Human epidermal growth receptor-2 overexpressing early operable primary breast cancers in older (>=70 years) women: biology and clinical outcome in comparison with younger (less than 70 years) patients

Introduction: There is dearth of literature reporting the prevalence and biological characteristics as well as the long-termclinical outcome of human epidermal growth factor receptor-2 (HER2) overexpressing tumours in older women. Currently,research involving trastuzumab at large focuses on the younger population. This study aimed to analyse their biological characteristicsand to compare them with their younger counterparts from a single centre with a long-term clinical follow-up.Methods: Over 37 years (1973–2010), 1758 older (≥70 years) women with early operable (less than 5 cm) primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these, 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. Comparison was made with data from a well-characterised younger (70 years = 70%, P = 0.51).Conclusion:HER2 overexpressing tumours in older women showed relatively a less aggressive phenotype and did not show any inferior long-term clinical outcome despite not having received chemotherapy when compared with the younger patients. The precise role of different adjuvant systemic therapies in this population needs to be delineated

Elevated anti-human factor Xa activity in rabbit and rodent plasma: implications for preclinical assessment of human factor X in animal models of hemostasis

A wide variety of animal models on thrombosis and hemostasis are used in thrombosis and hemostasis research for the preclinical assessment of hemostatic agents. While the vertebrate coagulome is highly conserved, human and animal plasmas differ considerably when evaluated in coagulation assays such as prothrombin time (PT), activated partial thromboplastin time (APTT), and calibrated automated thrombography (CAT). Here, we have aimed to provide a reference framework for the evaluation of coagulation assays and inhibition of activated human FXa (hFXa) in various animal plasmas. To do so, a side-by-side evaluation of the extrinsic and intrinsic pathway of coagulation was performed by means of PT, APTT, and CAT measurements on (diluted) pooled plasmas from goats, pigs, rabbits, rats, mice, and humans. Plasma anti-FXa activity was assessed by determining the rate of recombinant hFXa inhibition through chromogenic activity analyses and immunoblotting. In general, rabbit, rat, and mouse plasmas exhibited robust clotting upon stimulation of both the extrinsic and intrinsic pathway, produced more thrombin during CAT upon plasma dilution, and displayed relatively high hFXa inhibitory activities. By comparison, goat, porcine, and human plasma displayed a similar profile in PT and APTT assays, produced less thrombin during CAT upon plasma dilution, and displayed comparable hFXa inhibitory activities. In conclusion, the observed differences in clotting parameters and anti-hFXa activity point to a higher anticoagulant threshold in plasma from rabbits, rats, and particularly in mice relative to human, goat, and porcine plasma. Finally, rat plasma was found to be more relevant to the preclinical assessment of human FX(a) in comparison to murine plasma.Thrombosis and Hemostasi

The incidence of all-cause, cardiovascular and respiratory disease admission among 20,252 users of lisinopril vs. perindopril: a cohort study

Background: Major international guidelines do not offer explicit recommendations on any specific angiotensin-converting enzyme inhibitor (ACEI) agent over another within the same drug group. This study compared the effectiveness of lisinopril vs. perindopril in reducing the incidence of hospital admission due to all-cause, cardiovascular disease and respiratory disease. Methods: Adult patients who received new prescriptions of lisinopril or perindopril from 2001 to 2005 in all public hospitals and clinics in Hong Kong were included, and followed up for ≥2 years. The incidence of admissions due to all-cause, cardiovascular disease and respiratory disease were evaluated, respectively, by using Cox proportional hazard regression models. The regression models were constructed with propensity score matching to minimize indication biases. Results: A total of 20,252 eligible patients with an average age of 64.5 years (standard deviation 15.0) were included. The admission rate at 24 months within the date of index prescription due to any cause, cardiovascular disease and respiratory disease among lisinopril vs. perindopril users was 24.8% vs. 24.8%, 13.7% vs. 14.0% and 6.9% vs. 6.3%, respectively. Lisinopril users were significantly more likely to be admitted due to respiratory diseases (adjusted hazard ratios [AHR] = 1.25, 95% CI 1.08 to 1.43, p = 0.002 at 12 months; AHR = 1.17, 95% CI 1.04 to 1.31, p = 0.009 at 24 months) and all causes (AHR = 1.12, 95% CI 1.05 to 1.19, p < 0.001 at 24 months) than perindopril users. Conclusions: These findings support intra-class differences in the effectiveness of ACEIs, which could be considered by clinical guidelines when the preferred first-line antihypertensive drugs are recommended

Evolutionary Adaptations in Pseudonaja Textilis Venom Factor X Induce Zymogen Activity and Resistance to the Intrinsic Tenase Complex

The venom of the Australian snake Pseudonaja textilis comprises powerful prothrombinactivators consisting of factor X (v-ptFX)- and factor V-like proteins. While all vertebrateliver-expressed factor X (FX) homologs, including that of P. textilis, comprise anactivation peptide of approximately 45 to 65 residues, the activation peptide of vptFXis significantly shortened to 27 residues. In this study, we demonstrate thatexchanging the human FX activation peptide for the snake venom ortholog impedesproteolytic cleavage by the intrinsic factor VIIIa–factor IXa tenase complex. Furthermore,our findings indicate that the human FX activation peptide comprises anessential binding site for the intrinsic tenase complex. Conversely, incorporation ofFX into the extrinsic tissue factor–factor VIIa tenase complex is completely dependenton exosite-mediated interactions. Remarkably, the shortened activation peptide allowsfor factor V-dependent prothrombin conversion while in the zymogen state. Thisindicates that the active site of FX molecules comprising the v-ptFX activation peptidepartially matures upon assembly into a premature prothrombinase complex. Takentogether, the shortened activation peptide is one of the remarkable characteristics of vptFXthat has been modified from its original form, thereby transforming FX into apowerful procoagulant protein. Moreover, these results shed new light on thestructural requirements for serine protease activation and indicate that catalyticactivity can be obtained without formation of the characteristic Ile16–Asp194 saltbridge via modification of the activation peptide.Thrombosis and Hemostasi

Hypothalamic AMP-Activated Protein Kinase Regulates Glucose Production

OBJECTIVE—The fuel sensor AMP-activated protein kinase (AMPK) in the hypothalamus regulates energy homeostasis by sensing nutritional and hormonal signals. However, the role of hypothalamic AMPK in glucose production regulation remains to be elucidated. We hypothesize that bidirectional changes in hypothalamic AMPK activity alter glucose production. RESEARCH DESIGN AND METHODS—To introduce bidirec-tional changes in hypothalamic AMPK activity in vivo, we first knocked down hypothalamic AMPK activity in male Sprague-Dawley rats by either injecting an adenovirus expressing the dominant-negative form of AMPK (Ad-DN AMPK2 [D157A]) or infusing AMPK inhibitor compound C directly into the medio-basal hypothalamus. Next, we independently activated hypotha-lamic AMPK by delivering either an adenovirus expressing the constitutive active form of AMPK (Ad-CA AMPK1312 [T172D]

Visiting urban green space as a climate-change adaptation strategy: Exploring push factors in a push–pull framework

Urban green space (UGS) offers users multiple ecosystem services and amenities. This study investigated whether residents used UGS visitation in summer as a sustainable measure to tackle hot weather and associated climate-change impacts in humid-subtropical Hong Kong. Attributes of the indoor residential environment, seldom examined in park-visitation studies, were evaluated as push factors to visit UGS through a push–pull theoretical framework. A questionnaire survey of 483 respondents targeted urban park users. The results indicated that UGS visit frequency and stay duration were relatively low in hot summer. Ordinal multiple regression showed that indoor living conditions, residence location, living routine, and habit and personal health impacts were significantly correlated with UGS visits. Interdependence between push and pull factors was detected, demonstrating that intrinsic UGS environmental conditions could constrain UGS visits despite the motivations of push factors. The results indicated the need to improve the microclimate-regulating function in UGS. It could be achieved mainly by optimizing the nature-based design to promote UGS as an adaptive measure to combat the thermal stress brought by climate change. The findings yielded hints to shape visiting habits and suggestions to improve UGS management

Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors

Thrombosis and Hemostasi

Sexual violence against women and children in Chinese societies

This article provides a comprehensive overview of the reported patterns of sexual violence against women and children in China. It reviews the prevalence of and risk factors for various types of sexual violence and discusses community knowledge and perceptions of these violent acts. It also critically examines three major problems of sexual violence research in China. First, the diversity of findings and study methods reported by surveys and criminal reports reflects the problems in obtaining accurate figures on the scope of the problem. Second, precautions must be taken in reading studies on Chinese culture-specific risk factors for domestic violence. Third, the study of culture-specific factors should not focus solely on cultural factors in a vacuum but rather, should examine traditional culture in the context of modern societies and consensus international standards of human rights. Recommendations for future research are also discussed. © 2009 Sage Publications.postprin