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Background To investigate the role of the synthetic steroid tibolone in the progression of osteoarthritis (OA) and in nociceptive behaviour in an experimental rat model of OA and ovariectomy (OVX)-induced osteoporosis. Methods OA was induced in Wistar rats by anterior cruciate ligament transection (ACLT) of the right knee. Osteoporosis was induced by bilateral OVX. Groups of animals were subjected to ACLT, OVX, sham or OVX + ACLT. In addition, two groups were subjected to OVX + ACLT surgeries and were orally administered 0.1 or 0.5 mg tibolone every other day for 14 consecutive weeks, starting 6 weeks after surgery. Nociceptive behaviours (secondary mechanical allodynia and weight-bearing distribution of the hind paws) were analysed prior to and every 3 weeks after surgery up to 24 weeks. At 24 weeks, histopathological studies were performed on the cartilage and synovial membranes of the knee joints, and bone metabolism was assessed by measuring serum concentrations of calcium, phosphorus and alkaline phosphatase. Results Rats undergoing ACLT or OVX + ACLT surgeries showed obvious OA changes in the joints. Animals subjected to ACLT + OVX and treated with tibolone had significantly less cartilage degeneration and synovitis and showed improved nociceptive tests compared with animals undergoing ACLT + OVX surgeries alone. OVX increased the severity of the ACLT-induced OA changes. There was a significant increase in serum alkaline phosphatase in the tibolone-treated ACLT + OVX groups. Conclusions Treatment with tibolone attenuated the development of OA, concomitantly reduced nociception and increased serum alkaline phosphatase in ACLT + OVX rats.

This chapter examines the phenomenon of Islamization in Malaysia. The hallmark of Islamism is its ‘quintessentially political agenda’ involving ‘the politicization of Islam through the aligning of structures of governance and society with Islamic strictures’. In contemporary Malaysia, Islamization puts into the spotlight the reconciliation of this phenomenon with the Malaysian Constitution, which was crafted as a governing instrument for a multiracial, multilingual, and multireligious society. The general unease of the non-Muslim segment of Malaysian society was aggravated by a highly publicized pronouncement of Prime Minister Mahathir, on 29 September 2001, that Malaysia was already an Islamic State. The remainder of the chapter discusses controversial episodes that have engendered concern over the Islamization phenomenon and its significance for constitutionalism in Malaysia.

This concluding chapter presents some reflections about the trajectory of constitutional development in Malaysia. The Malaysian Constitution was conceived with a clear aim of dividing powers among the political entities of executive, legislature, judiciary, and the Malay Rulers. However, in contemporary Malaysia now, there is increasing unease over the unconstrained expansion of executive power, as well as strong distrust in the unbridled exercise of powers in the name of protecting public order and security. The Malaysian nation’s ability to traverse the path of harmony and national advancement in a shrinking world will depend on the fidelity of its political leaders and its many peoples to the constitutional understandings embodied in the Merdeka Constitution, the constitutional principles of fairness, justice, and equality, as well as a common subscription to the fundamental importance of upholding the rule of law.

This chapter examines the constitutional crisis of 1983, which focused on the King’s power to assent to legislation in relation to federal legislation and on the State Rulers’ equivalent power in relation to State legislation. The crisis should be viewed while considering that amendments to the Federal Constitution are common in Malaysia. However, intense national interest was generated by the refusal of the Yang di-Pertuan Agong, Sultan Ahmad Shah, to assent to the Constitution (Amendment) Bill 1983. What was the significance of the 1983 Amendment Bill? What were the motives of the government in mooting the amendments? The chapter reviews the chain of events and clarifies many of the constitutional issues that were clouded by the confrontation between the dissenting parties.

This introduction describes the constitutional developments in Malaysia. The Constitution of the Federation of Malaysia functions for an ever-increasing population estimated at 30.26 million in 2015; ethnic groups comprised of Malay, Chinese, indigenous, Indian, and others; and diverse religions including Islam, Buddhism, Christianity, Hinduism, and others. The Constitution envisages a separation of powers doctrine, dividing powers amongst the different organs of government. Legislative power resides in the Federal Parliament, whereas judicial power, before 1988, was vested in the judiciary. The executive authority of the Federation is vested by Article 39 in the Yang di-Pertuan Agong (or King) and is exercisable, subject to the provisions of any federal law and the Second Schedule of the Constitution, by him, the Cabinet, or any minister authorized by the Cabinet. Constitutional conflicts in 1983, 1988, and 1992–23 altered the equilibrium in the powers balance by eroding the influence of the Rulers and judiciary.

This chapter discusses the constitutional history and political developments in Malaysia. An independent Federation of Malaya began on 31 August 1957. Though described as a ‘federal’ Constitution of an ‘orthodox’ nature, the chequered history of the birth of the then Malayan Constitution indicated that the negotiations were concerned not with the distribution of federal and State powers, but rather with the tortuous hammering out of acceptable terms and compromises among the various racial components of the Malaysian society, especially on matters of communal interests. The chapter covers establishment of the Malayan Union; the Federation of Malaya Agreement of 1948; creation of the independent Constitutional Commission under the chairmanship of Lord Reid; formation of Malaysia; the separation of Singapore from Malaysia; the 1966 Sarawak crisis; the 1983 and 1993 constitutional crises; the 1988 judiciary crisis; 1988 constitutional amendments; the Anwar Ibrahim saga and rise of Reformasi; and the 2009 general elections.

This chapter explores the constitutional and political dimensions of the crisis that rocked the Malaysian judiciary in 1988. For the first time in Malaysian legal history, the highest judicial officer in the land was suspended and, after an inquiry to determine whether he should be removed for alleged misbehaviour, was subsequently removed. Following this unprecedented development, two other senior judges of the Supreme Court were also removed from office after an inquiry by a second tribunal. The political dimension cannot be divorced from the constitutional dimension because the legal and constitutional manoeuvrings were consonant with political skirmishes that involved, at one stage, the political survival of Prime Minister Mahathir.

The dismissal of Tun Salleh Abas and two senior Supreme Court judges was traumatic from the viewpoint of the dismissed judges; it also had a demoralizing impact on the judiciary and severely dented public confidence in them. In 2008, Chief Justice Dato’ Abdul Hamid Mohamad, in addressing a Judges’ Conference, said, ‘We cannot deny that the Judiciary is now suffering from negative perceptions by the public…. Politicised to the hilt, the full effect is now felt and we bear the burden of trying to redeem those negative perceptions.’ The chapter contains an excursus on a number of episodes arising in the aftermath of the 1988 judiciary crisis, which sapped public confidence in the judiciary as an independent and impartial institution. It then analyses the reforms introduced under Prime Minister Abdullah Badawi, considering their efficacy in restoring public confidence in the judiciary.

Episodes involving Malay Rulers and the constitutional dimension of their exercise of discretionary powers are evaluated. The future trajectory of their evolving role is discussed. After two major confrontations with the Mahathir government, by the mid-1990s, the Malay Rulers’ power was considerably diminished. The Rulers remained constitutional monarchs, functioning under advice unless permitted by the constitutional system to exercise discretionary powers. However, by 2008, the fortunes of the Malay Rulers had revived. The resurgence of the Rulers’ power is attributed to their decision to adapt to the requirements of a modern, democratic Constitution to preserve their powers. The changing political landscape has assisted the resurgence of the Malay Rulers. In the political vacuum left by the weakened national coalition, the popular vote lost or the first time since 1969. UMNO found it expedient to rehabilitate the Sultans for political uses; thus, providing opportunities for the Sultans to rebuild their power base.

The dynamic behavior of an Euler beam with multiple point constraints traversed by a moving concentrated mass, a \'\'moving-force moving-mass\'\' problem, is analyzed and compared with the corresponding simplified \'\'moving-force\'\' problem. The equation of motion in matrix form is formulated using Lagrangian approach and the assumed mode method. The effects of the presence of intermediate point constraints in reducing the fluctuation of the contact force between the mass and the beam and the possible separation of the mass from the beam are investigated. The equation of motion and the numerical results are expressed in dimensionless form. The numerical results presented are therefore applicable for a large combination of system parameters.

Background Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.Methods Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.Findings Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p < 0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p < 0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p < 0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p < 0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p < 0.01 for both comparisons).Interpretation The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.Funding Cancer Research UK.

Background The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. Methods Individual data on 53297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. Findings The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95% CI] in current users 1.24 [1.15-1.33], 2p

The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on breast cancer risk and use oi hormonal contraceptives. Original data from 54 studies, representing about 90% of the information available on the topic, were collected, checked and analysed centrally. The 54 studies were performed in 26 countries and include a total of 53,297 women with breast cancer and 100,239 women without breast cancer. The studies were varied in their design, setting and timing. Most information came from case-control studies with controls chosen from the general population; most women resided in Europe or North America and most cancers were diagnosed during the 1980s. Overall 41% of the women with breast cancer and 40% of the women without breast cancer had used oral contraceptives at some time: the median age at first use was 26 years, the median duration of use was 3 years, the median year of first use was 1968, the median time since first use was 16 years, and the median time since last use was 9 years. The main findings, summarised elsewhere,I are that there is a small increase in the risk of having breast cancer diagnosed in current users of combined oral contraceptives and in women who had stopped use in the past 10 years but that there is no evidence of an increase in the risk more than 10 years after stopping use. In addition, the cancers diagnosed in women who had used oral contraceptives tended to be less advanced clinically than the cancers diagnosed in women who had not used them. Despite the large number of possibilities investigated, few factors appeared to modify the main findings either in recent or in past users. For recent users who began use before age 20 the relative risks are higher than for recent users who began at older ages. For women whose use of oral contraceptives ceased more than 10 years before there was some suggestion of a reduction in breast cancer risk in certain subgroups, with a deficit of tumors that had spread beyond the breast, especially among women who had used preparations containing the highest doses of oestrogen and progestogen. These findings are unexpected and need to be confirmed. Although these data represent most of the epidemiologi cal evidence on the topic to date, there is still insufficient information to comment reliably about the effects of specific types of oestrogen or of progestogen. What evidence there is suggests, however, no major differences in the effects for specific types of oestrogen or of progestogen and that the pattern of risk associated with use of hormonal contraceptives containing progestogens alone may be similar to that observed for preparations containing both oestrogens and progestogens. On the basis of these results, there is little difference between women who have and have not used combined oral contraceptives in terms of the estimated cumulative number of breast cancers diagnosed during the period from starting use up to 20 rears after stopping. The cancers diagnosed in women who have used oral contraceptives are, however, less advanced clinically than the cancers diag nosed in never users. Further research is needed to establish whether the associations described here are due to earlier diagnosis of breast cancer in women who have used oral contraceptives, to the biological effects of the hormonal contraceptives or to a combination of both. Little information is as yet available about the effects on breast cancer risk of oral contraceptive use that ceased more than 20 years before and as such data accumulate it will be necessary to reexamine the worldwide evidence. RI Ranstam, Jonas/A-4386-2009; Colditz, Graham/A-3963-2009

Although oligomeric β-amyloid (Aβ) has been suggested to have an important role in Alzheimer disease (AD), the mechanism(s) of how Aβ induces neuronal cell death has not been fully identified. The balance of pro- and anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2 and Bcl-w versus Bad, Bim and Bax) has been known to have a role in neuronal cell death and, importantly, expression levels of these proteins are reportedly altered in the vulnerable neurons in AD. However, the roles of apoptotic proteins in oligomeric Aβ-induced cell death remain unclear in vivo or in more physiologically relevant models. In addition, no study to date has examined whether Bax is required for the toxicity of oligomeric Aβ. Here, we found that treatment with oligomeric Aβ increased Bim levels but decreased Bcl-2 levels, leading to the activation of Bax and neuronal cell death in hippocampal slice culture and in vivo. Furthermore, the inhibition of Bax activity either by Bax-inhibiting peptide or bax gene knockout significantly prevented oligomeric Aβ-induced neuronal cell death. These findings are first to demonstrate that Bax has an essential role in oligomeric Aβ-induced neuronal cell death, and that the targeting of Bax may be a therapeutic approach for AD.

In this paper we describe resource and service discovery mechanisms available in iGrid, a novel Grid Information Service based on the relational model. iGrid is developed within the GridLab project by the ISUFI Center for Advanced Computational Technologies (CACT) at the University of Lecce, Italy and it is deployed on the European GridLab testbed. The GridLab Information Service provides fast and secure access to both static and dynamic information through a GSI enabled web service. Besides publishing system information, iGrid also allow publication of user’s or service supplied information. The adoption of the relational model provides a flexible model for data, and the hierarchical distributed architecture provides scalability and fault tolerance.