N-dimethylanilinyl)fulvene (3a), 6-(p-methoxyphenyl)fulvene (3b) or 3,5-(dimethoxyphenyl)fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanium tetrachloride was added "in situ", obtaining titanocenes 5a-C, respectively. When these titanocenes were tested against pig kidney carcinoma (LLC-PK) cells, inhibitory concentrations (IC50) Of 3.8 x 10(-5) M, 4.5 x 10(-5) M, and 7.8 x 10(-5) M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues. (c) 2006 Elsevier Ltd. All rights reserved.

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and indolyl-substituted titanocene anti-cancer drugs

From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different ortho-lithiated indole derivatives (5-methoxy-N-methylindole, N-methylindole and N,N-dimethylaminomethylindole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes (5a-c). When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 37 and 71 mu M for titanocenes 5a and 5b respectively. The most cytotoxic titanocene in this paper, 5c showed an IC50 value of 8.4 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 250 times better than titanocene dichloride itself.

Statistical methods for examining genetic influences of resistance to anti-epileptic drugs

It is generally accepted that genetics may be an important factor in explaining the variation between patients’ responses to certain drugs. However, identification and confirmation of the responsible genetic variants is proving to be a challenge in many cases. A number of difficulties that maybe encountered in pursuit of these variants, such as non-replication of a true effect, population structure and selection bias, can be mitigated or at least reduced by appropriate statistical methodology. Another major statistical challenge facing pharmacogenetics studies is trying to detect possibly small polygenic effects using large volumes of genetic data, while controlling the number of false positive signals. Here we review statistical design and analysis options available for investigations of genetic resistance to anti-epileptic drugs.