bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial angiotensin II receptor expression and ischemia-reperfusion injury
Authors: Yang Baichun , Li Dayuan , Phillips M Ian , Mehta Paulette , Mehta Jawahar L
Published: January 2007

The renin-angiotensin system plays an important role in myocardial ischemia-reper-fusion injury. Angiotensin II (Ang II) contributes to the evolution of ischemic coronary events through its hemodynamic, hemostatic and mitogenic effects. Angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor antagonists have been shown to be cardioprotective in experimental animal models, with ischemia-reperfusion injury and in patients with congestive heart failure. Ang II receptors include at least two different subtypes, AT1 and AT2. Both AT1 and AT2 are expressed in the rat heart. Myocardial AT1 receptor density increases in association with ACE expression, and AT1 receptor activation is related to collagen formation following myocardial infarction in rats. Studies from the authors' laboratory have shown significant myocardial dysfunction in association with a concurrent increase in AT1 receptor expression in the rat myocardium immediately following a brief period of ischemia and reperfusion. Application of antisense oligodeoxynucleotides (AS-ODN) directed at AT1 receptor messenger RNA and AT1 receptor antagonist, losartan, significantly attenuates myocardial dysfunction induced by ischemia-reperfusion in the isolated rat heart. These observations suggest that myocardial AT1 receptor expression is involved in myocardial dysfunction following ischemia-reperfusion. Unlike losartan, which upregulates the plasma Ang II level, administration of AS-ODN does not affect plasma Ang II level. Although the reason for this is not clear, the difference in plasma Ang II levels implies that AS-ODN may be, at least theoretically, more beneficial than losartan in limiting ischemia-reperfusion-induced cardiac dysfunction. Apoptosis, or programmed cell death, also contributes to the outcome of myocardial ischemia-reperfusion injury. Recent studies from the authors' laboratory have demonstrated that Ang II induces apoptosis in cultured human coronary artery endothelial cells via activation of AT1 receptors and this can be blocked by losartan. These observations collectively underscore the importance of myocardial AT1 receptor expression in ischemia-reperfusion injury.
Impaired endothelial regulation of vascular tone in patients with systemic arterial hypertension
Authors: Cardillo Carmine , Panza Julio A
Published: January 2007

The discovery of the endothelium as a major regulator of vascular tone triggered intense research among basic and clinical investigators to unravel the physiologic and pathophysiologic significance of this phenomenon. Importantly, endothelial modulation of the contractile state of vascular smooth muscle has been shown to be impaired in atherosclerosis and in several conditions known to be associated with the premature development of atherosclerosis. Studies in several different animal models of arterial hypertension, and in patients with both essential and secondary hypertension, have demonstrated an association between elevated systemic blood pressure and impaired endothelium-dependent vascular relaxation. More recently, a diminished bioavailability of nitric oxide (NO) has been identified as a mechanism responsible for endothelial dysfunction in hypertensive patients. Different processes may, in turn, explain this decreased vascular activity of NO. The present review focuses on those clinical studies that are aimed at identifying the precise abnormality responsible for reduced NO-depen-dent vasodilation in patients with essential hypertension. Understanding of the basic mechanisms of this process may prove to be beneficial for the development of more specific therapies and ultimately for the outcome of hypertensive patients.
Clinical pharmacology of the adenosine diphosphate (ADP) receptor antagonist, clopidogrel
Authors: Schrör Karsten
Published: January 2007

Antiplatelet compounds interfere with the platelet activation cascade at different levels. The antiplatelet effect of the thienopyridine, clopidogrel, results from antagonism of a platelet ADP receptor, P2T, resulting in inhibition of platelet activation. This antagonism is non-competitive, irreversible, and results in a 50-70% inhibition of platelet fibrinogen binding. Additionally, clopidogrel may also antagonize the ADP-induced inhibition of adenylate cyclase, possibly resulting in an elevated platelet cyclic adenosine monophosphate level after stimulation by an appropriate agonist, such as prostacyclin. This spectrum of antiplatelet activities is different from that of aspirin. Further, clopidogrel is associated with a reduction in gastrointestinal hemorrhage, making it a valuable therapeutic alternative to aspirin in oral, long-term prevention of atherothrombotic vascular occlusion.
A systematic review of compression therapy for venous leg ulcers
Authors: Palfreyman Simon J , Lochiel Rona , Michaels Jonathan A
Published: January 2007

The aim of the study was to determine the relative effectiveness of compression therapies used in the treatment of venous leg ulcers. Randomized controlled trials (RCT) were sought using a search strategy that aimed to identify relevant RCT by searching eight electronic databases (including Medline, Embase and CINHAL), conference proceedings and hand searching key journals. In addition, citations within papers were scrutinized to identify any relevant studies. Suitability for inclusion in this review was determined by a critical appraisal of key determinants of the quality of the trials. Trials that included patients of mixed ulcer aetiology were excluded unless the results of patients with venous disease were reported separately. Data was extracted independently by two reviewers and synthesized quantitatively and qualitatively. Losses to follow-up/withdrawals were assumed to be failures of treatment.

A total of 132 articles were identified, and of these eight fulfilled the inclusion criteria. The remaining 126 trials were excluded due to trial design flaws, the inclusion of mixed/arterial aetiology ulcers or because they were non-RCT. Meta-analysis using a random-effects model showed the benefits of multi-layer and elastic compression bandages. It was concluded that more high-quality trials are required and that more emphasis should be placed on economic and quality of life data to try to ascertain the cost-effectiveness and utility of the treatment options available.
Management of intracranial aneurysms
Authors: Chang Steven D , Steinberg Gary K
Published: January 2007

Intracranial aneurysms are lesions commonly encountered by neurosurgeons, usually as a result of subarachnoid hemorrhage. The preferred treatment of these aneurysms is either surgical clipping or endovascular coiling, both of which eliminate the aneurysm from the normal circulation to prevent aneurysmal enlargement or additional hemorrhage. Despite advances over the last several decades in the understanding of intracranial aneurysms, morbidity from treatment of these lesions remains significant. This review will discuss the epidemiology, anatomy and pathophysiology, clinical and radiographic diagnosis, various treatment options, and potential complications from aneurysm treatment.
Antiphospholipid antibody syndrome in a patient with neurosarcoidosis
Authors: Satti Srinivasa D , Bartholomew John , Gordon Steven M , Longworth David L , Adal Karim A
Published: January 2007

The case of a 56-year-old woman who developed neurosarcoidosis and was discovered to have inferior vena cava and lower extremity thromboses is described. She was found to have anticardiolipin antibodies. This newly described association of antiphospholipid antibody syndrome with sarcoidosis is discussed and the relevant literature reviewed.
Circadian variation and triggering of cardiovascular events
Authors: Willich Stefan N
Published: January 2007

Myocardial infarction and sudden cardiac death demonstrate a marked circadian variation with an increased risk during the morning after awakening and arising. The recognition of the morning increase of acute cardiovascular events has convinced many that they may be triggered by morning activities. It is of note, however, that cardiovascular events occur throughout the day - even if at lower frequency compared with the morning.

There is a strong association between external triggers and the onset of myocardial infarction and sudden cardiac death beyond what is to be expected by chance alone. The magnitude of this association (relative risk two-to threefold) is comparable with the known long-term risk factors of cardiac disease. Trigger factors occur relatively frequently and may play a causative role in up to 20% of cases of acute coronary syndromes. Physical exertion, bursts of anger and sexual activity have been proved to have triggering potential. Other possible triggers include external and environmental events such as earthquakes, war threat and climatic factors.

The pathophysiological links between external triggers and the onset of cardiovascular events are important in addressing the question of a causal relationship between triggers and disease onset and in perhaps improving preventive strategies.
Incidence and determinants of mortality and cardiovascular events in diabetes mellitus: a meta-analysis
Authors: Kanters Suzan DJM , Banga Jan-Dirk , Stolk Ronald P , Algra Ale
Published: January 2007

Patients with diabetes mellitus are at increased risk of developing atherosclerotic disease. The extent of this additional risk and its determinants are not well known, but this information is needed for sample-size estimations in intervention studies. Therefore, a meta-analysis of epidemiologic studies on this subject was performed. Medline was searched from 1966 onwards, including the reference lists of all relevant publications. A total of 27 prospective follow-up studies in the English language that allowed calculation of the unadjusted incidence of one of the predefined outcome events were included. The influence of age, sex, type of diabetes, duration of diabetes, year of study, HbA1c, cholesterol level, blood pressure and smoking on these incidences was studied by means of univariate Poisson regression analysis.

Overall total mortality was 2.9% per year (95% CI 2.8-3.0; 27 studies), and for death from all vascular causes was 1.4% per year (95% CI 1.3-1.4; 16 studies). Only two studies were found that reported on the incidence of the composite outcome `event death from all vascular causes, non-fatal myocardial infarction, or non-fatal stroke'. In univariate analysis, age, year of study, total cholesterol and systolic blood pressure were positively related to total mortality and death from all vascular causes. After adjustment for age, or limiting the analyses to studies in patients with type 2 diabetes only (n = 11), these relationships remained statistically significant. In conclusion, the overall yearly total mortality in diabetes mellitus is 2.9% and for death from all vascular causes is 1.4%. There are few data on the incidence of composite cardiovascular outcome events.
Ulnar artery aneurysm with digital ischemia
Authors: Torre Joanne
Published: January 2007

The case of a young male patient with a thrombosed distal ulnar artery aneurysm and digital emboli is presented. The hypothenar hammer syndrome is reviewed, with particular attention to clinical presentation, differential diagnosis and the non-invasive and invasive diagnostic evaluation. Surgical and thrombolytic therapeutic options are reviewed with reference to the available literature.
Acute coronary ischemia: troponin I and T
Authors: Sacks David B
Published: January 2007

Despite advances in diagnosis and management, ischemic heart disease remains the leading cause of death in the USA. Serum cardiac enzymes, one of the three fundamental criteria for establishing the diagnosis of myocardial infarction, are not specific for cardiac muscle and have a narrow time-window. The recent development of monoclonal antibodies to cardiac troponin I and troponin T has resulted in cardiac-specific assays. Several published studies have documented the utility of troponin proteins in the evaluation of myocardial necrosis. A brief overview of the characteristics and clinical utility of troponin T and I is presented here.
Physiological response in the injured transplant patient
Authors: Jones TJJ , Hyde JAJ , Wilson IC , Graham TR
Published: January 2007

Solid organ transplantation as a treatment for end organ failure is increasing in success. Consequently there are more transplant recipients leading more active lifestyles, resulting in an increasing number presenting as an emergency to hospitals remote from their transplant centre as victims of trauma. A basic knowledge of the anatomy, physiology and pharmacology specific to this group of patients is prerequisite to their successful management. Following a brief history, the incidence and indication for each type of solid organ transplant is detailed, followed by relevant anatomy and physiology. An overview of current immunosuppression and its related side-effects is followed by a discussion concerning vascular access and invasive monitoring.
Airway management: the difficult airway
Authors: Bryden DC , Gwinnutt CL
Published: January 2007

Maintenance of a patent airway to allow ventilation with high concentration oxygen is an essential procedure during the resuscitation of all trauma patients. A range of equipment is available to help achieve and maintain a clear airway, with endotracheal intubation remaining the gold standard. However, in trauma patients attempts at intubation are often impeded by the presence of associated injuries and the application of devices to immobilize the cervical spine. In the situation of ‘can’t ventilate, can’t intubate’ a surgical airway can be life-saving while expert help is sought. Recently, new devices, in particular the laryngeal mask airway and Combitube®, have gained recognition as having a role in difficult airway management when other methods have failed, thereby reducing the need for surgical intervention. This paper presents an overview of the currently accepted methodology of managing the difficult airway in the trauma patient.
Female genital mutilation
Authors: Khaled MA , Cox Charles
Published: January 2007

Female genital mutilation (FGM) is practiced worldwide, including in the UK. The term ‘female circumcision’ suggests a relatively benign procedure, inviting comparison with male circumcision, which, although usually medically unnecessary and uncomfortable, rarely causes long-term problems. In fact, the female procedure is responsible for long-term gynaecological morbidity and greatly increased mortality and morbidity in childbirth for both mother and baby.

For many reasons - cultural, religious and sexual - worldwide efforts to reduce the practice are meeting resistance. This paper sets out the methods and classification of FGM, the position of the World Health Organization and other international agencies, and considers the problems from a British perspective.
Pre-hospital fluids - when and how much?
Authors: Revell Matthew P , Porter Keith M
Published: January 2007

When to give intravenous fluids, how much to give and whether intravenous fluids improve patient outcome remain controversial areas. Hypovolaemic shut down patients are difficult to connulate. The on scene is protracted and invariably relatively small volumes of fluid are infused. Those patients who are hypotensive invariably require definitive surgical intervention, therefore, any delay in reaching hospital can worsen outcome. Intravenous fluids given in states of uncontrolled and noncompressible bleeding will enhance blood loss. There is therefore a need to define those patient groups requiring pre-hospital intervention and optimal recusitation objectives in terms of blood pressure in the pre-hospital scene. This paper examines the current evidence base in both animal and human trials and makes recommendations for optimal fluid management in the trauma patient.
Colorectal trauma
Authors: Amin SN , Rowlands BJ
Published: January 2007

The management of traumatic injuries to the colon and rectum has undergone a significant change since World War II. Penetrating injuries are the most common cause of trauma to the colon and rectum. Colon and rectal perforation after blunt trauma are uncommon but not rare. For years, colostomy formation was considered the only acceptable form of treatment for injuries penetrating the colonic mucosa. With the realization that dictums governing colonic injuries during military conflicts were, for the most part, not applicable to civilian injuries, the pendulum has swung from mandatory colostomy to immediate repair in the management of uncomplicated cases. Accompanying these changes in management together with improvement in perioperative care, trauma service and the use of more powerful antibiotics, a significant reduction of mortality rates to less than 5% has been seen in many centres. In the presence of other risk factors, for example multiple associated injuries, severe shock, Penetrating Abdominal Trauma Index (PATI) of more than 25, colostomy is still an option to be considered.
Long-term psychiatric effects of trauma on children
Authors: Trickey David , Black Dora
Published: January 2007

Even minor physical trauma can lead to significant psychological difficulties in children and adolescents, which are often overlooked. Their immediate reactions include behavioural, emotional and cognitive difficulties. Their thinking about the world can be disrupted, leading to further problems. Initial reactions can have a further knock-on effect, with significant consequences sometimes leading to an impact upon their adult personality. Major disaster plans should include a psychosocial aspect. Immediately following trauma, children should be re-united with their carers or a familiar adult as soon as possible. They should be offered an age-appropriate, careful, explanation of what has happened to them and what their treatment involves. Routine screening for psychological problems may help to prevent chronic psychological sequelae. Various treatments are available for psychological problems that persist.
Abdominal compartment syndrome
Authors: Demetriades D
Published: January 2007

The classical abdominal compartment syndrome, which is characterized by abdominal distention, and cardiorespiratory and renal function compromise, is a late manifestation of intra-abdominal hypertension. Significant organ dysfunction occurs much earlier and it is important to recognize and treat the problem at its early stages. Prolonged hypotension requiring massive fluid resuscitation or other conditions associated with bowel hypoperfusion are the most critical factors in the development of intra-abdominal hypertension, even in the absence of abdominal trauma. Close monitoring by means of clinical examination and bladder pressure measurements are essential for all patients at risk. Decompression by means of laparotomy and temporary abdominal wall closure with a prosthetic material should be performed as early as possible.
The role of recreational drugs in trauma
Authors: Vidhani Kim , Parr Michael
Published: January 2007

The association of trauma with illicit/recreational drugs is being increasingly recognized but is difficult to quantify. Significant amounts of these substances are readily available and may be taken alone, in combination with other drugs or with alcohol. The acute and chronic effects of these drugs result in numerous difficulties in management. Health-care workers involved in the treatment of trauma must have a high index of suspicion for the presence of drugs and a detailed knowledge of their effects. In this article we will review the scale of the problem, the common drugs abused and their effects, and we will discuss guidelines for management.
Critical pitfalls in the immediate assessment of the trauma patient
Authors: Little George , Kelly Michael , Glucksman E
Published: January 2007

In the immediate assessment of trauma patients, critical pitfalls exist that may interfere with optimal clinical care. Failure to recognize the need for early anaesthesia and endotracheal intubation may put the patient at unnecessary risk and delay the assessment and treatment process. Pressure to clear the cervical spine may lead to inadequate imaging and premature removal of neck immobilization devices. The limitations of the initial chest X-ray in diagnosing pneumothoraces may not be appreciated and needle thoracentesis may be ineffective. ‘Springing’ the pelvis to assess for instability may cause life-threatening haemorrhage and should not be done prior to the initial pelvic X-ray. Log rolling may dislodge crucial clot formation and promote bleeding, and should only be used for diagnostic purposes. Applying clinical common sense to the assessment of trauma patients may avoid the pitfalls whilst allowing the clinician to operate within internationally agreed assessment and treatment frameworks.
Hyperbaric medicine in soft tissue trauma
Authors: Cosgrove Helen , Bryson Phil
Published: January 2007

Severe crush injuries of the soft tissues can result in tears of the large vessels and destruction of the microcirculation. This produces ischaemia and tissue necrosis and contributes to the development of oedema and compartment syndromes. All these factors compromise tissue survival. Immediately following a crush injury some areas of tissue are obviously irreversibly damaged, and others undamaged. It is common to have a ‘grey area’ between these, where there is uncertainty as to what will survive. Management of crush injury must involve surgical repair of vessels and soft tissues, debridement of obviously dead tissue, and bone stabilization. At the same time tissue perfusion must be maintained by manoeuvres such as fluid replacement and diminution of oedema, and when necessary fasciotomy. It has been proposed that hyperbaric oxygen therapy has a role, as an adjunct, in the maintenance of tissue oxygenation under these conditions, and will improve survival of tissues in the grey area, and thus minimize tissue loss. Hyperbaric oxygen therapy involves breathing 100% oxygen at pressures greater than one atmosphere. Presently, the pressures most often used are in the range 2-3 atmospheres absolute.
Managing the trauma patient: critical decision making and when to call for help
Authors: Anderson ID
Published: January 2007

Caring for the injured patient poses challenges to doctors of every grade but junior doctors can quickly contribute effectively and usefully to the management of the injured patient provided certain principles are followed. This paper seeks to set out some of these principles but is by no means exhaustive. Preparations necessary for the reception of injured patients centre around getting the right patient to the right doctor at the right time. Receiving hospitals should be well equipped and staff should have been trained along protocol guidelines such as Advanced Trauma Life Support (ATLSR) and a hospital trauma team should be established and functional. On arrival the injured patient is managed along ATLS-type guidelines with immediate assessment and treatment of life-threatening injuries. Once stabilized, a full evaluation of the patient can take place and selective investigation conducted. On occasion immediate surgery will be necessary but more commonly, plans can be made for prompt, but less dramatic, definitive care. It is well recognized that injured patients do not show all their injuries when they present and it is not infrequent for patients to deteriorate while undergoing investigation or on the ward subsequently. Thus there is a need for ongoing multidisciplinary care and for a high level of observation. The principles used for initial resuscitation can be extended to the ward-based phase of care. The complexities of trauma demand that every doctor involved has a low threshold for involving other specialists in the management of the patient in a prompt fashion. Conversely, it is important that one team take over all responsibility for the care of the patient and that other teams contribute proactively to the management plan.
Examination of the injured eye: single system injury
Authors: Jacks AS , Shah P
Published: January 2007

Eye trauma is common and all trauma doctors should receive instruction in ocular examination techniques. This article considers different elements of eye examination: facial asymmetry and orbital fractures, lacerations, eye movements, pupils, anterior segment, posterior segment, and the optic nerve. Emphasis is placed on paediatric patients and those who will be particularly difficult to examine, such as those patients with occult rupture of the eye or brain penetration. The eye should be examined as part of the secondary survey in all trauma patients once they have been stabilized as blinding injuries can be treated and sight saved.
The eye as part of a multi-system trauma
Authors: Jacks AS , Shah P
Published: January 2007

This article aims to help the clinician prioritize the ocular trauma patient. The patient should be assessed for signs which indicate the necessity for urgent referral. The eye may be difficult to assess, particularly in children. Examination of the eye may be unfamiliar to the clinician and if there is any doubt the patient should be referred for ophthalmic assessment. Key features of each of the aspects of the ophthalmic examination are highlighted and advice provided about those patients which require urgent referral. Emphasis is placed on the acutely compromised optic nerve and perforated globe requiring urgent referral.
Prevention of post-traumatic clinical capillary leak syndrome
Authors: Gosling Peter
Published: January 2007

Systemic capillary leak is an early feature of the inflammatory response to localized injury, and is proportional to the severity of the inflammatory insult. Loss of local control of inflammation leads to an exaggerated systemic inflammatory response known as systemic inflammatory response syndrome (SIRS). SIRS is associated with multiple organ failure and death when there is failure to maintain homeostasis.

Whilst the application of molecular biology and recombinant techniques have produced major advances in our understanding of the mediation of the inflammatory response, there is no agent currently available which will prevent SIRS and reduce the incidence of post-traumatic multiple organ failure. In the meantime, a more practical approach to the avoidance of SIRS and its attendant capillary leak syndrome is to attempt to reduce the deleterious effects of interstitial oedema by tailoring treatment to the rapid changes in capillary permeability.
The trauma patient - critical decision making - when to explore the chest?
Authors: Odell John A
Published: January 2007

The critical decisions regarding thoracotomy for trauma occur soon after the injury, when decisions have to be made that may influence survival or have an impact on morbidity if operation is delayed. Roadside thoracotomy is impractical, and should not be considered; instead, patients should be taken rapidly to the nearest hospital. Endotracheal intubation prior to transport appears to be beneficial, but the application of MAST trousers and the infusion of large volumes of fluid for hypovolaemia before control of haemorrhage offers no advantage and may be hazardous. On the whole, resuscitative thoracotomy is associated with a low salvage rate, especially for the patient sustaining blunt trauma, but may be worthwhile in the patient with penetrating trauma. Urgent, as opposed to immediate thoracotomy, should be undertaken once the patient has been stabilized. This may occur in most patients with penetrating injuries of the heart who survive to reach hospital, those with continuing, significant haemorrhage through chest drains, and those with tracheal, oesophageal and diaphragmatic injuries. Extensive open chest wounds require considerable ingenuity in closure, often with plastic surgical help. Patients with blunt traumatic rupture of the aorta often have multiple injuries, which may also be life threatening. If bleeding into the abdomen is demonstrated, then laparotomy should precede thoracotomy: musculoskeletal injuries and neurological injuries can usually be dealt with after the aortic rupture has been repaired.
Maxillofacial trauma: principles of management, priorities and basic techniques
Authors: David DJ
Published: January 2007

The management of maxillofacial trauma involves organs and regions managed by various well-established health care disciplines and is therefore multidisciplinary. The organization of this multidisciplinary care includes:

•Facility and personnel - the facility requires all the relevant diagnostic material and the personnel must have a special interest in maxillofacial trauma and form a dedicated team.

•Principles of management of facial fractures - these involve setting priorities, understanding the indications for operative intervention and developing techniques, of which one of the most significant is the wider exposure of the maxillofacial skeleton. This, together with interosseous fixation with mini- and microplates and the use of primary bone grafting, has brought about the most significant advances in this area of patient management.

Three case studies are presented, the first of which illustrates the management of a fractured zygoma requiring open reduction and internal fixation, using modern radiology to make the diagnosis and to check the correction. Case study two is an orbito-cranial fracture with major cranio-cerebral injury, highlighting the problems associated with a breech of the anterior cranial base and a cerebrospinal fluid rhinorrhoea. The third case illustrates a complex fracture involving the orbit and nasoethmoid complex, maxilla and mandible and illustrates the practical implication of the principles outlined in the paper.
Athletic injuries
Authors: Brown Malcolm W , Brown Ruth C
Published: January 2007

Injuries are common in the various disciplines that make up the sport of athletics. Diagnosis depends on an accurate history and competent examination, possibly assisted by imaging techniques such as ultrasound, magnetic resolution imaging and computerized tomography. It is also important to consider the influence of various intrinsic and extrinsic factors in deciding on the mechanism of injury. Most acute injuries relate to overstretching of soft tissue, whereas overuse injuries reflect repetitive microtrauma with degenerative or inflammatory consequences. Steroid injections should be restricted to situations where inflammation predominates. Surgery may be required for specific acute injuries and when supervised rehabilitation over 6 months fails to resolve chronic injury. Following surgery, physical and psychological rehabilitation should be carefully planned.
The role of archived photographs in Native California archaeology
Authors: Schneider Tsim D.
Published: January 2007

Archived photographs are discussed as a proven and principal means to understand cultural landscapes and the archaeological sites within. Photographs offer one means to include the voices and oral traditions of Native American descendent communities in an archaeological project by emphasizing the visceral ties between places and the people who created them. As artifacts, archived photographs act as touchstones to generate stories about people and places. They are capable of solidifying ties between people and ancestral territories, and their ability to engage Native Americans and other audiences in interpretive settings suggests their role as teaching devices. These three roles of archived photographs complement an indigenous archaeology by involving and empowering Native American communities, integrating oral traditions, and fostering a sense of site stewardship.
Blue Sky Boys, Professional Citizens, and Knights-in-Shining-Money: Philadelphia's Penn Center Project and the Constraints of Private Development
Authors: McKee Guian A.
Published: January 2007

During the 1950s, urban analysts frequently cited Philadelphia's Penn Center office project as emblematic of an urban “renaissance” in the United States. The development of Penn Center, however, was characterized by a series of conflicts that belie notions that the shared interests of public and private actors led to the quick formation of progrowth coalitions after the Second World War. Penn Center clearly demonstrated that local planners lacked the political, legal, and financial tools to control urban redevelopment projects implemented by private actors. Such constraints help to explain why even housing-oriented liberal officials such as those in Philadelphia supported the broadening of federal urban redevelopment legislation beyond its original “primarily residential” orientation.
Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2– versus IL-15–activated NK cells
Authors: Chiossone Laura , Vitale Chiara , Cottalasso Francesca , Moretti Sara , Azzarone Bruno , Moretta Lorenzo , Mingari Maria Cristina
Published: January 2007

Steroids have been shown to inhibit the function of fresh or IL-2–activated natural killer (NK) cells. Since IL-15 plays a key role in NK-cell development and function, we comparatively analyzed the effects of methylprednisolone on IL-2– or IL-15–cultured NK cells. Methylprednisolone inhibited the surface expression of the major activating receptors NKp30 and NKp44 in both conditions, whereas NK-cell proliferation and survival were sharply impaired only in IL-2–cultured NK cells. Accordingly, methylprednisolone inhibited Tyr phosphorylation of STAT1, STAT3, and STAT5 in IL-2–cultured NK cells but only marginally in IL-15–cultured NK cells, whereas JAK3 was inhibited under both conditions. Also, the NK cytotoxicity was similarly impaired in IL-2– or IL-15–cultured NK cells. This effect strictly correlated with the inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity in a redirected killing assay against the FcRγ+ P815 target cells upon cross-linking of NKp46, NKG2D, or 2B4 receptors. In contrast, in the case of CD16, inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity were not impaired. Our study suggests a different ability of IL-15–cultured NK cells to survive to steroid treatment, thus offering interesting clues for a correct NK-cell cytokine conditioning in adoptive immunotherapy.
The C/EBPδ tumor suppressor is silenced by hypermethylation in acute myeloid leukemia
Authors: Agrawal Shuchi , Hofmann Wolf-Karsten , Tidow Nicola , Ehrich Mathias , Boom Dirk van den , Koschmieder Steffen , Berdel Wolfgang E. , Serve Hubert , Müller-Tidow Carsten
Published: January 2007

Aberrant DNA methylation is the most frequent molecular alteration in acute myeloid leukemia (AML). To identify methylation-silenced genes in AML, we performed microarray analyses in U937 cells exposed to the demethylating agent 5-aza-deoxy-cytidine. Overall, 274 transcripts were significantly induced. Interestingly, C/EBPδ expression was significantly induced (more than 10-fold) by demethylation whereas expression of all other C/EBP family members remained unchanged. The C/EBPδ promoter was strongly methylated in different leukemic cell lines and showed signs of a repressed chromatin state. Analyses of the promoter regions of the entire C/EBP family (α, β, γ, δ, ϵ, ζ) in bone marrow samples from AML patients (n = 80) and controls (n = 15) by mass spectrometry revealed that C/EBPδ is the most commonly hypermethylated C/EBP gene in AML. Hypermethylation occurred in more than 35% of AML patients at primary diagnosis. A significant correlation (P = .016) was observed between hypermethylation of the C/EBPδ promoter and low expression of C/EBPδ in AML patients. C/EBPδ promoter activity was strongly repressed by methylation in vitro, and transcriptional repression partially depended on MeCP2 activity. C/EBPδ exhibited growth-inhibitory properties in primary progenitor cells as well as in Flt3-ITD–transformed cells. Taken together, C/EBPδ is a novel tumor suppressor gene in AML that is silenced by promoter methylation.
Sphingosine 1-phosphate regulates peritoneal B-cell trafficking for subsequent intestinal IgA production
Authors: Kunisawa Jun , Kurashima Yosuke , Gohda Masashi , Higuchi Morio , Ishikawa Izumi , Miura Fumi , Ogahara Ikuko , Kiyono Hiroshi
Published: January 2007

Sphingosine 1-phosphate (S1P) is known to play a pivotal role in the regulation of lymphocyte emigration from organized lymphoid tissues such as the peripheral lymph nodes and thymus, but its immunologic role in unorganized and diffused tissues remains to be elucidated. Here we show that the trafficking of peritoneal B cells is principally regulated by S1P. All peritoneal B cells including B1a, B1b, and B2 B cells express comparable levels of the type 1 S1P receptor. Thus, treatment with FTY720, an S1P receptor modulator, caused the rapid disappearance of peritoneal B cells by inhibiting both their emigration from parathymic lymph nodes and their recirculation from the blood into the peritoneal cavity without affecting their progenitor populations. These changes did not affect natural plasma antibody production or phosphorylcholine (PC)–specific antibody production in serum after peritoneal immunization with heat-killed Streptococcal pneumoniae (R36A). However, FTY720 dramatically reduced peritoneal B cell-derived natural intestinal secretory IgA production without affecting the expression of J-chain and polyimmunoglobulin receptors. Additionally, FTY720 impaired the generation of PC-specific fecal IgA responses after oral immunization with R36A. These findings point to a pivotal role for S1P in connecting peritoneal B cells with intestinal B-cell immunity.
HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development
Authors: Magnusson Mattias , Brun Ann C. M. , Miyake Noriko , Larsson Jonas , Ehinger Mats , Bjornsson Jon Mar , Wutz Anton , Sigvardsson Mikael , Karlsson Stefan
Published: January 2007

The Homeobox (Hox) transcription factors are important regulators of normal and malignant hematopoiesis because they control proliferation, differentiation, and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. In transgenic mice we show that the expression of HOXA10 is tightly regulated by doxycycline. Intermediate concentrations of HOXA10 induced a 15-fold increase in the repopulating capacity of hematopoietic stem cells (HSCs) after 13 days of in vitro culture. Notably, the proliferation induction of HSC by HOXA10 was dependent on the HOXA10 concentration, because high levels of HOXA10 had no effect on HSC proliferation. Furthermore, high levels of HOXA10 blocked erythroid and megakaryocyte development, demonstrating that tight regulation of HOXA10 is critical for normal development of the erythroid and megakaryocytic lineages. The HOXA10-mediated effects on hematopoietic cells were associated with altered expression of genes that govern stem-cell self-renewal and lineage commitment (eg, hepatic leukemia factor [HlF], Dickkopf-1 [Dkk-1], growth factor independent-1 [Gfi-1], and Gata-1). Interestingly, binding sites for HOXA10 were found in HLF, Dkk-1, and Gata-1, and Dkk-1 and Gfi-1 were transcriptionally activated by HOXA10. These findings reveal novel molecular pathways that act downstream of HOXA10 and identify HOXA10 as a master regulator of postnatal hematopoietic development.
How I treat refractory acute GVHD
Authors: Deeg H. Joachim
Published: January 2007

Graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with considerable morbidity and mortality, particularly in patients who do not respond to primary therapy, which usually consists of glucocorticoids (steroids). Approaches to therapy of acute GVHD refractory to “standard” doses of steroids have ranged from increasing the dose of steroids to the addition of polyclonal or monoclonal antibodies, the use of immunotoxins, additional immunosuppressive/chemotherapeutic interventions, phototherapy, and other means. While many pilot studies have yielded encouraging response rates, in most of these studies long-term survival was not improved in comparison with that seen with the use of steroids alone. A major reason for failure has been the high rate of infections, including invasive fungal, bacterial, and viral infections. It is difficult to conduct controlled prospective trials in the setting of steroid-refractory GVHD, and a custom-tailored therapy dependent upon the time after HCT, specific organ manifestations of GVHD, and severity is appropriate. All patients being treated for GVHD should also receive intensive prophylaxis against infectious complications.
Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution
Authors: Laperriere David , Wang Tian-Tian , White John H , Mader Sylvie
Published: January 2007

Background

Nuclear receptors are hormone-regulated transcription factors whose signaling controls numerous aspects of development and physiology. Many receptors recognize DNA hormone response elements formed by direct repeats of RGKTCA motifs separated by 1 to 5 bp (DR1-DR5). Although many known such response elements are conserved in the mouse and human genomes, it is unclear to which extent transcriptional regulation by nuclear receptors has evolved specifically in primates.

Results

We have mapped the positions of all consensus DR-type hormone response elements in the human genome, and found that DR2 motifs, recognized by retinoic acid receptors (RARs), are heavily overrepresented (108,582 elements). 90% of these are present in Alu repeats, which also contain lesser numbers of other consensus DRs, including 50% of consensus DR4 motifs. Few DR2s are in potentially mobile AluY elements and the vast majority are also present in chimp and macaque. 95.5% of Alu-DR2s are distributed throughout subclasses of AluS repeats, and arose largely through deamination of a methylated CpG dinucleotide in a non-consensus motif present in AluS sequences. We find that Alu-DR2 motifs are located adjacent to numerous known retinoic acid target genes, and show by chromatin immunoprecipitation assays in squamous carcinoma cells that several of these elements recruit RARs in vivo. These findings are supported by ChIP-on-chip data from retinoic acid-treated HL60 cells revealing RAR binding to several Alu-DR2 motifs.

Conclusion

These data provide strong support for the notion that Alu-mediated expansion of DR elements contributed to the evolution of gene regulation by RARs and other nuclear receptors in primates and humans.
Improved single-chain transactivators of the Tet-On gene expression system
Authors: Zhou Xue , Symons Jori , Hoppes Rieuwert , Krueger Christel , Berens Christian , Hillen Wolfgang , Berkhout Ben , Das Atze T
Published: January 2007

Background

The Tet-Off (tTA) and Tet-On (rtTA) regulatory systems are widely applied to control gene expression in eukaryotes. Both systems are based on the Tet repressor (TetR) from transposon Tn10, a dimeric DNA-binding protein that binds to specific operator sequences (tetO). To allow the independent regulation of multiple genes, novel Tet systems are being developed that respond to different effectors and bind to different tetO sites. To prevent heterodimerization when multiple Tet systems are expressed in the same cell, single-chain variants of the transactivators have been constructed. Unfortunately, the activity of the single-chain rtTA (sc-rtTA) is reduced when compared with the regular rtTA, which might limit its application.

Results

We recently identified amino acid substitutions in rtTA that greatly improved the transcriptional activity and doxycycline-sensitivity of the protein. To test whether we can similarly improve other TetR-based gene regulation systems, we introduced these mutations into tTA and sc-rtTA. Whereas none of the tested mutations improved tTA activity, they did significantly enhance sc-rtTA activity. We thus generated a novel sc-rtTA variant that is almost as active and dox-sensitive as the regular dimeric rtTA. This variant was also less sensitive to interference by co-expressed TetR-based tTS repressor protein and may therefore be more suitable for applications where multiple TetR-based regulatory systems are used.

Conclusion

We developed an improved sc-rtTA variant that may replace regular rtTA in applications where multiple TetR-based regulatory systems are used.
Silencing of the AV2 gene by antisense RNA protects transgenic plants against a bipartite begomovirus
Authors: Mubin Muhammad , Mansoor Shahid , Hussain Mazhar , Zafar Yusuf
Published: January 2007

Whitefly-transmitted geminiviruses (genus Begomovirus) are phytopathogens that cause heavy losses to crops worldwide. Efforts to engineer resistance against these viruses are focused mainly on silencing of complementary-sense virus genes involved in virus replication. Here we have targeted a virion-sense gene (AV2) to develop resistance against Tomato leaf curl New Delhi virus, a bipartite begomovirus prevalent throughout the Indian subcontinent. We show that tobacco plants transformed with an antisense construct targeting this gene are resistant to the virus. Following challenged with the virus, transgenic plants remained symptomless, although viral DNA could be detected in some plants by PCR. This is the first report of transgenic resistance against a bipartite begomovirus obtained by targeting a virion-sense gene. The relatively conserved nature of the gene suggests that the technology may be useful to develop broad-spectrum resistance which is required because of the fact that plants are often infected with multiple begomoviruses in the field.
Stem cell factor-mediated activation pathways promote murine eosinophil CCL6 production and survival
Authors: Dolgachev Vladislav , Thomas Molly , Berlin Aaron , Lukacs Nicholas W
Published: January 2007

Eosinophil activation during allergic diseases has a detrimental role in the generation of pathophysiologic responses. Stem cell factor (SCF) has recently shown an inflammatory, gene-activating role on eosinophils and contributes to the generation of pathophysiologic changes in the airways during allergic responses. The data in the present study outline the signal transduction events that are induced by SCF in eosinophils and further demonstrate that MEK-mediated signaling pathways are crucial for SCF-induced CCL6 chemokine activation and eosinophil survival. SCF-mediated eosinophil activation was demonstrated to include PI-3K activation as well as MEK/MAPK phosphorylation pathways. Subsequent analysis of CCL6 gene activation and production induced by SCF in the presence or absence of rather specific inhibitors for certain pathways demonstrated that the MEK/MAPK pathway but not the PI-3K pathway was crucial for the SCF-induced CCL6 gene activation. These same signaling pathways were shown to initiate antiapoptotic events and promote eosinophil survival, including up-regulation of BCL2 and BCL3. Altogether, SCF appears to be a potent eosinophil activation and survival factor.