bluuebunny/crossref_metadata_2025 huggingface dataset:
Viva 37
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 37 asks what kinds of data there are in orthopaedic surgical literature and what common statistical tests are used for these data, followed by what is understood by the sensitivity and specificity of a test, and what factors should be identified in an outcome scoring system?
Viva 38
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 38 asks what a systematic review is, what a meta-analysis is, what levels of evidence do orthopaedic surgeons recognize, what types of study are there, what the difference is between bias and confounding, and what the Cochrane Collaboration is?
Viva 40
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 40 asks for identification of the apparatus in the image, how it is constructed, and how it works.
Viva 41
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 41 shows a 27-year-old involved in a road traffic accident (RTA). Describe what can be seen in this picture and explain the initial management, followed by when to take this patient to theatre and what will be done there. Additionally, explain the biggest concern in the early post-operative period and how to monitor for this? How is a lower leg fasciotomy performed, and how soon should there be get soft tissue cover – additionally, please offer information about free flaps.
Viva 42
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 42 shows a patient who was the driver in a high-speed RTA. Describe this picture and what causes this type of injury, followed by what other information needed and the standard treatment for this fracture. Additionally, what complications should be anticipated in this patient, what is the probability of AVN in this case and what would present, and what is the blood supply to the talus.
Viva 50
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 50 shows a woman who fell while out shopping. Describe these radiographs, and explain who gets subtrochanteric fractures and how they are classified. How should this patient be managed in the pre-operative phase? How are these fractures fixed, and when can union be expected, and what is the risk of non-union?
Viva 51
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 51 shows a 35-year-old man who has been involved in a motocross accident and fallen off his bike. Wearing all the protective clothing and helmet he is brought into the emergency department complaining of neck pain. Give comments about this radiograph, and how to manage him now. There is no access to an MRI scanner; could this be reduced with the patient awake? How would a Halo be applied?
Viva 54
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 54 shows a 19-year-old rugby player who presents to A&E with a first time injury to his dominant shoulder. Comment on the radiograph and answer why does the shoulder dislocate and what stops it normally? The A&E staff have tried to reduce this without success — describe how to reduce this dislocation. What is the risk of this shoulder causing problems again? What approach can be taken for an open reduction?
Viva 60
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 60 shows a patient with rheumatoid arthritis. What are the common deformities seen in the foot with rheumatoid arthritis? How do these deformities occur? Describe how to manage this patient.
Viva 71
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 71 shows a 67-year-old man who has fallen onto his face and presents with an abnormal neurological examination and neck pain. Describe what shows in the image and the most likely pattern of incomplete cord injury? What are the clinical features of this injury and how should the patient be managed? How do the clinical features of Brown–Sequard syndrome differ? Is there a grading system for cord injury? How is motor strength graded and upper extremity myotomes tested? What is spinal shock?
Viva 72
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 72 asks for a description of the picture above and to name the condition that is demonstrated. What is the common clinical presentation for this condition? Is there an anatomical classification for the condition? What are the indications for surgery in this condition? When should a fusion be performed in this condition?
Viva 74
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 74 asks for a description of the radiograph and a diagnosis. This is a 70-year-old fit and healthy patient with significant pain and stiffness. She has failed a trial of non-operative treatment. She wants surgery. What should be offered her? Explain how to consent her. What surgical approaches are could be taken? If the patient had a massive cuff tear, what should be done?
Viva 75
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 75 asks what is understood by the term ‘frozen shoulder’ and what are the classical stages described? What are the factors associated with this condition and how should it be managed? Are there any operative procedures for this condition? What are the typical findings during arthroscopy?
Viva 79
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 79 asks for a description of the abnormalities seen on these radiographs. What is the likely diagnosis? What is the inheritance pattern and natural history of this disease? What sites are commonly affected? What clinical problems does it cause?
Life beyond psychiatry
Authors: Boevink Wilma
Published: May 2013

This chapter illustrates the concept of recovery, drawing on the author's experiences of a long period as a psychiatric inpatient and as a user of outpatient care. Dealing with the consequences of childhood trauma and psychotic vulnerability, she found that recovery can be seen as a subjective, natural process, which can (also) take place independently of the help offered. The concept of recovery provides the users of psychiatric services with something to hold on to in the process of 'un-psychiatrizing' themselves, and allows them to see what is happening to them as something that is also part of ordinary life. Recovery is something that people experiencing severe human distress have to do themselves; it is inextricably linked to the empowerment of users of psychiatric care. The most that professionals in psychiatry can do in this process is to follow and support it.
Cultural contexts and constructions of recovery
Authors: Adeponle Ademola , Whitley Rob , Kirmayer Laurence J.
Published: May 2013

This chapter examines the social and cultural roots and implications of current concepts of recovery. Consistent with biomedical notions of illness and disease, psychiatry has tended to frame “recovery” largely in terms of outcomes, as “recovery from illness”. However, during the last decade the term “recovery” has come to refer to a social movement promoting a reorientation in psychiatric care, toward ensuring that individuals can live a full life in their communities. Along with this reorientation, recovery is increasingly conceived of as a process, rather than an outcome, with individuals described as “being in recovery” rather than as “recovering from” an affliction. The new recovery “movement”, with its roots in civil rights and independent living movements, arose in part as a reaction to perceived attitudes of pessimism and paternalism inherent in conventional psychiatric care. It envisions for individuals with mental illness a reassertion of their rights to a dignified and meaningful life in the community and a renewed sense of agency, with an active say in the direction of their own healthcare. Although sometimes framed in the universalistic language of human rights, recovery is rooted in specific cultural concepts of self and personhood. The consumer-oriented recovery model, which is popular in the USA, builds on a Euro-American individualistic and egocentric concept of the person. However, in other cultures, sociocentric, ecocentric, or cosmocentric conceptions of personhood may have more salience. These differing cultural concepts of the person influence the trajectories of illness, modes of adaptation, response to interventions, and definitions of positive outcome. In particular, cultural notions of the person's connection to family, community, and spirituality play a key role in local notions of recovery. This will be illustrated with examples from qualitative research with African-Americans in the USA, indigenous peoples in Canada, and patients in Nigeria. Understanding the cultural and historical roots of recovery provides a framework for considering the relevance of recovery for diverse cultural groups, both within North American and European societies and in other parts of the world.
Significance and preliminary investigation of urological symptoms and signs
Authors: Reynard John , Brewster Simon , Biers Suzanne
Published: May 2013

Haematuria I: definition and types 8

Haematuria II: causes and investigation 10

Haemospermia 14

Lower urinary tract symptoms (LUTS) 16

Nocturia and nocturnal polyuria 18

Loin (flank) pain 20

Urinary incontinence 24

Genital symptoms 26

Abdominal examination in urological disease 28

Digital rectal examination (DRE) ...
Infections and inflammatory conditions
Authors: Reynard John , Brewster Simon , Biers Suzanne
Published: May 2013

Urinary tract infection: definitions and epidemiology 176

Urinary tract infection: microbiology 178

Lower urinary tract infection: cystitis and investigation of UTI 182

Urinary tract infection: general treatment guidelines 184

Recurrent urinary tract infection 186

Upper urinary tract infection: acute pyelonephritis 190

Pyonephrosis and perinephric abscess ...
Paediatric urology
Authors: Reynard John , Brewster Simon , Biers Suzanne
Published: May 2013

Embryology: urinary tract 646

Embryology: genital tract 648

Undescended testes (UDT) 650

Urinary tract infection (UTI) 654

Antenatal hydronephrosis 658

Vesicoureteric reflux (VUR) 662

Megaureter 666

Ectopic ureter 668

Ureterocele 670

Pelviureteric junction (PUJ) obstruction 672

Posterior urethral valves (PUV) 674

Cystic kidney disease 676...
Head and neck surgery
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Thyroglossal cyst, sinus, and fistula 222

Branchial cyst, sinus, and fistula 224

Salivary calculi 226

Acute parotitis 228

Salivary gland tumours 230

Head and neck cancer 232

Facial trauma 234

Neck space infections 236

• Thyroglossal cyst is a fluid-filled sac resulting from incomplete closure of the thyroglossal duct....
Major trauma
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Management of major trauma 478

Thoracic injuries 480

Abdominal trauma 482

Vascular injuries 484

Head injuries 486

• Trauma is the leading cause of death in the first four decades of life, but three people are permanently disabled for every one killed.

• Death from injury occurs in one of three time periods (trimodal)....
Plastic surgery
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Suturing wounds 590

Skin grafts 594

Surgical flaps 596

Management of scars 598

Excision of simple cutaneous lesions 600

Skin cancer 602

Burns: assessment 604

Burns: management 606

Soft tissue hand injuries 610

Hand infections 612

Dupuytren's disease 614

Breast reduction 616

Breast augmentation 617...
Common operations
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Diagnostic laparoscopy 730

Principles of laparotomy 732

Cholecystectomy 734

Appendicectomy 736

Inguinal hernia repair 738

Perforated peptic ulcer repair 740

Haemorrhoid surgery 742

Pilonidal sinus excision (Bascom II) 744

Femoral embolectomy 746

Right hemicolectomy 748

Stoma formation 750

Wide local excision—breast 752

Below knee amputation ...
Eponymous terms and rarities
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Pigmentation of the axillary skin associated with breast or gastric cancer.

Familial dwarfism in which growth of the long bones and skull is defective.

Thickening of the gall bladder wall with occasional intramural sinuses that may partially occlude the gall bladder lumen....
Glutamate Receptors in Epilepsy
Authors: Bianchi Riccardo , Wong Robert K. S. , Merlin Lisa R.
Published: May 2013

In the early 1990s, the epileptogenic potential of metabotropic glutamate receptor (mGluR) activation in the hippocampus was first suggested by data using the then newly developed broad- spectrum mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD).1 These studies revealed that mGluR activation had the potent ability to recruit the hippocampal network to express robust synchronized discharges. These synchronized bursts had features suggestive of typical seizure discharges in that (1) their length was on the order of seconds and (2) they were comprised of an intrinsic oscillatory series of discharges that began at a high frequency and gradually slowed. And indeed, work in other labs confirmed that ACPD application does elicit seizures in the intact organism.2 A hypothesis was developed proposing that the group I mGluRs, which are predominantly localized to the edges of synapses (perisynaptic),3 were likely to be activated at times of intense glutamate release, and this could result in the expression of acute seizures such as the impact seizure that occurs acutely in the setting of head trauma. However, subsequent studies using the selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) revealed a potential additional consequence of group I mGluR activation: long- lasting changes in network excitability.4
Plasticity of Glutamate Synaptic Mechanisms
Authors: Nadler J. Victor
Published: May 2013

Epilepsy may be defined as a disorder of brain function characterized by the repeated and unpredictable occurrence of seizures. Seizures involve the disordered, rhythmic, and synchronous firing of central nervous system (CNS) neuron populations. Seizures originate in neuronal populations capable of bursting, develop because of an imbalance between neuronal excitation and inhibition, and are characterized by high-frequency firing associated with membrane depolarization. Neuronal excitation and inhibition may become unbalanced in many different ways. This chapter focuses on the contribution to seizures of glutamate synaptic plasticity, both anatomical plasticity that creates new excitatory synapses and functional plasticity that enhances the efficacy either of excitatory synapses or of glutamate itself. Observations made with human tissue are emphasized. Glutamate is the principal excitatory neurotransmitter in mammals. About 60%–70% of all synapses in the CNS appear to be glutamate synapses (see Fig. 12–1). Glutamate also serves as the principal neurotransmitter utilized by sensory neurons. Autonomic neurons and motoneurons are about the only excitatory neurons in mammals that utilize a transmitter other than glutamate. Thus, the formation of enhanced or novel glutamate circuits, enhanced excitatory transmission, and/or an excess of glutamate itself could disrupt the balance of excitation and inhibition leading to the occurrence of seizures.
Fast Oscillations and Synchronization Examined with In Vitro Models of Epileptogenesis
Authors: Traub Roger D. , Whittington Miles A. , Cunningham Mark O.
Published: May 2013

For many years, interictal spikes, recorded in a patient's electroencephalogram (EEG), were considered to be a primary indicator that the patient might indeed have epilepsy and that the patient's seizures (when they occurred) were likely to begin in the vicinity of the interictal spike generator. That interictal spikes could often be recorded at the scalp, without the necessity of invasive recording procedures, contributed to their clinical usefulness. A question of continuing importance to basic epilepsy research was naturally this: what factors determine whether “epileptogenic tissue” will produce interictal spikes,1 unequivocal seizure activity, or something intermediate?
Fever, Febrile Seizures, and Epileptogenesis
Authors: Dubé Céline M. , McClelland Shawn , Choy ManKin , Brewster Amy L. , Noam Yoav , Baram Tallie Z.
Published: May 2013

Febrile seizures (FS) are the most common type of convulsions in infants and young children, occurring in 2%–6% of children.1,2 They are defined as seizures arising during fever, not caused by an infection of the central nervous system. However, their definition does not exclude children with preexisting neurological deficits, a fact that might confound studies on the outcome of these seizures. Although there is limited evidence for adverse outcomes of simple (defined as short, with no focal motor phenomena) FS on the immature brain, complex FS, particularly long-duration FS or febrile status epilepticus (defined as seizures lasting for more than 30 min), have been associated with subsequent limbic epilepsy, as indicated by both prospective and retrospective studies as well as by recent data in animal models.3–14 Some investigators have suspected that long-duration FS might result in cognitive defects in a subset of children.15–17 Understanding the basic mechanisms of FS, and the potential epileptogenesis that follows them, requires animal models that enable direct examination of the causal mechanisms for the generation and consequences of these seizures. The mechanisms by which fever leads to FS, the outcome of FS measured as the risk of epilepsy, the properties of FS associated with limbic epilepsy, and the mechanisms of epileptogenesis are discussed in the following sections.
The Time Course and Circuit Mechanisms of Acquired Epileptogenesis
Authors: Dudek F. Edward , Staley Kevin J.
Published: May 2013

In order to develop and test possible therapeutic strategies for preventing or suppressing epileptogenesis, the temporal features of acquired epilepsy and its underlying mechanisms must be understood. These temporal features include the frequency, duration, and cortical extent of spontaneous seizures; this review focuses primarily on seizure frequency. Traumatic brain injury, stroke, status epilepticus, and infection/inflammation are some of the major causes of acquired epilepsy. The spontaneous recurrent epileptic seizures of acquired epilepsy usually occur after a latent period following the injury, and in at least some patients, the epilepsy is progressive (i.e., the seizures become more frequent and severe). Nearly all patients receive antiepileptic drugs (AEDs) after one or a few clinical seizures. Therefore, quantitative analyses of the temporal features of acquired epileptogenesis, independent of the effects of AEDs, cannot be studied in humans. Animal models of acquired epilepsy can circumvent this problem. The research summarized here analyzed the development of spontaneous recurrent seizures (1) in kainate-treated rats,1 an animal model of temporal lobe epilepsy, and (2) in rats subjected to hypoxic-ischemic brain damage at postnatal day 7, a model of perinatal stroke.2–4
Perturbations of Dendritic Excitability in Epilepsy
Authors: Tang Cha-Min , Thompson Scott M.
Published: May 2013

The dendrite is where thousands of excitatory and inhibitory synaptic inputs are received by the neuron. But rather than just being a simple antenna, the dendrite is also the location where these inputs actively interact with intrinsic conductances. The interactions are complex and are still incompletely understood. The synaptic inputs are distributed in time and space, and each of the many intrinsic dendritic conductances is also distributed in its own unique spatial pattern. The interactions lead to signal transformations whose significance may be best appreciated in terms of elementary steps in signal processing and computation. Under pathological conditions, changes to these interactions may result in aberrant excitability and contribute to neurological disease. Rather than compiling a list of dendritic conductances and their linkages with epilepsy, which is done in other chapters of this book, the purpose of this chapter is to integrate these results, with an emphasis on how perturbations of the elementary steps in dendritic integration affect the way neurons process their inputs and promote aberrant neuronal excitability.
Temporal Lobe Epilepsy and the BDNF Receptor, TrkB
Authors: McNamara James O. , Scharfman Helen E.
Published: May 2013

Actions of estrogen and progesterone have been used to explain the changes in seizure frequency or severity in women with catamenial epilepsy. An alternative hypothesis is that BDNF is responsible, because estrogen causes an increase in BDNF expression that can have both acute effects on excitability and delayed, indirect effects by changing GABAergic transmission and GABAA receptors. Allopregnanolone may hold many of the excitatory effects in check during the luteal phase, but two phases of the cycle may be unprotected, the periovulatory and perimenstrual phases. This hypothesis helps explain why progesterone therapy may not always be efficacious in catamenial epilepsy and suggests that control of BDNF would be a logical complementary strategy.
GABAA Receptor Plasticity in Alcohol Withdrawal
Authors: Olsen Richard W. , Spigelman Igor
Published: May 2013

Alcohol, the fruit of the vine and the braumeister's ware, has been one of the most popular drugs in the world throughout history and one of the most abused. The development of dependence after chronic use of ethanol (EtOH) depends on two parallel effects of the drug on the brain each time it is used: stimulation of the reward pathway and subsequent triggering of a small but significant withdrawal. There is rebound hyperexcitability following the initial action of EtOH as a central nervous system (CNS) depressant and triggering of some adaptive process, that is, molecular changes associated with tolerance.1,2 Each of these “mini-withdrawals” reflects transient plasticity in the brain affecting the balance of excitation and inhibition. The simplest description of the changes could be, for example, the ratio of glutamate and gamma-aminobutyric acid (GABA) neurotransmitter activities.
Regulation of GABAA Receptor Gene Expression and Epilepsy
Authors: Brooks-Kayal Amy R. , Russek Shelley J.
Published: May 2013

Results of research in animal models as well as from human retrospective studies suggest that an initial precipitating event such as status epilepticus (SE), stroke, or traumatic brain injury can increase the risk of later development of the recurrent spontaneous seizures that define epilepsy. The process by which a normal brain transforms into one capable of producing recurrent spontaneous seizures, known as epileptogenesis, is likely to be complex and multifactorial. Among the many changes that occur during epileptogenesis are alterations in expression of a wide variety of genes. Determining what molecular pathways regulate these changes in gene expression, and which of them are consequential or causative of disease, are two of the major challenges of research in this area, and are critical to effectively utilizing this information to develop new therapies for the prevention and treatment of epilepsy.
The Voltage-Gated Calcium Channel and Absence Epilepsy
Authors: Noebels Jeffrey L.
Published: May 2013

Voltage-gated calcium channels were the first of now many genetic starting points for tracing the molecular mechanisms of spike-wave seizures, and in so doing, we have gained equally valuable information regarding the neurobiology of the P/Q-type calcium channel and its family members. Perhaps the most important lesson is that the solution of the neurological phenotype requires two steps: first, analyzing how the mutation affects the biology of the channel in a single neuron; second, determining how and when the misbehavior converts normal rebound bursting patterns in the thalamocortical network into an unstable pathological substrate for epilepsy in the developing brain. The “temporary failure of motor and mental functions” defined by Jackson arises not from enhanced excitatory release, as might be expected in paroxysmal hypersynchronous activity, but from the opposite: reduced synaptic strength within the thalamocortical network due to impaired calcium entry and diminished interactions with transmitter release machinery. This reduction in synaptic strength joins other molecular triggers, such as loss of vesicular exocytosis proteins or postsynaptic AMPA receptors, to induce downstream elevations in low voltage-activated T-type calcium channels, which may suffice to generate a spike-wave seizure phenotype. There is ample clinical and genetic evidence to suggest that there will be no uniform thalamocortical molecular pathology underlying this disorder and that alternative routes to the clinical spectrum of absence epilepsy remain to be discovered. Comparisons of their monogenic mechanisms will prove highly instructive in subsequent attempts to unravel the most elusive causes of sporadic generalized epilepsies, those that arise out of polygenic combinations. This category comprises the majority of individuals with absence seizures, and to them we remain obliged to confess our continuing ignorance of the causes of their condition.
Targeting SV2A for Discovery of Antiepileptic Drugs
Authors: Kaminski Rafal M. , Gillard Michel , Klitgaard Henrik
Published: May 2013

Synaptic vesicle 2A constitutes the unique binding site for LEV and plays an important role in synaptic vesicle function. Affinity–potency correlations in several models of partial and generalized epilepsy indicate that SV2A is a broad-spectrum anticonvulsant target. The anticonvulsant activity of LEV is closely linked with occupancy and availability of SV2A, whereas SV2A deficiency leads to increased seizure vulnerability and accelerated epileptogenesis. Taken together, existing experimental data prove that SV2A plays a crucial role in mediating the anticonvulsant action of LEV in vivo and indicate that the SV2A protein represents an important and well-validated target for the discovery of novel AEDs. Finally, the finding that SV2A protein is a clinically validated target for epilepsy has triggered further discovery programs exploring the therapeutic potential for SV2A ligands with different binding properties.
Mechanisms of Ketogenic Diet Action
Authors: Masino Susan A. , Rho Jong M.
Published: May 2013

The evidence for a KD as a successful epilepsy treatment is clear. Multiple retrospective, multi-center, and randomized prospective studies document consistent and significant clinical benefits. The true efficacy of dietary treatments for epilepsy may be underestimated, as the KD is rarely used as a first-line therapy. Certainly, by the time the KD is initiated to thwart medically refractory epilepsy, in some instances the severity of the epileptic condition may be too difficult to overcome. But remarkably, the KD works in the majority of patients who failed to respond to numerous antiepileptic drugs. A detailed understanding of key KD mechanisms could offer a meaningful adjuvant or ultimately the development of a “diet in a pill.”3 But while clinical applications of metabolism-based therapy appear to be growing rapidly, there is a continuing need to develop modified diet formulations with improved efficacy and tolerability (as well as palatability) and to identify new pharmacological targets for drug discovery.
Antiepileptogenesis, Plasticity of AED Targets, Drug Resistance, and Targeting the Immature Brain
Authors: Beck Heinz , Yaari Yoel
Published: May 2013

The cellular basis of epileptic seizures consists of high-frequency, synchronized discharges of neuronal ensembles. The ultimate goal of all antiepileptic therapies is to prevent the occurrence of such episodes or to substantially attenuate their severity. To this end, a multitude of antiepileptic compounds have been developed that are currently in clinical use. However, seizures remain uncontrolled by carefully monitored drug treatment in a substantial portion (∼30%) of epilepsy patients. Therefore, a better understanding of the mode of action of different antiepileptic drugs is mandatory, along with an improved understanding of why these compounds fail in some epilepsy patients, with the ultimate goal of developing new therapeutic avenues. So far, two hypotheses have been advanced to account for the cellular basis of pharmacoresistance in chronic epilepsy. The first hypothesis proposes that pharmacoresistance involves an upregulation of multidrug transporters at the blood-brain barrier. This upregulation limits the access of antiepileptic drugs to the brain parenchyma and therefore leads to a reduced drug concentration at the respective drug target. Because multidrug transporter proteins are of central importance to this hypothesis, it has been termed the transporter hypothesis. The second hypothesis contends that the molecular targets of antiepileptic drugs are modified in chronic epilepsy. Consequently, they are less sensitive to these compounds. This hypothesis has been named the target hypothesis.1,2 Clearly, these two hypotheses are not mutually exclusive. Rather, the underlying mechanisms may coexist and perhaps even act in synergy. The subject of this chapter is the target hypothesis. We describe the molecular mechanisms that alter the targets of antiepileptic drugs and how these mechanisms may interact with altered drug transporter function to cause pharmacoresistance.
Adenosine Augmentation Therapy
Authors: Boison Detlev
Published: May 2013

The ribonucleoside adenosine is based on the purine base adenine, which was most likely already present on the prebiotic primitive Earth.1 Being the core molecule of the energy metabolite adenosine-5′-triphosphate (ATP) as well as being an integral component of both DNA and RNA, adenosine likely played an important role in early evolution as an ideally positioned negative feedback regulator to adjust cellular activity (DNA, RNA) to available energy supplies (ATP). Adenosine has therefore evolved as an important modulator of function in brain, but also in heart, skeletal muscle, kidney, and adipose tissue, in the sense of a “retaliatory metabolite” that protects the cell against excessive external stimulation.2
Late-Onset Mood Disorders
Authors: Peele Roger
Published: May 2013

The history of the International Classification of Diseases [ICD] and the history of the Diagnostic and Statistical Manual [DSM] is reviewed including the present status of both as to the recognition of Late-Onset Depression. Opportunities and challenges to increasing the recognition of Late-Onset Depression in DSMs and ICDs are described, targeting DSM-5, ICD-10-CM or ICD-11.
Comorbid Neurological Illness
Authors: Wint Dylan , Cummings Jeffrey
Published: May 2013

Cerebrovascular disease, movement disorders, epilepsy, and other neurological diseases disproportionately affect the elderly. Prevalence rates of mood disorders, particularly depression, exceed 20% in most neurological disorders. Thus, many mood disturbances in the elderly are comorbid with neurological illness. Furthermore, elderly individuals and neurological patients have high rates of mood-related morbidity and mortality. Unfortunately, mood disorders in neurological conditions are poorly recognized and under-treated. This chapter discusses the problem of mood disorders in specific neurological conditions in the elderly, and provides a general framework for approaching and treating these problems.
Use of Adjunctive Therapy in Older Depressed Adults Who are Resistant to Antidepressant Treatment
Authors: Nelson J. Craig
Published: May 2013

While antidepressants are effective in late life depression, similar to younger patients, a minority of older adults achieve remission with initial treatment. In the 10 placebo controlled trials of second generation antidepressants in older adults, the remission rate was 32.6%. As a consequence adjunctive treatments (addition of a drug not approved for use in depression) or combination treatments (use of two approved antidepressants) are frequently employed, especially in partial responders or to target specific residual symptoms. This chapter reviews the evidence for the efficacy of adjunctive and combination treatments in late life depression. Limited evidence suggests that with 3 to 4 sequential trials, a substantial percentage of older depressed adults will achieve remission.
Novel Platforms for Care Delivery
Authors: Pim Cuijpers Heleen Riper , Beekman Aartjan
Published: May 2013

Internet-guided and Telepsychiatry interventions may save costs and time from patients and therapists, they may reach depressed older adults who are not reached with traditional therapies, solve transportation problems, stimulate empowerment of patients, and reduce the stigma associated with mental illness. Although a growing number of studies has examined the effects of Internet-based interventions and telephone-supported interventions, few have examined these in older adults. However, research shows that these interventions are promising and there is no reason to assume that they are not effective in older adults. More research is needed, especially since technological developments are going fast and innovative types of interventions and new possibilities to reduce the disease burden in depressed older adults are emerging rapidly.
Structural Neuroimaging in Late-Life Mood Disorders
Authors: Colloby Sean J. , O’Brien John T.
Published: May 2013

Affective disorder research has mainly focussed on studying many of the structures implicated within the limbic-cortical-striatal-pallidal-thalamic circuit. This chapter concentrates on structural MRI brain changes associated with unipolar major depression and bipolar disorder (BD) of late-life, with particular attention to structural imaging, white matter hyperintensities (WMH) and diffusion tensor imaging (DTI). Structural brain deficits are associated with LLD and LLBD, with a pattern supporting the notion of ‘frontostriatal’ disturbances in affective disorders of late-life. Increased prevalence of WMH is another characteristic of LLD and LLBD, with perhaps location rather than burden being more important to their pathogeneses, but may also indicate their increased cerebrovascular risk factors. Microstructural DTI changes are largely in frontal regions in LLD but in LLBD have not been investigated. Future studies with larger clinically representative populations with further aid to elucidate the specific anatomy and aetiology of structural MRI changes in late-life mood disorders and investigate their relationship with clinical factors.
Genetics of Bipolar Disorder and Schizophrenia
Authors: Talkowski Michael E. , Chowdari Kodavali V. , Mansour Hader , Prasad Konasale M. , Wood Joel , Nimgaonkar Vishwajit L.
Published: May 2013

In this chapter, we consider the genetic epidemiology of schizophrenia and bipolar disorder. We review their diagnostic history as well as the evidence for shared genetic risk factors and pathophysiology between them. We discuss the strengths and considerable weaknesses of various linkage and association-based research paradigms employed over the years to understand the genetic basis of these disorders, and more recent data robustly implicating shared genetic etiological factors. As the data from large-scale genomic studies accumulate, it has become clear that hundreds to thousands of single nucleotide polymorphisms that are common in the general population confer very small but significant risk to both disorders, while large genomic rearrangements represent highly penetrant, but rare and often non-recurrent genetic contributors. We conclude that significant progress has been made in understanding the complex genetic factors underlying schizophrenia and bipolar disorder, much of which suggests a model of genetic variation spanning the allelic spectrum will ultimately be required to explain both the disease-specific and shared genetic risk contributing to the pathophysiology of these disorders.
Left–right asymmetry: cilia stir up new surprises in the node
Authors: Babu Deepak , Roy Sudipto
Published: May 2013

Cilia are microtubule-based hair-like organelles that project from the surface of most eukaryotic cells. They play critical roles in cellular motility, fluid transport and a variety of signal transduction pathways. While we have a good appreciation of the mechanisms of ciliary biogenesis and the details of their structure, many of their functions demand a more lucid understanding. One such function, which remains as intriguing as the time when it was first discovered, is how beating cilia in the node drive the establishment of left–right asymmetry in the vertebrate embryo. The bone of contention has been the two schools of thought that have been put forth to explain this phenomenon. While the ‘morphogen hypothesis’ believes that ciliary motility is responsible for the transport of a morphogen preferentially to the left side, the ‘two-cilia model’ posits that the motile cilia generate a leftward-directed fluid flow that is somehow sensed by the immotile sensory cilia on the periphery of the node. Recent studies with the mouse embryo argue in favour of the latter scenario. Yet this principle may not be generally conserved in other vertebrates that use nodal flow to specify their left–right axis. Work with the teleost fish medaka raises the tantalizing possibility that motility as well as sensory functions of the nodal cilia could be residing within the same organelle. In the end, how ciliary signalling is transmitted to institute asymmetric gene expression that ultimately induces asymmetric organogenesis remains unresolved.
AIDS, speech and silence in South Africa (Respond to this article at http://www.therai.org.uk/at/debate)
Authors: Niehaus Isak
Published: May 2013

Confessional technologies are frequently deployed to deal with the HIV/AIDS pandemic. In South Africa, these are most eagerly embraced by activists of the urban‐based Treatment Action Campaign, who use speech such as public confession and testimony to overcome pathos. However, fieldwork in the Bushbuckridge area of the South African lowveld shows wide resistance to direct speech about AIDS. In this article I explore reasons for such resistance. In addition to the stigma of labelling and poor treatment options, I argue that villagers feared the innate power of words such as ‘HIV’ and ‘AIDS’ to crystalize sickness, and bring fears of death into consciousness. In conclusion, I suggest that rather than insist upon confession, health providers could use speech and silence as alternative modes of dealing with AIDS.
Conservation marketing and education for less charismatic biodiversity and conservation businesses for sustainable development
Authors: Di Minin E. , Fraser I. , Slotow R. , MacMillan D. C.
Published: May 2013

Read the Feature Paper: Understanding heterogeneous preference of tourists for big game species: implications for conservation and management

Commentaries on this Feature Paper: To use tourism as a conservation tool, first study tourists; The Big 5 and conservation
Relationship between preoperative serum TSH levels and expression of VEGF in papillary thyroid carcinoma
Authors: Li Jin , Teng Lisong , Jiang Honggang
Published: May 2013

Aim

Vascular endothelial growth factor (VEGF) stimulates angiogenesis, increases vascular permeability and seems to correlate to aggressiveness of tumors. Increased expression of VEGF has been observed in papillary thyroid carcinoma (PTC). Thyroid stimulating hormone (TSH) is the major thyroid hormone, but its relationship with VEGF has seldom been studied. Therefore, we explored whether the immunohistochemical expression of VEGF was related to the serum TSH level.

Methods

VEGF expression was analyzed in 43 archived PTC specimens using immunohistochemistry, with adjacent normal thyroid tissues used as controls. Serum TSH was measured by immunoradiometric assay before surgery and correlated to VEGF expression.

Results

Positive VEGF expression was found in 90% of 43 PTC tissue specimens, but not in normal tissue. The serum TSH levels revealed a positive correlation with VEGF expression, R = 0.592 (P < 0.01).

Conclusions

TSH is a major thyroid hormone. Whether TSH promotes the progression of PTC is not known but the serum TSH levels reveal a positive correlation with VEGF expression.
Review article: strategies for the management of chronic unremitting ulcerative colitis
Authors: Mehta S. J. , Silver A. R. , Lindsay J. O.
Published: May 2013

Background

Chronic active ulcerative colitis (UC) is associated with significant morbidity, loss of productivity, increased colorectal cancer risk and cost. Up to 18% of patients suffer chronic active disease, with 30% requiring colectomy at 10 years. The management remains challenging given the relatively few clinical trials in this area.

Aim

To summarise the evidence regarding optimal management strategies for patients with chronic active UC of differing disease extents and degrees of treatment refractoriness.

Method

A literature search using the PubMed and Medline databases was performed. No time limit was set on article publication for inclusion.

Results

The principles of management should focus on confirming disease activity, exclusion of alternative diagnoses, adherence and treatment escalation. Infliximab and topical tacrolimus are options in refractory proctitis, although the evidence for these therapies is limited. Both infliximab and adalimumab are effective in corticosteroid‐refractory disease, although the proportions of patients achieving corticosteroid‐free remission remain modest (24% at 30 weeks and 16.9% at 8 weeks respectively). Alternatives include ciclosporin and tacrolimus, and possibly methotrexate. Colectomy often leads to an improved quality of life; medical strategies unlikely to provide durable corticosteroid‐free remission should not be pursued.

Conclusions

No current pharmacological treatment delivers mucosal healing in the majority of patients. Newer treatments such as vedolizumab and tofacitinib may represent valuable future therapies. Available medical options should be discussed with patients at every step of their management, with an honest appraisal of the evidence. Surgery should always be considered in patients with chronic refractory disease of any extent.
Indirect comparison of randomised controlled trials: comparative efficacy of dexlansoprazole vs. esomeprazole in the treatment of gastro‐oesophageal reflux disease
Authors: Wu M. S. , Tan S. C. , Xiong T.
Published: May 2013

Background

Dexlansoprazole is a new proton pump inhibitor (PPI) with a dual delayed‐release system. Both dexlansoprazole and esomeprazole are an enantiomer of lansoprazole and omeprazole respectively. However, there is no head‐to‐head trial data or indirect comparison analyses between dexlansoprazole and esomeprazole.

Aim

To compare the efficacy of dexlansoprazole with esomeprazole in healing erosive oesophagitis (EO), the maintenance of healed EO and the treatment of non‐erosive reflux disease (NERD).

Methods

Randomised Controlled Trials (RCTs) comparing dexlansoprazole or esomeprazole with either placebo or another PPI were systematically reviewed. Random‐effect meta‐analyses and adjusted indirect comparisons were conducted to compare the treatment effect of dexlansoprazole and esomeprazole using a common comparator. The relative risk (RR) and 95% confidence interval (CI) were calculated.

Results

The indirect comparisons revealed significant differences in symptom control of heartburn in patients with NERD at 4 weeks. Dexlansoprazole 30 mg was more effective than esomeprazole 20 mg or 40 mg (RR: 2.01, 95% CI: 1.15–3.51; RR: 2.17, 95% CI: 1.39–3.38). However, there were no statistically significant differences between the two drugs in EO healing and maintenance of healed EO. Comparison of symptom control in healed EO was not able to be made due to different definitions used in the RCTs.

Conclusions

Adjusted indirect comparisons based on currently available RCT data suggested significantly better treatment effect in symptom control of heartburn in patients with NERD for dexlansoprazole against esomeprazole. No statistically significant differences were found in other EO outcomes. However, these study findings need to be interpreted with caution due to small number of studies and other limitations.
Pharmacological Characterisation of a Structurally Novel α2C ‐Adrenoceptor Antagonist ORM‐10921 and its Effects in Neuropsychiatric Models
Authors: Sallinen Jukka , Holappa Johanna , Koivisto Ari , Kuokkanen Katja , Chapman Hugh , Lehtimäki Jyrki , Piepponen Petteri , Mijatovic Jelena , Tanila Heikki , Virtanen Raimo , Sirviö Jouni , Haapalinna Antti
Published: May 2013

The α2‐adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α2‐AR subtypes (α2A, α2B and α2C) have been available, the pharmacological profile of a new α2C‐selective AR antagonist ORM‐10921 is reported. Standard in vitro receptor assays and antagonism of α2, and α1‐AR agonist ‐evoked responses in vivo were used to demonstrate the α2C‐AR selectivity for ORM‐10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK‐801. The Kb values of in vitro α2C‐ AR antagonism for ORM‐10921 varied between 0.078–1.2 nM depending on the applied method. The selectivity ratios compared to α2A‐AR subtype and other relevant receptors were 10‐100 times in vitro. The in vivo experiments supported its potent α2C‐antagonism combined with only a weak α2A‐antagonism. In the pharmacodynamic microdialysis study, ORM‐10921 was found to increase extracellular dopamine levels in prefrontal cortex in the baseline conditions. In the behavioural tests, ORM‐10921 displayed potent antidepressant and antipsychotic‐like effects in the forced swimming test and prepulse‐inhibition models analogously with the previously reported results with structurally different α2C‐selective AR antagonist JP‐1302. Our new results also indicate that ORM‐10921 alleviated the NMDA‐antagonist‐induced impairments in social behaviour and watermaze navigation. This study extends and further validates the concept that α2C‐AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α2C‐antagonism to treat such disorders.