The American Heart Association (AHA) developed a behavioral roundtable to address cardiovascular disease (CVD) disparities, with a focus on the primary prevention of obesity. This roundtable considered the preventable differences in the indicators of health of different population groups, often defined by race, ethnicity, sex, educational level, socioeconomic status, and geographic location of residence. To reduce the rates of CVD in disproportionately affected population groups, we explored behavioral strategies for each of the 5 risk stages: 1) no known cardiovascular risk, 2) known cardiovascular risk, 3) acute CVD, 4) rehabilitation, and 5) chronic CVD. We examined sample AHA programs targeting each of the risk stages to consider how to pose questions about reach, efficacy/effectiveness, adoption, implementation, and maintenance . The strategies outlined in this article can be used to develop collaborations for planning, implementing, and evaluating possible interventions to reduce CVD disparities.The AHA Nutrition Committee, with support from its Industry Nutrition Advisory Panel (INAP), established several behavioral roundtables to address behavioral issues and translation to practice focusing on the AHA mission. Each roundtable, with representatives from the Nutrition Committee, INAP, and AHA staff, brainstormed ideas to help the Nutrition Committee integrate behavioral issues into strategic and program planning. The special population behavioral roundtable, which focused on behavioral issues for populations with disparate rates of cardiovascular risk, included 2 Nutrition Committee members who became the authors of the report. Using an iterative process, we examined potential applications of the roundtable's recommendations to existing AHA programs. Our goal was to provide a framework to help AHA staff and volunteers at the national and affiliate levels as they plan and implement AHA programs that address the needs of special population groups. This article can also help other agencies as they implement AHA programs and focus on reducing health disparities.Our roundtable focused on preventable differences in the widening gap in CVD morbidity and mortality ,2. To exThe Institute of Medicine's multilevel approach  providesThe variables that we thought were important in addressing special population needs at each risk stage are listed in the We considered the importance of community partnerships — in which community representatives participate in defining research problems, interpreting data, and applying findings — in fostering community-based participatory research methods for the evaluation of disparate rates of CVD or its risk factors ,11. Our www.HealthierGeneration.org) is a joint initiative between the AHA and the William J. Clinton Foundation. The Alliance for a Healthier Generation was created to stop the nationwide increase in childhood obesity by 2010 and is taking bold, innovative steps to help all children live longer and healthier lives. The 4 strategic initiatives target industry, health care, schools, and children themselves.The Alliance for a Healthier Generation ? How many of the participating schools are in vulnerable communities with disparate rates of obesity, diabetes, and heart disease?Efficacy/EffectivenessWhat was the impact of programs on fitness and weight measures ? Does the target population buy or use (or intend to buy or use) the products or services  that promote a healthful lifestyle? How did beverage consumption change in the schools? Does the program efficacy vary by community demographics and resources?AdoptionHow many of the potential providers or stakeholders  provide the intervention components? How does this compare to the need and the goal? Is variability in providing components related to resource disparities in the community? What are the community resources for promoting a healthy lifestyle? How much are the available resources used? How did beverage policy change in the schools?ImplementationWhat are the barriers to providing the targeted service? Are the programs developed consistent with the AHA and Alliance recommendations for a healthful lifestyle? How feasible is intervention implementation in a variety of real-world settings?MaintenanceAre school and other programs sustainable based on annual reviews? Will the target population continue to use the facility , goods or services  after the program or campaign is over?www.americanheart.org/presenter.jhtml?identifier=2114 and www.americanheart.org/presenter.jhtml?identifier=3044887).The AHA does not provide direct services to people with cardiovascular risk factors. However, the AHA's Web site provides decision trees to guide health professionals in treating risk factors and self-help programs for people who have cardiovascular risk factors, for example, diabetes or hypertension (ReachHow many people with the identified risk factor (diabetes or hypertension) use the Web site? How many health professionals accessed risk factor reduction information?Efficacy/EffectivenessHow well did patient users achieve goals for a healthy lifestyle and reduce CVD risk status? Potential measures include self-reported control of CVD risk factors such as lipid profile, blood pressure, and blood glucose as well as measures such as body weight, dietary intake, and physical activity. Do rates of achieving goals differ?AdoptionHow do Web site users compare with the general population and the vulnerable subgroups with diabetes or hypertension? Are population groups with disparate rates of risk factors using the Web site? How do these health professionals compare to others in their profession?ImplementationWhich components of the programs were used? Were the Web site features used as planned? What are the barriers to implementing the recommendations for patients and health care providers? Are there more barriers for population groups with diabetes and hypertension health disparities? What is needed to make effective programs more translatable to the real world?MaintenanceWill program users continue desired patient or self-care behaviors? Will Web site links continue to have sponsorship and be available on the AHA Web site?www.americanheart.org/presenter.jhtml?identifier=10000046&title=Operation Heartbeat).At this risk stage, the focus shifts to immediate emergency care issues. The AHA has a national network of community-based programs designed to reduce response times to cardiac emergencies by improving access to automatic external defibrillators among laypeople. Success of these Operation Heartbeat programs depends in part on the public's knowledge of the warning signs of a myocardial infarction (MI) and the appropriate response to cardiac arrest victims ? Does response time vary based on community characteristics?AdoptionHow many public facilities employ staff who know how to use emergency services? How available are catheterization and revascularization services? Are some communities with excess morbidity and mortality lacking access to these services?ImplementationWhat are the barriers to increasing access to emergency or cardiac services? Can the findings be generalized and translated to programs elsewhere? What resources and other factors are needed to do so?MaintenanceHow can a program continue to address service needs? Examination of program sustainability can be based on audits of emergency responses, and cardiac event mortality can be evaluated based on medical charts and review of emergency service logs.www.americanheart.org/presenter.jhtml?identifier=3047638 and www.americanheart.org/presenter.jhtml?identifier=4713).The AHA promotes a partnership between patients and their doctors, nurses, pharmacists, and other health care professionals to help patients change their health habits. Patients take an active role in making these changes ? What is the availability of cardiac rehabilitation in the target community? What is the estimated need? How many people in the community know about or know how to use the service? Are some communities lacking access to rehabilitation services?Efficacy/EffectivenessWhat is the overall quality of life and health for people who have had a CVD event? How are demographic and community characteristics related to health and quality-of-life measures?AdoptionHow many facilities provide recommended components of rehabilitation? How does the quality of rehabilitation facilities relate to disparities in outcomes?ImplementationWhat are the barriers to offering comprehensive (including lifestyle counseling) rehabilitation services in underserved communities? Staff and patient interviews can provide insights about services offered and their use.MaintenanceHow well do patients maintain recommended lifestyle changes after participating in a rehabilitation program? What resources are institutionalized as ongoing rehabilitation services? Is a comprehensive rehabilitation program available over time?www.americanheart.org/presenter.jhtml?identifier=3049656). The GWTG program has 3 modules: coronary artery disease, heart failure, and stroke. Each module addresses specific clinical practices and lifestyle changes.The AHA launched the Get With the Guidelines (GWTG) program in 2000 to help hospitals treat patients with evidence-based medicine known to improve health outcomes  will allow the AHA to increase healthy lifestyle educational programs and the number of community organizations that implement these programs. These efforts could lead to changes in policies, including access to care, physician training on cultural awareness, and treatment guidelines sensitive to ethnic differences.We thank the AHA Industry Nutrition Advisory Panel for providing an unrestricted grant to address the needs of special populations in the nutrition behavioral roundtable, which led to the development of this paper. We are especially grateful to JoAnn Hamamura, MS, CNS, who served as industry cochair for the special populations workgroup, and Vickie Peters, MS, who served as the AHA facilitator.


Breast-cancer tissue from 60 patients was tested for oestrogen and testosterone sensitivity in vitro by measuring [3H]-dT incorporation in tissue fragments at various times during 48h culture. Hormone sensitivity in test culture was determined as an increase or decrease in dT uptake. In vitro cultures of breast cancer tissue demonstrate that some tumours are hormone-sensitive and others hormone-insensitive, but it cannot be predicted whether cell proliferation is stimulated or inhibited by hormone treatment. The data were related to the clinical stage of the patients, menopausal status, and the degree of anaplasia of the tumours tested. No correlation was observed between these parameters and in vitro hormonal sensitivity. However, when related to the response of patients to various kinds of hormonal treatment, a significant positive correlation was obtained.


A primer on new research by Fuentes-Medel and colleagues explains the important role of non-neural cells in clearing neural debris, which is continuously produced during the normal remodeling processes that establish and maintain neural connectivity. The nervous system is an intricately wired communication system that receives and responds to intrinsic and environmental information, allowing the organism to adapt to its surroundings. Proper nervous system function depends on the establishment of correct connectivity between neurons and their target cells. The target cells can be either neurons or non-neuronal peripheral cells, such as muscle cells. The axon of a typical neuron emerges from one end of the main cell body and, in humans, can extend up to several feet to form a connection with a target cell at a specialized site called the synapse. At the synapse, the presynaptic terminal of the axon communicates with target cells through dendrites of neurons or neuromuscular junctions (NMJs) of muscle cells. Therefore, the initial development of neural connectivity involves a series of steps including axonal growth, axonal pathfinding, and synapse formation with the right target cells In addition to these initial steps, however, extensive remodeling of preformed axons and connections are required to achieve precise neural connectivity. These remodeling processes include the elimination of excess axons, dendrites, synapses, and their debris During the initial phases of neural connectivity, neurons develop exuberant axonal and dendritic processes. These excess processes subsequently undergo selective elimination to shape mature neural circuits. This endeavor may include the local elimination of axons and dendrites through competition between cells for common targets As these two examples of remodeling processes illustrate, entire exuberant axon branches can be eliminated by either local retraction or degeneration. Neural circuits can also be remodeled on a much finer scale during synaptic plasticity regulation.Drosophila larval NMJ, new synapses and synaptic boutons (a button-like swollen end of an axon at a synapse) are constantly formed and stabilized as the target muscle cells grow in size PLoS Biology, Yuly Fuentes-Medel et al. Drosophila NMJ involves significant production of presynaptic membrane debris and detachment of undifferentiated synaptic boutons (“ghost boutons”)  . Ghost bHow is neural debris cleared away and what would be the significance of this mechanism? Studies in various species, including mammals and flies, have discovered that a population of non-neuronal cells known as glial cells play central roles in clearing neural debris through an engulfment process called phagocytosis Drosophila again turn out to be the main cell type responsible for eliminating excess axons during development As in the mammalian nervous system, glial cells in Drosophila NMJ have also been shown to clear synaptic debris, thereby helping to control synaptic connectivity within a single arbor. Glial cells were found to cover the NMJ and extend highly dynamic membrane projections to engulf presynaptic debris (Drosophila NMJ.Now, with these new findings from Fuentes-Medel et al., glial cells at the c debris . Glial cc debris . Surprisc debris . This obImportantly, the new findings of Fuentes-Medel et al. reveal the functional significance of these neural clearing mechanisms. Disruption of phagocytic activity either in glial or muscle cells caused the accumulation of presynaptic debris and ghost boutons, respectively, resulting in a severely reduced number of synaptic boutons and boutons displaying abnormal growth . This fiDrosophila NMJ continuously produces presynaptic remnants that require clearing to regulate synaptic connectivity, it is tempting to speculate that this process could be a more general phenomenon in many other synaptic connections. It would therefore be interesting to investigate whether synaptic connections in the mammalian NMJ or brain exhibit similar pre- or postsynaptic membrane shedding and subsequent clearance upon changes in synaptic plasticity.These new findings from Fuentes-Medel et al. raise several exciting questions. Why do glial and muscle cells have different effects in clearing neural debris? Does this simply reflect the fact that glial cells work at the NMJ with very thin membrane projections, so that they can only catch smaller debris? Or are there differences in molecular mechanisms, such that the presynaptic debris and ghost boutons are recognized in molecularly distinct ways? It is clear that Draper is required in clearing presynaptic debris and ghost boutons, implying that similar “eat me” signals may be present in both cases. Identifying these “eat me” signals that tag specific neural materials for phagocytic uptake is a critical goal for future studies. Given the fact that the The current repertoire of tissue resident phagocytes is likely to expand based on several studies


Leo Sher and colleagues discuss recent research on interventions to prevent secondary suicide and discuss the additional research that is needed. Suicide poses major threats to public health worldwide. In 2002, suicide accounted for about 30,000 deaths in the US alone Suicidal behavior has been conceptualized as a continuum of thoughts and behaviors ranging from suicidal ideation to completed suicide. Recent retrospective research delineates seven distinct categories of “suicidality”: (1) completed suicide, (2) suicide attempt, (3) preparatory acts toward imminent suicidal behavior, (4) suicidal ideation, (5) self-injurious behavior without intent to die, (6) nondeliberate self-harm, and (7) self-harm behavior with unknown suicidal intent Suicide prevention can be primary, secondary, or tertiary. Primary suicide prevention aims to reduce the number of new cases of suicide in the general population Secondary suicide prevention is particularly important but not always given the attention that it deserves, in part because research into secondary prevention is only just starting to be applied to clinical practice. In this article, we discuss recent research on the evaluation of suicidal risk and on different kinds of secondary suicide prevention interventions that aim to reduce that risk. We also indicate how these interventions are currently being applied and what additional research is needed.Suicide is often difficult to predict due to its complex nature Biological risk factors for suicide include:Low cerebrospinal fluid 5-hydroxyindolacetic acid levelsHypothalamic-pituitary-adrenal axis dysregulationLow blood cholesterol levelsMedical or neurological illnesses Cigarette smokingPsychological risk factors include:Acceptability of suicideA childhood history of physical or sexual abuseDiscouraged help-seeking behaviorAggressive/impulsive traitsPessimismHopelessnessLow self-esteemPoor access to psychiatric treatmentMore proximal stressors that indicate an increased suicide risk include:Relationship problemsFinancial troublesA family or personal history of suicideMajor depressionSubstance useThe clinical evaluation of the medical and psychiatric history of a patient and of their current state is the crucial and essential element of the suicide assessment process. This evaluation enables the clinician to identify risk factors and protective factors, to determine the patient's immediate safety and the best setting for treatment, and to develop a differential diagnosis and treatment strategies.Psychiatric illness is a major contributing factor to suicide risk, with mood disorders such as major depressive disorder and bipolar disorder being associated with about 60% of suicides Additional information about the individual who may be at risk for suicide, such as depositions, medical and psychiatric treatment records, and toxicology screenings, should also be incorporated into the assessment. Additional information of this sort may be especially helpful, because information from individuals with mood disorders, borderline traits, or psychosis can be unreliable. Interviews with friends and relatives may also be helpful in assessing suicide risk.Equally importantly, clinicians and other professionals in a position to offer help should not hesitate to ask patients about suicidal ideation because, while it may seem surprising, patients will often talk frankly about their suicidal thoughts and tendencies if given the opportunity. Failure to ask about suicidal ideation may be related to the care provider's discomfort with the topic, lack of time, or lack of skills in this area. Clinicians need to overcome these obstacles to provide appropriate care to their patients.A final component of the clinical assessment of suicide risk is the gathering of information about current and past suicidal ideation and behavior, and about psychiatric conditions associated with suicidal behavior. There are many self-report and clinician-administered scales that measure different aspects of suicidal behavior or mental health conditions related to it  [15]–[20The most widely used scales for rating suicidal behaviors include:The Scale for Suicidal Ideation The Suicide Intent Scale The Risk-Rescue Rating Scale The Columbia-Suicide Severity Rating Scale The Beck Hopelessness Scale The Hamilton Depression Rating Scale The Beck Depression Inventory Many researchers have been trying to find biological markers related to suicidal behavior that could improve secondary suicide prevention. Several biological features related to failures in neurotransmitter and neuroendocrine systems, such as the serotonergic, noradrenergic, dopaminergic, and hypothalamic-pituitary-adrenocortical (HPA) systems, have been proposed To date, the most promising biological predictors of suicidal behavior are low cerebrospinal fluid 5-hydroxyindoleacetic acid  and HPA axis dysregulation as indicated by dexamethasone nonsuppression In a recent systematic review of suicide prevention strategies, Mann et al. Antidepressant medications are the most widely used pharmacological interventions in secondary suicide prevention, but studies of their effectiveness in reducing suicide attempts and completed suicides have had mixed results A US Food and Drug Administration study recently reported that the risk of suicidality associated with use of antidepressants is age dependent In terms of psychological interventions, suicidal patients often benefit from therapies that address the repetition of suicidal thoughts and behaviors, treatment adherence, and other factors commonly associated with suicidality Follow-up care to maintain adherence to therapy  after suicide attempts is also an effective approach to secondary suicide prevention Many studies show that suicides by particular methods  decrease after the introduction of legal restrictions that reduce access to such means Finally, many studies have exposed a need for a decrease in reporting of suicide and for responsible reporting. Media blackouts in reporting suicide have coincided with a decrease in suicide rates Despite our increasing knowledge about secondary suicide prevention, there are still many gaps in the research. The prescription of SSRIs and their impact on suicidal inclinations, especially in depressed children and adolescents, remain hotly debated topics Nevertheless, much of what we have learnt about secondary suicide prevention through research can now be applied to the real world. For example, we know that to provide the best secondary suicide prevention, clinicians must learn how to evaluate at-risk individuals properly. We know that after completing these assessments, clinicians can now use well-researched psychological and pharmacological methods to decrease the levels of suicidality in their patients. We know that legally restricting access to lethal means and responsible media reporting of suicide correlate with a decrease in suicides worldwide Looking to the future, thorough evaluations and appropriate treatments of patients with depressive disorders and other psychiatric illnesses should help to improve the efficacy of secondary prevention of suicide. But, it is also clear that more research into new approaches for the prevention and treatment of suicidal behavior remains essential.


Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity. Of thesBesides VEGF, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), interleukin-8 and insulin-like growth factor (IGF) are factors involved in angiogenesis, and these factors have their own endothelial cell receptors.As angiogenesis is of crucial importance for tumour growth, inhibiting this process has become a major challenge in the development of new anticancer agents.Tumour-related angiogenesis is dependent on specific growth factors, the presence and activation of endothelial cell receptors, endothelial cell proliferative activity as such, and the interaction between proliferating endothelial cells and extracellular matrix components. All these specific steps can be inhibited by targeted agents.αvβ3 and αvβ5. In contrast to quiescent blood vessels where expression of integins is minimal, actively proliferating endothelial cells express integrins to a high extent. Integrin activity can be inhibited by antibodies or small molecule inhibitors.Neutralising VEGF prior to its attachment to endothelial receptors can be accomplished by monoclonal antibodies. Inhibiting the tyrosine kinase activity of VEGFR-2, PDGF and/or bFGF receptors following ligand binding can be achieved through specific inhibitors. Inhibiting endothelial cell proliferation can be achieved by mimicking the activity of naturally occurring antiangiogenic proteins such as thrombospondin-1 (TSP-1), endostatin and angiostatin. Inhibiting the interaction between proliferating endothelial cells and various extracellular matrix components can be accomplished by inhibiting the activity of the transmembrane endothelial cell integrins A different approach that may lead to diminished tumour vascularisation is the destruction of established vasculature. The so-called ligand-directed vascular targeting agents (VTAs) are able to induce a rapid and specific shutdown of tumour blood supply either by using antibodies, peptides or growth factors that deliver toxins and procoagulants or apoptotic effectors specifically to the tumour endothelium. The so-called small-molecule VTAs try to recognise the pathophysiological differences between the normal and tumour endothelium, and are thus able to induce vascular shutdown, specifically in tumours.In this review, we will give an overview of the results of clinical studies that have been performed with various classes of antiangiogenic and antivascular agents  administration schedules showed that the agent, given as single agent or in combination with various cytotoxic agents, was safe and did not cause dose-limiting toxicity (DLT) when given at predefined doses. Some bleeding episodes were seen that were not attributed to the agent. Antiangiogenic activity was assessed by contrast-enhanced dynamic magnetic resonance imaging (DEMRI), showing a decrease in tumour microvascular permeability. Biological activity was also demonstrated by a decline in serum levels of unbound VEGF , when bevacizumab was given in various doses and different dosing intervals, either as single agent or in combination with various cytotoxic agents. In these studies, the increased incidence of thromboembolic complications, bleeding episodes , hypertension and proteinuria was the reason for concern , but a rVEGF-trap is a specific antagonist that binds to and subsequently inactivates VEGF. It is claimed to have a higher affinity for VEGF than monoclonal antibodies, and can be administered subcutaneously. Phase I studies are ongoing  receptor tyrosine kinase activity. Following prolonged continuous oral administration, DLT consisted of diarrhoea, hypertension, hepatic toxicity and cutaneous rash, whereas asymptomatic QTc prolongation was seen throughout the dose levels studied  were performed. Dose-limiting toxicity consisted of neuropsychiatric effects  is a tubulin-depolymerising VTA that is able to induce a rapid change in endothelial cell shape, causing a disruption of the endothelial layer, vascular congestion and loss of blood flow. Preclinical studies showed selectivity for rapidly proliferating tumour endothelium, leaving mature endothelial cells unaffected. Dose-limiting toxicity in three phase I studies, exploring different treatment schedules, consisted of acute coronary syndrome, tumour pain and ataxia. QTc prolongation, cutaneous flushing and hot flashes and diffuse abdominal pain and tumour pain were associated with the drug infusion. One pathological complete response lasting 33 months was recorded in a patient with an anaplastic thyroid carcinoma.Reversible decreases of tumour blood flow were observed using either dynamic enhanced MRI scanning or PET scanning (AVE8062A is a combretastatin analogue that is undergoing phase I testing. Transient and reversible myocardial and central nervous system ischaemia were recorded at the highest dose levels studied (ZD6126 binds to endothelial tubulin, and is able to induce changes in endothelial shape, leading to vascular shutdown. Preclinical studies showed that only immature endothelial cells responded to ZD6126, whereas mature endothelial cells were not affected.In a phase I study exploring a 10-min single i.v. administration once every 21 days, abdominal pain and gastrointestinal toxicity were dose limiting. Significant changes in tumour blood flow were observed, as some cases of prolonged stable disease (DMXAA is a flavonoid that, in preclinical models, is able to induce TNF-α production and induce vascular disruption, selectively in the tumour microenvironment.In a phase I trial, DLT consisted of urinary incontinence, various seemingly central nervous system-related toxicities, dyspnea and cardiac toxicity (Biological activity was assessed by means of DEMRI analysis, showing changes in tissue perfusion, vessel permeability and vessel surface area (The first clinical studies with antiangiogenic agents were initiated 5 years ago, when preclinical studies in mice showed tumour disappearance and prolonged survival following the administration of endostatin and angiostatin. Scientists and especially the lay press were excited over these results.Clinical studies of these 5 years have shown that many angiogenesis inhibitors can be given safely to patients. Some antiangiogenic agents were even completely devoid of toxicity, and defining an optimal dose for subsequent activity testing of these agents was difficult, if not impossible. In the meantime, it became obvious that antiangiogenic activity of some agents occurred at very low doses, even more questioning the concept of dose escalation until toxicity. Determining optimal biological activity became an important new end point in phase I studies.How can we optimally define the optimal biologically effective dose, and which pharmacodynamic analysis should be used for this?Target inhibition, dormancy of endothelial cells or vascular shutdown with subsequent tumour ischaemia are important biologial end points that have the potential to predict antitumour activity, but the only reliable source to determine these end points is the tumour. Here we are facing practical problems, because most physicians consider taking repeated tumour biopsies to be very cumbersome for patients. Although some authors consider taking these biopsies repeatedly to be feasible (While trying to demonstrate biological activity in a less invasive manner, various surrogate markers of antiangiogenic or antivascular activity have been studied. The analysis of serum markers of endothelial cell proliferation thus far has failed to show consistent changes following treatment with most antiangiogenic agents, but changes in serum concentrations of VEGF and soluble VEGFR-2 seem to have more potential to predict tumour hypoxia (Noninvasive techniques such as DEMRI and PET scans are increasingly used to demonstrate the biological activity of antiangiogenic agents or VTAs. These techniques can show changes in tumour blood flow and tumour viability, respectively. In numerous studies, DEMRI and PET scan studies were able to demonstrate these pharmacodynamic effects, but it must be realised that both techniques are still unvalidated to predict antitumour activity or patient benefit. Only large clinical studies correlating the outcomes of DEMRI and PET scan studies with clinical outcome can definitely assess the role of these techniques in future patient management.Another method to assess the biological activity of antiangiogenic agents is by the use of pharmacokinetic studies. Drug exposure or peak plasma concentrations can be used to determine the dose that is most likely to give antiangiogenic or antitumour activity, but here it has to be realised that comparing human plasma concentrations to target inhibitory concentrations in preclinical models cannot and will not always be predictive for the same biological effect. Nevertheless, pharmacokinetic analysis will remain of crucial importance to prevent unnecessary dose escalation in case of incomplete or saturated absorption with maximal drug exposure, and to show the relations between clinical toxicity and plasma concentrations.Antiangiogenic agents are cytostatic agents that are not likely to cause tumour regressions in patients with advanced or metastatic cancer. In order to assess their antitumour activity in phase II studies, combining these agents with cytotoxic anticancer agents seems to be a logical step. Clinically, the combination of two antiangiogenic agents, each having a distinctive inhibitory mechanism of action, has not been tested thus far. A large number of studies combining cytotoxic and antiangiogenic agents have been performed. These phase II studies most often had a randomised design, comparing the response rates or time to disease progression. In order to define safe combination dosages, these studies were always preceded by phase I combination studies showing the safety of these combinations.As some of these randomised phase II trials were indeed able to demonstrate improved antitumour activity of the combination treatment, results of large randomised phase III trials were eagerly awaited. However, until recently, these phase III trials, mostly done in patients with metastatic colorectal or breast cancer, all failed to show improved survival, and serious concern was growing as to whether we would ever be able to demonstrate the clinical efficacy of any of these exciting and promising agents.It was with great excitement, therefore, that recently the first randomised phase III trial in patients with metastatic colorectal cancer showed improved survival when cytotoxic treatment was combined with bevacizumab. It is this trial that, on the one hand, has reconfirmed the conviction that we, currently, are testing effective new agents, whereas, on the other hand, it has become clear that the only way to assess clinical benefit or a complete generation of these agents will be through these large, costly and time-consuming randomised trials. Besides, we have to accept that more than one randomised trial will be needed, as at this moment it is not even fully clear that the dose tested in this study is in fact the most optimal one. Another intriguing question that remains is why the addition of bevacizumab was beneficial to this group of colorectal carcinoma patients, whereas results of randomised studies with various other antiangiogenic agents in a comparable population of patients all turned out to be negative.If one is to consider the currently perceived limited antitumour activity of single-agent antiangiogenic treatment, it can be argued that a combination of antiangiogenic agents with different targets or a combination of antiangiogenic agents and VTAs might show increased activity. Preclinical studies exploring such combinations are now being performed, and some promising data have been presented. In addition to this, it is also conceivable that combining antiangiogenic agents with other targeted agents should be explored, but for this the help of pharmaceutical companies who are willing to share their compounds and knowledge is urgently needed.If one is still to explore single agent antiangiogenic treatment, a situation of minimal residual disease following either cytoreductive surgery or cytotoxic treatment seems most appropriate to adequately assess the role of these agents in secondary cancer growth prevention. These adjuvant studies will, by their design, definitely be time and patient consuming, and here an important as yet unanswered question is that of patient convenience and optimal duration of treatment.In conclusion, 5 years of clinical studies with antiangiogenic agents have yielded promising results, and therefore antiangiogenic agents have the potential to play a role as active anticancer agents. To definitely confirm this role, specifically designed phase I studies, using the correct end points, must be able to define one or more safe and biologically active doses that can be tested in properly designed randomised phase II trials. Here, a wide array of possible combinations can be thought of. Finally, it is mandatory that in more than one randomised phase III trial patient benefit is demonstrated.The role of the VTAs is not yet established as only phase I studies have been performed so far, but considering their mechanism of action, more studies will definitely follow.After a period of flawing interest, antiangiogenic agents have regained their place in the centre of investigational antitumour treatment, and it is without any doubt that in the future their role in clinical practice will be established.


Crack cocaine can cause a variety of pulmonary and cardiac complications. Pulmonary findings in a 65- year-old man with non-Hodgkin lymphoma who presented with shortness of breath not resolving with antibiotics are presented here. The usual manifestation of “crack lung” in an unusual clinical circumstance underlines the importance of a clinical history in such cases. The finding of “crack lung” preceded the diagnosis of probable “crack heart.” No other similar published case reports could be identified in the literature. The differential diagnosis included Pneumocystis jiroveci, cytomegalovirus, pulmonary hemorrhage, idiopathic interstitial pneumonia, hypersensitivity pneumonitis, and pulmonary edema.Our patient presented with dyspnea and the Although smoking crack cocaine is supposed to increase susceptibility to pulmonary infection because of dysfunction of the pulmonary alveolar macrophages, a bronchoscopy did not reveal an infectious cause in our patient. Furthermore, bronchoscopy did not show any visual evidence of gross pulmonary hemorrhage. However, clinically unapparent alveolar hemorrhage can occur in healthy individuals who smoke crack cocaine The finding of significant left ventricular dysfunction on echocardiogram was felt to be most likely attributable to the crack cocaine. Cardiovascular events associated with crack cocaine include myocardial infarction, myocarditis, dilated cardiomyopathy, heart failure, coronary and peripheral vascular spasm, dysrhythmia, and sudden cardiac death Non-cardiogenic pulmonary edema was thought to be caused by increased alveolar permeability from exposure to crack cocaine; however, evidence suggests that, as compared with tobacco smokers and non-crack-and non-tobacco-smoking controls, no increase in alveolar permeability is evident Our patient received no chemotherapy agent that is generally thought to cause cardiac damage, although rituximab has been noted to cause immediate cardiotoxicity Our patient also had no burn marks on his hands, but in the presence of pulmonary infiltrates, evidence of burn marks on the hands caused by crack pipes used to smoke the cocaine should provide important clues to the diagnosis ct.Crack cocaine abuse is uncharacteristic in the age group represented by our patient, but nonetheless should be kept in the differential when the “ground glass” pattern of opacities with septal thickening is seen on thorax ct scan of the thorax in an immunocompromised host is a non-specific finding, with a wide differential; however, the present report highlights the fact that a careful history can sometimes provide valuable information to reach the diagnosis. This particular case also highlights the potential cardiac toxicity of repeated crack cocaine use. The increased use of this illegal drug in Canadian cities should alert clinicians to look for such manifestations in all age groups.“Ground glass” opacities on


Drosophila lethal giant larvae (lgl) is a tumour suppressor gene whose function in establishing apical-basal cell polarity as well as in exerting proliferation control in epithelial tissues is conserved between flies and mammals. Individuals bearing lgl null mutations show a gradual loss of tissue architecture and an extended larval life in which cell proliferation never ceases and no differentiation occurs, resulting in prepupal lethality. When tissues from those individuals are transplanted into adult normal recipients, a subset of cells, possibly the cancer stem units, are again able to proliferate and give rise to metastases which migrate to distant sites killing the host. This phenotype closely resembles that of mammalian epithelial cancers, in which loss of cell polarity is one of the hallmarks of a malignant, metastatic behaviour associated with poor prognosis. Lgl protein shares with its human counterpart Human giant larvae-1 (Hugl-1) significant stretches of sequence similarity that we demonstrated to translate into a complete functional conservation, pointing out a role in cell proliferation control and tumorigenesis also for the human homologue. The functional conservation and the power of fly genetics, that allows the researcher to manipulate the fly genome at a level of precision that exceeds that of any other multicellular genetic system, make this Drosophila mutant a very suitable model in which to investigate the mechanisms underlying epithelial tumour formation, progression and metastatisation. In this review, we will summarise the results obtained in these later years using this model for the study of cancer biology. Moreover, we will discuss how recent advances in developmental genetics techniques have succeeded in enhancing the similarities between fly and human tumorigenesis, giving Drosophila a pivotal role in the study of such a complex genetic disease. They arise from epithelial cells and are often highly invasive and metastatic. It has extensively been demonstrated that a clonal accumulation of subsequent mutations is the cause of cellular escape from mechanisms controlling its fate , 2. The may form .Drosophila as an in vivo model since epithelial cancers have long been described in flies and, so far, more than 50 genes have been found whose mutation gives rise to uncontrolled proliferation acting in a recessive manner [Drosophila tumour suppressor genes (TSG) and their mutations fall in two main categories. Genes whose loss of function (LOF) in the whole animal causes excessive proliferation of epithelial tissues without affecting monolayer organisation, overall tissue architecture and differentiation, are defined hyperplastic tumour suppressors [Drosophila. Several of the aspects of human carcinogenesis can be profitably investigated using e manner . For thepressors . On the pressors . Almost lethal giant larvae (lgl), scribble (scrib) and discs large (dlg) are of particular interest as their deprivation in the entire individual causes neoplastic growth of both the ectodermal derivatives: imaginal discs and larval brain [Drosophila and their monolayered structure perfectly recapitulates many morphological, structural and molecular features of human epithelia coating internal organs, from which carcinomas arise [Among the fly neoplastic TSG so far identified, al brain , 5. Imagas arise . lgl was the first neoplastic TSG described in Drosophila [locus deletion [lgl mutants; 5 days-old lgl wing discs indeed contain about one third cells respect to the wild type counterpart [-/-lglcells are unable to exit cell cycle, after many additional days of proliferation discs reach an enormous cell number and eventually form large amorphous masses which fail to form proper cellular contacts and do not differentiate, presenting all the main features of malignant carcinomas . They show loss of positional clues since, in lgl defective discs, cells straddle the anterior-posterior compartment boundary and intermix [1, Lower panel). Moreover they are able to fuse with nearby tissues, so displaying local invasiveness, and show a high metastatic potential upon transplantation [osophila , but itsdeletion . Its LOFnterpart ; despiteintermix   displays this metastatic behaviour [lgl mutant tumour cells after serial transplantations into adult hosts [Lineage analysis of these ehaviour . Moreoveehaviour . These tlt hosts .A correct apical-basal cell polarity is the main feature of a healthy epithelial tissue. From invertebrates to mammals, cells composing an epithelial sheet possess complex junctional structures that define apical and basolateral domains, favour cell-cell communication and cytoskeleton architecture, restrict motility and maintain tissue integrity, making the cell layer work as a functional unit , 16.Indeed, loss of apical-basal polarity is a hallmark of malignant carcinomas. Often, as the tumour progresses, morphological alterations typical of the so-called EMT  are observed: cells loosen their contacts, become rounded, grow in a disorganised multilayer and are prone to migration. From a molecular point of view ETM is characterised by the disruption of adherens junctions through functional inactivation of E-cadherins , 18.lgl, scrib and dlg are clearly involved in epithelial cell polarity establishment in Drosophila. Given the similarities between their phenotypes, the strong genetic interaction shown and their mutual requirement for correct localization, the three proteins are much likely part of the same genetic pathway and act as a complex in establishing the basolateral membrane domain identity as well as controlling proliferation [feration .Loss of apical-basal polarity caused by their LOF, due to failure to form proper adherens junctions , is peculgl encodes for a 127 kD protein with several WD40 repeats predicted to fold into a β-propeller domain involved in protein-protein contact [lgl zygotes lacking maternal supply die as embryos, so maternal pulse is sufficient to sustain the earliest stages of development [dgl and scrib encode for scaffolding proteins, rich in protein-protein interaction domains [Drosophila homologue of the vertebrate tight junction) which lies basal to the adherens junction and they function antagonizing the activity of the Par3/Par6/atypical Protein Kinase C (aPKC) complex, which localizes at the adherens junctions and participates in the specification of the apical domain identity [2).  contact . It is a contact . Lgl is  contact ; moreoveelopment . Also dgidentity , 24. TheDrosophila larval brain, called neuroblasts [2). Lgl in turn counteracts aPKC activity at the basolateral domain possibly sequestering it in an inactive form [lgl-/- tissues can indeed be reproduced by expanding aPKC activity domain in neuroblasts. The expression of a prenylated form, which is targeted to the entire cell cortex, results in an abnormal increase in neuroblast population and tumourous hyperproliferation due to an excess of self-renewal [The mechanism through which these complexes regulate each-other was initially investigated in the stem cells of the roblasts . Althougroblasts . It was roblasts . Upon phroblasts  ive form , 27. The-renewal .The same is true for epithelial tissues. The basolateral spreading of aPKC activity causes cytoplasmic release of Lgl from the basolateral membrane leading to hyperproliferation and massive overgrowth in the wing disc and deep morphogenetic alterations in the adult wing .lgl mutants through the mechanisms described above can result in excessive enrichment or dispersion of some transmembrane receptors, but also intracellular signalling molecules could no longer be able to find their canonical partners or target molecules, so triggering changes in cell metabolism and proliferation rate. How can loss of cell polarity due to Lgl deprivation be related to overproliferation and mass accumulation during tumorigenesis? A change in membrane architecture with consequent cytoskeletal modifications can lead to alterations of subcellular microterritories in which diverse signalling pathways may usually function. The spreading of the apical cortex occurring in lgl have been identified in many species including yeast, slime molds, worms, insects, mouse and man [Establishment of epithelial cell polarity seems to be a very conserved process from flies to humans . Homolog and man .Drosophila Lgl human homologues: Hugl-1 and Hugl-2 [Drosophila Lgl [There are two d Hugl-2 . Hugl-1 hila Lgl . 3), and we demonstrated that Hugl-1 is able to form heterocomplexes with Lgl in vitro. Fly and human proteins show a significant global sequence similarity of 62.5%  occurring at pediatric age [Interestingly, pronounced similarities with  KO mice . Lgl-1 -tric age . Noticeatric age .lgl homologues act as TSG so giving a major relevance to Drosophila lgl mutant in the study of human tumorigenesis.All these data strongly support the notion that also mammalian Drosophila genetics is undoubtedly the FLP(Flippase) / FRT(Flippase Recognition Target) based mitotic clonal analysis technique that allows researchers to generate marked patches of homozygous mutant tissue in an otherwise heterozygous animal [4a).One of the most useful and broadly utilised investigation system offered by s animal   as it ensures the possibility to control either the developmental stage in which to induce recombination or the clone number that is related to heat pulse length; the distribution of clones is instead random within the animal.Drosophila and it is routinely employed in almost all research fields because pericentromeric FRT sequences have been introduced to both arms of each of the Drosophila chromosomes allowing to generate clones homozygous mutants for nearly every gene. This, not only, makes it possible to uncover additional stage-specific functions of pleiotropic genes whose mutations in the whole animal are lethal in earlier stages, but also to investigate potential cross-talking between mutant and wild type tissue and non cell-autonomous effects due to certain mutations.Clonal analysis is an extremely feasible system in Induction of mitotic clones with this technique is also extremely helpful for the study of proliferation control: it is indeed possible to precisely assess the proliferation rate/behaviour of a mutant clone comparing it to that of the wild type one, named the ‘twin clone’, generated from the same cell following to a recombination event.p53 -/- cells were generated in various organs mimicking the loss of heterozygosity (LOH) typical of patients affected by Li-Fraumeni syndrome [Drosophila in this field.Mitotic recombination has begun revealing its potential also in mouse. For example, clones of syndrome . Howeversyndrome , confirm4c). It is thus possible to create groups of cells where loss-of-function mutations of oncosuppressor genes and gain-of-function mutations of protooncogenes are simultaneously present and that are surrounded by wild type tissue, clearly mimicking very closely mammalian cancer onset. An interesting improvement of the FRT/FLP based clonal analysis for its application in cancer research is the MARCM  technique . It allolgl, scrib and dgl mutants a strong cooperation between different genetic lesions in tumour growth and metastatic activity [This sophisticated genetic tool has enabled researchers to find out in activity , 45. ey-FLP construct was employed in order to confine clone induction to a specific territory: this eyeless promoter is active throughout embryonic and larval development in the eye imaginal discs and optic lobes  [An e adult) .scrib clones within an otherwise wild type eye disc showed loss of cell polarity and overproliferation; however very little mutant tissue was recovered in the adult organ implying its obliteration during metamorphosis. But, when a second oncogenic mutation, such as a constitutively activated form of the onco-proteins Ras (RasACT) or Notch (NotchACT), was introduced in the scrib background, a dramatic overgrowth was observed. The clonal tissue overwhelmed the wild type tissue fusing with the nearby imaginal discs and brain and formed totally undifferentiated masses [d masses .in vivo assay: taking advantage of the possibility to generate GFP-marked eye disc clones, the authors were able to follow tumoral cells migration in the whole animal throughout larval development. Clones expressing RasACT alone overgrew to form non invasive tumours. However, when RasACT expression was combined with scrib, dlg or lgl null mutations, these tumours became highly metastatic. They displayed a consistent invasion of the ventral nerve cord, an area of the larval brain not immediately adjacent to the territories of eyeless promoter expression. Cancer cells were also found to spread to other tissues. Very similarly to what is known to happen for human carcinomas, active basement membrane degradation was observed and tumourous cells also showed a lowered expression of E-cadherin in association to metastatic behaviour [The same strong cooperation was also demonstrated for the metastatic phenotype . In thisehaviour . scrib clones, with the intention to reproduce the possible consequences of Ras activation, failed to give rise to the neoplastic phenotype [In both cases, however, the simultaneous expression of cell-cycle promoters and apoptosis inhibitors in henotype , 45. ThiDrosophila as in humans, simultaneous mutations of oncosuppressors and protoncogenes are required [These two papers were maybe the most convincing evidence that for a tumour to arise, in required , 45. locus mutations that regulated lgl malignant phenotype upon transplantation of larval tissues into adult wild type hosts [semaphorin 5c (sema5c). Semaphorin 5c protein contains extracellular thrombospondin type I repeats, known to regulate TGF-β signalling in mammals. Indeed, whereas lgl null mutant primary tumours show an increased Drosophila TGF-β homologue Decapentaplegic (Dpp) signalling, in lgl and sema5c double mutants Dpp signalling levels are comparable to wild type tissue. This implicates the Dpp/TGF-β signalling pathway in cancer emergence as it is known to happen for many types of human malignancies [This cooperation model has been subsequently taken as a starting point from which to isolate novel genes involved in tumour formation and metastasis. A mutagenesis screening was carried out to search for second pe hosts . Interesgnancies .lgl clonal behaviour appears to be quite different compared to that of the whole mutant animal. X-rays induced lgl clones generated in a wild type background did not show aberrant growth or morphological abnormalities in the adult wing [lgl clones are invariantly smaller than wild type twins and are nearly completely disappeared by the time the adult tissue forms. As discussed above, lgl cells are much slower growing than wild type cells [lgl clones could fall prey of cell competition. Cell competition is an interesting phenomenon that has been fully characterized in Drosophila wing imaginal discs and that is involved in maintaining of developmental homeostasis of organ dimensions [Minute mutation were eliminated by surrounding wild type tissue [Minute mutations are dominant, homozygous lethal LOF mutations of different ribosomal proteins. Heterozygous Minute cells are viable but display a slow growing phenotype.ult wing . Our unppe cells  and it imensions . Cells te tissue . The Minlgl LOF described in the previous sections such as aberrant cell-cell interaction and loss of pattern can indeed be observed if mutant clones are generated in a Minute heterozygous background [lgl cells with the growth advantage necessary to escape cell competition and to express their neoplastic potential.The neoplastic features typical of ckground . This colgl clonal phenotype has also been investigated in another developing organ, the eye imaginal disc. In lgl clones embedded in a wild type tissue, ectopic S-phases were observed in areas that should have already exited cell cycle to differentiate as photoreceptors, however overall clone size was not affected as apoptotic death was also induced and cell polarity was maintained [More recently, intained .Minute background, ey-FLP generated lgl clones showed prominent loss of cell polarity especially in not yet differentiated tissue. Moreover individuals were seen to undergo extended larval period and die as giant larvae very similarly to the homozygous mutants [In a  mutants . ey-FLP construct allows to generate clones within a defined territory with a high frequency but differently from what happens for X-rays or heat-shock induced clones, the point in development in which the recombination event takes place can neither be estimated nor controlled. Clone formation rather occurs throughout embryonic and larval development, thus large amounts of mutant tissues are produced and this results in a stronger outcompetition of the background tissue leading to extremely enhanced phenotypes. The more dramatic consequences observed for eye clonal output with respect to those seen in the wing are probably due to differences in the experimental system used. The employment of the Minute background, delaying development, induces extra proliferation in the lgl patches so that maternal supply of Lgl protein can be completely depleted [lgl tissue neoplastic potential. Further to this hypothesis, a Minute background possibly rescues lgl cells from their proliferative disadvantage so that mutant clone can reach a critical mass where a second mutation is more likely to occur providing lgl cell with new survival tricks. Authors say the use of the depleted ; this woDrosophila follicular epithelium , in which cells cease dividing during mid oogenesis and it can be therefore compared to a non-proliferating tissue.It is worth concluding discussing an adult tissue: the lgl and dgl alleles at non permissive temperature displayed increased proliferation and loss of monolayered organization with follicular cells accumulation at both the egg chamber poles. Additionally, groups of cells were seen to recurrently invade between the germ-line derived nurse cells and the oocyte [Follicular epithelia carrying temperature-sensitive e oocyte , 52. lgl, scrib and dgl LOF mutations in follicular cells also resulted in overgrowth and invasion [Clonal induction of invasion , 19, 52.lgl mutant clones, despite slow growing, may have in this case a greater proliferative advantage since embedded in a context of a no longer proliferating epithelium. This situation most faithfully recapitulates what happens in those carcinomas which arise from quiescent tissues, and may thus represent a complementary approach for epithelial cancer modelling.5), making it impossible for membrane degradation to be investigated. Nevertheless, it remains a very good system in which to gain knowledge of fundamental processes associated with cancer progression like EMT, migration and the complex interactions between tumourous cells and an adult microenvironment. The only drawback in this system is that there is not basement membrane between follicular epithelium and nurse cells/oocyte, since follicular cells point towards the inner egg chamber with their apical surfaces (Fig. Cell cultures and mammalian models have undoubtedly provided a large amount of information about how lesions affecting various aspects of cell physiology, such us proliferation, apoptosis, differentiation and migration can eventually lead to cancer emergence and metastasis. It is however becoming increasingly clear that understanding of these complex processes unavoidably needs to go through the comprehension of the cross-talks between cancer cells and the environment in which they develop.Drosophila lethal giant larvae mutant as a powerful in vivo system where many of the aspects of carcinogenesis, including those of tumour-microenvironment interactions, can be fruitfully genetically recapitulated.In this review we presented in vivo model is therefore a golden opportunity for cancer research.All the major pathways involved in tumorigenesis are extremely conserved between flies and humans  and the


Among persons who inject drugs (IDU), illicit drug use often occurs in hospitals and contributes to patient expulsion and/or high rates of leaving against medical advice (AMA) when withdrawal is inadequately managed. Resultant disruptions in medical care may increase the likelihood of several harms including drug resistance to antibiotics as well as costly readmissions and increased patient morbidity. In this context, there remains a clear need for the evaluation of harm reduction strategies versus abstinence-based strategies with respect to addressing ongoing issues related to substance use among addicted hospitalized patients. While hospitalization can be used to stabilize addicted patients as they recover from their acute illness and help them to achieve abstinence, patients unable to maintain abstinence should not be penalized for failing to do so at the expense of their health. This article describes harm reduction activities within hospitals and areas for future investigation. Soft-tissue infections and other injection-related infections are among the main contributors to health service use among people who inject drugs (IDU) -6. In maAs a result, IDU often present to EDs later in the course of their illness, and this in turn increases the likelihood for hospital admission ,4,5. DruHowever, IDU are more likely than other patients to discharge from hospitals against medical advice (AMA) ,12. A 20In addition to the high costs associated with increased health utilization, these findings also suggest that patients are not fully recovering from their illness the first time they are treated. Incomplete therapy or treatment failure may also increase the likelihood for drug resistance to antibiotics ,13,14. AWhile an abstinence-based approach to drug use generally requires that complete cessation from all non-prescribed drugs is a pre-requisite for effective addiction treatment , harm reIn terms of specific strategies, methadone maintenance treatment (MMT) has been associated with reductions in the need for hospitalization and generally results in improvements in health care access ,20. NEPsWhile achieving abstinence from illicit drug use is ideal, for many individuals, this may be difficult, particularly without adequate support. Health care for drug users often follows psychiatric models of care that involve the use of contracts developed for addiction management. When this contract is breached , the patient may be discharged back into the community with cessation of care . Such apNegative experiences with the medical establishment may also impede health care delivery for IDU . LeavingIndeed, harm reduction programs have already shown success when integrated with medical care. Increased integration of low- and medium-threshold harm reduction strategies with primary and acute care has been associated with increasing the proportion of IDU who have regular health care .For instance, the Dr. Peter Centre in Vancouver which provides low-threshold access to care for people living with HIV/AIDS including a high proportion of IDU offers one example where harm reduction has been successfully integrated with a medical facility. Many conventional barriers have been removed at the Centre including the need to remain drug-free. MMT and the distribution of condoms and clean needles are also provided . An inteAt the Dr. Peter Centre, participants are able to build trusting relationships with healthcare staff; such a facility offers an important solution to increase acceptability of care while reducing stigma among IDU. Importantly, the continuity of care from both nurses and doctors has shown to be an effective means for reducing injection-related complications and the need for hospital admission ,30.Specific harm reduction strategies including drug substitution for opioid addiction, smoking rooms for tobacco and illicit drugs, and protocols to help manage drug withdrawal symptoms have already demonstrated success in their integration into health care facilities and should continue to be fully implemented into hospitals. For example, in-patient MMT has been associated with a reduced likelihood of leaving AMA which may reflect adequate and appropriate management for opioid withdrawal . CertifyOther strategies, while proven effective in community settings, still require further study given their potential role in reducing harm among hospital-admitted IDU. Supervised injecting areas and NEPs, in particular, could be evaluated as services that could be made accessible for hospital patients, particularly those with longer stays or in wards that are designated for dealing with addicted individuals. Ideally, the availability of these services would also help to facilitate positive patient-provider relationships.Active drug use occurs in hospitals and contributes to high rates of leaving AMA among IDU. As discussed, if active drug use was accommodated through more of a harm reduction approach rather than banned in hospitals, rates of leaving AMA would likely decline. Regardless, there remains the need for evaluation of several novel harm reduction interventions versus abstinence-based strategies with respect to addressing ongoing issues related to stigmatization and elevated rates of leaving AMA. This may lend itself to a randomized trial or perhaps it is better examined via observational data where the objective would be to evaluate whether the incorporation of a different harm reduction programs  in hospitals results in reduced rates of patients leaving AMA and overall improvements in health outcomes for IDU who are able to access these services versus those who do not. Given the contact that many IDU have with EDs, it seems fitting that harm reduction programs should continue to expand to the hospital setting, particularly when the number of IDU being treated is high. The goal is to use hospitalization to stabilize addicted patients as they recover from their acute illness and see if they can be helped to achieve abstinence. However, patients unable to maintain abstinence should not be penalized for failing to do so at the expense of their health.The authors declare that they have no competing interests.EW and BR developed the concept of the manuscript. BR drafted the original version. TK, EW, and JSG assisted with revisions. All authors approved the final manuscript.


Azhdarchid pterosaurs were among the most widespread and successful of pterosaur clades, but their paleoecology remains controversial. Morphological features common to all azhdarchids include a long, shallow rostrum; elongate, cylindrical cervical vertebrae that formed a long and unusually inflexible neck; and proportionally short wings with an abbreviated fourth phalanx. While azhdarchids have been imagined as vulture-like scavengers, sediment probers, swimmers, waders, aerial predators, or stork-like generalists, most recent authors have regarded them as skim-feeders, trawling their lower jaws through water during flight and seizing aquatic prey from the water's surface. Although apparently widely accepted, the skim-feeding model lacks critical support from anatomy and functional morphology. Azhdarchids lack the many cranial specialisations exhibited by extant skim-feeding birds, most notably the laterally compressed lower jaw and shock absorbing apparatus required for this feeding style. Well-preserved azhdarchid skulls are rare, but their rostra and lower jaws appear to have been sub-triangular in cross-section, and thus dissimilar to those of skim-feeders and sediment probers. Taphonomic data indicates that azhdarchids predominately inhabited inland settings, and azhdarchid morphology indicates that they were poorly suited for all proposed lifestyles bar wading and terrestrial foraging. However, azhdarchid footprints show that their feet were relatively small, padded and slender, and thus not well suited for wading. We argue that azhdarchids were stork- or ground hornbill-like generalists, foraging in diverse environments for small animals and carrion. Proficient terrestrial abilities and a relatively inflexible neck are in agreement with this interpretation. Quetzalcoatlus northropi from the Maastrichtian of the USA (wingspan c. 10 m). Not all azhdarchids are enormous however, and the clade also includes smaller forms such as Montanazhdarcho minor from the Campanian of Montana (wingspan c. 2.5 m), Zhejiangopterus linhaiensis from the early Campanian of China (wingspan c. 3.5 m), and Bakonydraco galaczi from the Santonian of Hungary (wingspan c. 3.5 m) Q. northropi in size, with Hatzegopteryx thambema from the Maastrichtian of Romania having an estimated wingspan greater than 12 m Eoazhdarcho liaoxiensis, once thought to be a diminutive azhdarchid with a wingspan of 1.6 m Azhdarchids were a highly successful Cretaceous pterosaur clade, distributed virtually worldwide Quetzalcoatlus, Zhejiangopterus, Hatzegopteryx), broad morphological similarities can be identified across the group: all azhdarchids exhibit large skulls with long, edentulous rostra, elongate, cylindrical cervical vertebrae, proportionally short wings with an abbreviated fourth phalanx, and elongate hindlimbs Azhdarchids share a suite of characters with a number of smaller Cretaceous pterosaurs , and are united with them in the pterodactyloid clade Azhdarchoidea Rynchops , a highly specialised group of gull-like birds that fly low over the water surface, trawling their unusually elongate, laterally compressed lower jaws through the water and grabbing animal prey that they contact. In contrast to that of many other birds, the feeding behaviour and cranial morphology of skimmers has been well described . Supposedly, the long neck would enable azhdarchids to reach food at depth whilst flying or swimming, thereby circumventing the need to dive An entirely different paleoecological role was imagined for azhdarchids by Nessov Quetzalcoatlus and Rynchops have been cited as further evidence for skim-feeding behaviour Of these proposed lifestyles, in-flight piscivory appears to have gained the most acceptance impaired in-flight feeding suggest in-flight feeding by others , and Kellner and Langston regarded skim-feeding as plausible for Quetzalcoatlus on the basis that it had been ‘previously advocated for Rhamphorhynchus … and later assumed for many other pterosaurs, including the larger toothless pterosaurs’ . An assessment of azhdarchid trace fossils was used to evaluate their terrestrial competence. Additionally, we tested the notion that azhdarchids were, as has been suggested for other pterosaurs, predominately shore-dwelling animals with a quantitative assessment of their geological context. Using sedimentary and other fossil remains as evidence of paleoenvironment, azhdarchid fossils were scored as occurring in settings that were fully terrestrial, coastal, marine with terrestrial input or fully marine with no terrestrial input. This dataset of 33 azhdarchid-bearing localities was then assessed along with consideration of the completeness and abundance of their remains to develop an understanding of preferred azhdarchid habitat.Quetzalcoatlus 400 km from the nearest contemporary shoreline The notion that pterosaurs were predominantly analogues of seabirds seems to have arisen from their frequent occurrences in marine deposits Although interpreting the ecology of extinct organisms from their depositional settings is problematic due to taphonomic influences en route to other locations An alternative hypothesis suggests that azhdarchids were migratory Quetzalcoatlus sp. and Zhejiangopterus linhaiensis , but the relationship between this and skull length cannot be ascertained due to its fragmentary nature. Azhdarchid mandibles are slender in lateral view with a mandibular symphysis that extends for 45–66% the length of the jawline. The jaws are straight and edentulous Bakonydraco possesses a low transverse ridge across the dorsal surface of the mandibular symphysis Quetzalcoatlus may have a ventrally convex palatal region beneath the posterior half of the nasoantorbital fenestra: four Quetzalcoatlus specimens with this region preserved have broken palatal elements that extend below the ventral margin of the maxilla and jugal bars .By contrast, the condylar articular surfaces suggest that a moderate amount of dorsal extension was permitted between vertebrae. The bulbous posterodorsal convexity of the condyle would have facilitated moderate degrees of dorsal rotation during which the prezygapophyses would slide ventrolaterally beneath the postzygapophyses of the preceding vertebra (a motion confirmed by the articular surfaces of these processes). The dorsoventrally compressed but laterally expanded condyle and cotyle appear to have been hinge-like in that they permit flexion in one plane  to the exclusion of others. The longer prezygapophyses of the mid-cervicals may have limited extension in this region, but the anterior-most vertebrae have shorter zygapophyses that may have permitted greater degrees of dorsal rotation. These observations are corroborated by comparisons of zygapophyseal shape with animals bearing flexible necks: forms with increased cervical flexibility have short, high-angle zygapophyses with mediodorsally inclined articulator facets, allowing the zygapophyses to slide as the neck flexes. Manipulation of the posterior PteranodonAnhanguera; The relative inflexibility of the mid-cervicals may have served to strengthen inter-vertebral joints, thereby forgoing the need for large epaxial ligaments. The reduced extent of such soft tissue is verified by the lack of sculpting for deep muscle or ligament attachment on all azhdarchid cervicals with the exception of cervicals eight and nine, which contrast with their predecessors in bearing prominently developed neural spines and, on cervical nine, transverse processes ZhejiangopterusPteranodon in Quetzalcoatlus and AzhdarchoAralazhdarcho atlas-axis demonstrates a morphology similar to that of other azhdarchid cervical vertebrae with posterolaterally directed exapophyses and a dorsoventrally compressed condyle ZhejiangopterusThe atlas-axis articulation may also have had limited flexion, despite proposals that this was a main source of flexibility in the azhdarchid neck Hatzegopteryx supraoccipital bears a well-developed medial ridge similar to that of ornithocheirids TapejaraRhamphorhynchusCombined, these observations suggest a relatively limited range of motion in the azhdarchid cervical series. Azhdarchids probably held their necks in a manner similar to lizards and crocodiles with relatively little curvature of their vertebral columns PteranodonAnhangueraResearch into pterosaur flight has principally focused on ornithocheiroids like Quetzalcoatlus with an 11–12 m wingspan may have weighed 86 kg and, with a 15.5 m wingspan, 136 kg. Citing Bramwell and Whitfield's Pteranodon, Wellnhofer Quetzalcoatlus could be too high and that its weight may have been comparable to modern ultra-light aircraft. Shipman Drawing conclusions about the flight of pterosaurs is problematic due to our limited understanding of their paleobiology. Modelling flight is particularly difficult for the larger forms due to the lack of equivalently sized extant analogues 3 in order to allow masses of under 125 kg . We note that the masses of not only giant azhdarchids but all pterosaurs have been grossly underestimated and suggest that the flight calculations based on these hyper-lightweight estimates be treated with caution.It is noteworthy that all mass estimates of azhdarchids have been based on methods for which pterosaur soft tissue density has to be estimated. Many pterosaurs exhibited extensive skeletal pneumaticity e.g.  and azhdSome conclusions on azhdarchid flight can be drawn from their wing morphology alone. Wing planform is highly diagnostic of flight style in extant animals Quetzalcoaltus of 1.13, one of the lowest limb ratios for any pterodactyloid. This contrasts with the limb ratio of 1.45 present in Zhejiangopterus: a more typical pterodactyloid limb ratio . Consequently, with their abbreviated wing fingers and long hindlimbs incorporated into the wing membrane, azhdarchids possessed relatively short, broad wings. Reconstructing the azhdarchid wing with broad brachiopatagia  are thought to have been produced by an azhdarchid , and sub-equal digit lengths (a character shared with Zhejiangopterus). Tapejarid feet show some of these characters but bear large claws on all digits Pteraichnus sp. from Mexico Haenamichnus, albeit produced by a considerably smaller azhdarchid.While the terrestrial abilities of pterosaurs were once regarded as non-existent to poor, reassessments of pterosaur trace fossils indicate that pterodactyloids were competent walkers and runners hdarchid . HaenamiZhejiangopterus as a template, the Haenamichnus trackmaker can be estimated to have stood almost 3 m tall at the shoulder and to have had a wingspan of over 10 m. In concert with the large size of this trackmaker, one Haenamichnus trackway has a length of 7 m and is the longest pterosaur trackway yet known Haenamichnus trackway demonstrates that the presumed azhdarchid trackmaker had a particularly narrow gait with pes prints regularly overlying manus prints, an observation suggesting particularly efficient terrestrial locomotion compared to that inferred from other pterosaur trackways. The Haenamichnus pes prints show that the feet possessed soft tissue pads on the digits, metatarsal heads and heel in the manner of some tapejarids Using Quetzalcoatlus are relatively robust compared to those of Pteranodon. This contrasts with the relative pes length of azhdarchids, which was comparatively small for their body size. The pes of Quetzalcoatlus is approximately 25% of tibial length, and that of Zhejiangopterus 30% tibial length Pteranodon and HuaxiapterusGermanodactylus, 69% in Pterodactylus and 84% in Pterodaustro. In modern birds, long feet with large surface areas are often associated with swimming or wading behaviour Good descriptions of azhdarchid pes material are lacking, but Bennett Zhejiangopterus demonstrates longer limbs relative to body length than any other pterosaur. Increased forelimb length is mainly achieved through elongation of the wing metacarpal, creating limb bones proportions similar to those of cursorial ungulates. However, the plantigrade hindlimb does not resemble that of cursorial tetrapods, with a tibia only 20% longer than the femur Further evidence of terrestrial competence in azhdarchids stems from their atypically long limbs. With the exception of ornithocheirids with their disproportionately long forearms and small bodies, Quetzalcoatlus was an obligate scavenger is partially based on the association of sauropod remains with the pterosaur material, but this was refuted by Martill Lawson's Quetzalcoatlus remains with invertebrate trace fossils The suggestion that azhdarchids may have probed into sediments in search of infaunal invertebrates is based on the association of The possibility that azhdarchids were aerial predators of smaller flying animals Although many modern birds regularly swim or dive in pursuit of food, there is no anatomical evidence that azhdarchids did the same . Extant birds demonstrate multiple approaches to feeding on and in water, including surface feeding, plunge diving, and surface diving Quetzalcoatlus-bearing Javelina Formation might refute a piscivorous diet, but the occurrence of azhdarchids in a variety of depositional settings with associated fish fossils  cross-sections Rynchops, no portion of the azhdarchid mandibular symphysis extended beyond the premaxilla, and the rhamphothecae preserved in other azhdarchoid taxa No azhdarchid exhibits any of these adaptations nor any functional alternatives, and in many details azhdarchids appear maladapted for skim-feeding. While slender, the dorsal surfaces of the mandibular symphyses in Quetzalcoatlus and Rynchops. Although the quadrate-articular joint of Quetzalcoatlus shows some additional lateral bracing RynchopsCrucially, other than in their gape, there is little similarity between the jaw articulation in RynchopsRynchops that produces high mechanical advantage through relatively tall neural spines and pronounced dorsal curvature of the cervical series The azhdarchid neck also lacks the structures needed to cope with the drag forces and jarring impacts incurred during skim-feeding. Not only is the azhdarchid neck totally incapable of the considerable flexion needed for skim-feeding, it also lacks sculpting for strong ligament and muscle attachment that are unusually prominent in Rynchops that facilitate fast, efficient ‘flap-gliding’ Furthermore, it is highly unlikely that ventral rotation of the azhdarchid skull at the occipital condyle could have absorbed skimming impacts in compensation for the stiffened neck. The apparent inflexibility of the axis-cervical three joint requires that all rotation took place at the occiput-axis and atlas-axis junctions, both of which are small and wholly insufficient to absorb jarring impacts. The position of the occiput also precludes extending the jaw tips to the combined length of the jaw and neck, as the skull cannot be rotated enough to align the jaws and neck on the same plane [contra. 27]. Equally, the suggested strategy of keeping the wings held at neck's length from the water surface may compromise the wing-in-ground effect benefits that are known to be important in the flight of modern skimmers Many elements of the azhdarchid skeleton that preclude skim-feeding also apply to their inability to dip-feed . This feeding method has been proposed for azhdarchids by various authors Haenamichnus footprints suggest that their extremities had relatively small surface areas, a condition quite different to the splayed feet of wading birds The wading ecology proposed for azhdarchids by several workers Haenamichnus trackway: bringing the limbs closer to the midline allowed grounded azhdarchids to support their weight largely through compressive forces acting on sub-vertical limbs. Other trackways show that non-azhdarchid pterosaurs had partially abducted limbs when moving terrestrially Our interpretation of the evidence has led us to conclude that azhdarchids severed the ties with aquatic foraging conventionally assumed for pterosaurs e.g. , and thaThe unusual pterosaur manual morphology and lack of large claws suggests that azhdarchids did not employ their limbs in apprehension of prey, even when grounded. It is assumed, therefore, that the jaws were the primary agents of prey apprehension, and would need to be lowered to ground level to procure food. Due to the long azhdarchid hindlimb, relatively little flexion is required in the forelimbs to bring the skull and neck towards the ground . MoreoveThe azhdarchid skull has a similar construction to modern birds that habitually stalk terrestrial environments , or Anastomus, the open-billed stork (which possesses scopate tomial edges and upper and lower jaws that bow away from each other. These are apparently specializations that assist in the holding of hard-shelled prey Hence, although azhdarchid anatomy is unique in a number of aspects, they appear to have been stork- or ground hornbill-like terrestrial stalkers , with thStudies of pterosaur ecology have suffered from the dogmatic attitude that pterosaurs were predominately aerial piscivores living in coastal settings, in spite of steady accretion of evidence that they occupied a variety of ecological roles in a suite of environments. The unusual anatomy of azhdarchids strongly indicates that they had a unique ecology and inhabited unusual environments compared to many other pterosaurs: these details have been overlooked by most authors who have interpreted azhdarchids as marine piscivores occupying niches conventionally considered typical of pterosaurs as a whole. This unusual lifestyle may explain the resilience of azhdarchids to decline in contrast to other Cretaceous pterosaur lineages, few or none of which persisted to the late Maastrichtian as did azhdarchids. It is hoped that this re-revaluation of azhdarchid ecology will inspire much-needed descriptions of azhdarchid material, empirical testing of the hypotheses presented here, and further research into the lifestyles of pterosaurs beyond their flight capability.


Breast cancer incidence may be increasing in Thailand but very little research has assessed core breast cancer risk factors in this country.We used baseline questionnaire data from a national cohort study of Thai Open University students in an exploratory case-control study of breast cancer. The study included 43 female cases and 860 age-matched controls selected from the remaining 47,271 female cohort participants. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression.The women were predominantly premenopausal. Taller women had an increased risk of breast cancer  as did women with non-insulin dependent diabetes mellitus . Women with older siblings had a reduced risk of breast cancer compared to those firstborn .Although limited by small case numbers, our findings suggest substantial increases in breast cancer rates in Thailand could be expected in the future. Although there have been positive health benefits associated with Thailand's rapid socio-economic development, some negative health consequences of Western-style disease patterns are also emerging. Breast cancer is one example of this. In Western terms breast cancer is still relatively uncommon in Thai women  is implementing programs for breast cancer control, including promoting breast self-examination. However, primary prevention, a challenge in all countries, is hindered by the limited data on risk factors in Thailand. To our knowledge only three studies investigating breast cancer etiology in Thailand have been published,To help redress the lack of risk factor information, we have conducted a case-control study of breast cancer, analysing associations with a large set of exposures. Our data derive from baseline records for the Thai Cohort Study (TCS), a national Open University cohort currently under study for health-risk transitions.The TCS includes 87,134 students of the Sukhothai Thammathirat Open University (STOU) who completed a mailed baseline survey in 2005. They represent 44% of the enrolled students contacted The questionnaire listed 24 diseases (including breast cancer), and participants were asked to mark any ever diagnosed by a doctor. All women who reported a diagnosis of breast cancer were contacted by mail or by telephone and asked to confirm their self-report, and to further provide their age at diagnosis, specifics of diagnostic procedures and treatments, and where these occurred. A definite diagnosis was established on clinical grounds for 43 women. For each confirmed case, 20 female controls matched on year of age were chosen at random from the rest of the cohort.A wide variety of variables were assessed for possible associations with breast cancer: sociodemographic , reproductive , lifestyle  and personal .Women were asked how many children they had and, their age at their first birth. Breastfeeding history was collected for a woman's last birth only.2) and categorised this using suggested cut-points for overweight and obesity amongst Asian populations.Participants were asked if they had ever smoked cigarettes or consumed alcohol, but regular amounts were not captured. Dietary questions targeted the balance of traditional and modern eating practices and requested limited quantitative information about food such as fruit and vegetables, soy-based foods, milk and deep-fried foods. Women were asked to record their height and weight. The relationship between height and breast cancer was assessed in three categories based on approximate thirds in the control women. We calculated body mass index (BMI – weight (kg)/height (m)In separate analysesWe examined relations with selected reported diseases including diabetes mellitus, hypertension, heart disease, asthma and various other cancers. We did not specifically ask for family history of breast cancer, but used whether their mother had died of cancer (where breast cancer would be a fairly major contributor) as an approximation of family history.Data analysis was initiated with simple univariate case-control comparisons and tables were examined for differences in distributions that warranted further consideration. The relatively small case numbers precluded extensive stratified analyses.Conditional logistic regression retaining the matching on age was then used to assess relations of variables with breast cancer after adjustment for potential confounders. A core model was established, including ever having had children (yes/no), height (in cm) and income . Other variables of interest were added to measure their adjusted effects, with models kept as parsimonious as possible in light of the small case numbers.Menopausal status was not recorded in the questionnaire so we used age as a proxy, and repeated analyses restricted to women 45 years and younger at diagnosis  to examine the effects in this group alone.There was no significant difference in the occurrence of breast cancer between women who had and had not had children , nor was there a significant relation with number of births or the age a woman was when her first child was born . A similar result was seen for breastfeeding (of the youngest child) amongst parous women . The number of case women with only one birth, and thus complete breastfeeding information, was too small . Although there were no significant differences in breast cancer according to BMI, odds ratios were elevated in women who were classified as underweight or obese compared to women of normal weight . When analyses were restricted to women aged 45 years or less at diagnosis , the association with underweight became stronger  and that with obesity weakened , although the interaction was not statistically significant.There was no significant association between breast cancer and the selected measures of physical activity/sedentary behaviour .Very few women were smokers or had drunk alcohol and we found no relation between these factors and breast cancer occurrence.The occurrence of breast cancer was reduced in women reporting consumption of milk  and increased in those reporting daily versus less than weekly consumption of soy products . Intake of fruit and vegetables did not vary by case-control status.n = 3). No other reported diseases showed any association, nor was there one between our measure of family history of cancer and breast cancer.Women who were the second or subsequent child born in their families had a significantly reduced risk of breast cancer when compared to those first born. There was also very strong and significant relation between non-insulin dependant diabetes (NIDDM) and breast cancer  although this was based on a very small number of affected case women , but our findings with respect to recent behaviours require cautious interpretations. The other usual challenges to validity are less likely to be troublesome here: The women in our study are relatively young and were mostly premenopausal at diagnosis and thus our findings may be less applicable to older women, but in low-incidence populations such as Thailand the peak incidence occurs in women between the ages of 40 and 55The main established reproductive risk factors for breast cancer are nulliparity, late age at first birth, early age at menarche and late age at menopause;The most consistent patterns we have observed here relate to body size. We found the tallest women had a two-fold increase in risk of breast cancer compared to the shortest. The association between height and breast cancer may reflect the influence of early diet or growth factors on breast cancer development2 had more breast cancer, as did those who were overweight or obese.With respect to BMI, amongst this group of mostly premenopausal women, those who were underweight or obese had the strongest association with breast cancer, although the non-significant nature of the findings needs bearing in mind. With older women excluded the effect of underweight appeared to strengthen and that of obesity to attenuate. Overall most studies have found elevated BMI associated positively with breast cancer in post-menopausal women and inversely in premenopausal women We also found an inverse relationship between higher birth order and breast cancer risk. Such a link is biologically plausible given that those first born are exposed to higher levels of oestrogens in utero compared to those later born.A diagnosis of NIDDM was also significantly associated with breast cancer occurrence in this population, although based on only three affected case women. As the cases were prevalent it is possible that the association reflects more regular medical surveillance in these women. However, other chronic diseases such as hypertension and arthritis were no more likely to be diagnosed in cases than controls suggesting diagnostic bias is not so likely; and a recent meta-analysis supports this positive relation, perhaps indicating a link between elevated insulin or IGF-1 levels and breast cancer development.We did not observe any clear evidence of a relation between physical activity or sedentary behaviours and breast cancer risk, but the study was underpowered to detect the moderate differences in risk generally associated with these. Physical activity may also be less relevant to this younger group of women as most evidence suggests that physical activity decreases the risk of post-menopausal breast cancer only.n = 47,314), the youngest group of women (15–19yrs) are on average 3 centimetres taller than the oldest group of women (50+yrs) and there is a highly significant trend of increasing height with decreasing age (p < 0.0001). Our results and those of others suggest therefore, that as the cohorts of taller women age in Thailand, breast cancer incidence will increase accordingly. Other secular changes, such as a decrease in the average age at menarcheOur results require confirmation in prospective data sets with full arrays of relevant variables, and in older post-menopausal women. However, put into context with other studies of breast cancer undertaken in similar populations, our findings suggest a substantial increase in breast cancer incidence could be anticipated in Thailand, but also point to potential avenues for cancer control in the country. Average heights have been increasing over the past few decades in several transitioning Asian populations,Other risk factors identified here may be more amenable to primary prevention. Increasing rates of obesityAlthough rates of breast cancer amongst Thai women are relatively low at present, the findings we have presented here, along with those of others, suggest a substantial increase could be expected in the future.There are no conflicts of interest. The funding bodies had no role in the study design; the collection, analysis and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication.The study has ethics approval from the Australian National University, the Sukothai Thammathirat Open University (STOU) and the University of Queensland. All participants gave informed consent to the study.


Natural selection sculpts phenotypes to enable adaptation to local conditions. Biologists have long been interested in the phenotypic and molecular response to selection, but we still know little about the genetic basis of adaptation. With continuing improvements in molecular technologies, we now have the tools to investigate the genes that underlie ecologically important traits. Assessing the geographic distribution of allelic variation at these loci can point to the agents of selection, if different alleles are advantageous in contrasting environmental conditions Arabidopsis thalianaFew studies have linked geographic variation in allele frequencies with variation in phenotypes but see . StudiesPLoS Genetics, Baxter et al. AtHKT1;1 in European populations of A. thaliana. In a laboratory experiment, Baxter and colleagues grew Arabidopsis accessions in non-saline soil (without elevated Na+) and found substantial variation in the accumulation of sodium in leaf tissue, which indicates tolerance to saline soils. Furthermore, foliar Na+ of these genotypes decreased with distance from the collection site to nearby regions with saline soils In this issue of AtHKT1;1 candidate gene and foliar Na+ accumulation +, in conjunction with gene expression studies, and found that elevated salinity tolerance is associated with hypofunctional alleles of AtHKT1;1. These molecular data can be brought to bear on the geographic cline in salinity tolerance: accessions with a hypofunctional allele at AtHKT1;1 occur in areas where the soil is likely to be saline.A genome-wide association study revealed a significant association between the AtHKT1;1 is an adaptive response to variation in soil salinity. In addition, human disturbance could contribute to this allelic cline, as the genotype associated with salt tolerance is distributed primarily near major ports and could have been dispersed along shipping lanes , which can maintain genetic variation within species For the past decade, QTL (quantitative trait loci) cloning has been the rate-limiting step for many laboratories. Now, improvements in technology and resources are enabling advances such as the current study, and biologists can turn to functional elucidation of newly identified genes and ecological analyses of plants in their environments. As the field matures, molecular biologists and ecologists should work together towards field studies of allelic adaptation to local environments. Experimental plants can be grown under ecologically relevant conditions, e.g., in soil of different salinities collected from multiple sites, or in common garden field experiments at high and low salinity sites. Quantification of traits and fitness components under natural conditions is essential for measuring selection on phenotypes and on alleles at candidate genes. In this instance, field studies could test whether the hypofunctional allele at Determining the mechanistic basis of geographic clines will be considerably more complicated for studies of quantitative traits controlled by multiple loci. Nature is far more complex than laboratory conditions, and candidate genes identified in the lab might not be associated with traits in the field