Clazosentan: prevention of cerebral vasospasm and the potential to overcome infarction

Cerebral vasospasm is a common complication occurring after aneurysmal subarachnoid hemorrhage (SAH). It is recognized as a leading preventable cause of morbidity and mortality in this patient group, but its management is challenging, and new treatments are needed. Clazosentan is an endothelin receptor antagonist designed to prevent endothelin-mediated cerebral vasospasm. Vajkoczy et al. (Neurosurg 103:9-17, 2005) initially demonstrated that clazosentan reduced moderate/severe angiographically proven vasospasm by 55% relative to placebo. These findings led to the initiation of the CONSCIOUS trial program to further examine the efficacy and safety of clazosentan in reducing angiographic vasospasm and improving clinical outcome after aneurysmal SAH. In the first of these studies, CONSCIOUS-1, 413 patients were randomized to placebo or clazosentan 1, 5 or 15 mg/h. Clazosentan reduced angiographic vasospasm dose-dependently relative to placebo with a maximum risk reduction of 65% with the highest dose. Despite this, there was no benefit of clazosentan on the secondary protocol-defined morbidity/mortality endpoint; however, additional post-hoc and modified endpoint analyses provided some evidence for a potential clinical benefit. Two additional large-scale studies (CONSCIOUS-2 and CONSCIOUS-3) are now underway to further investigate the potential of clazosentan to improve long-term clinical outcome.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments.

Diagnosis and treatment of an obsessive-compulsive disorder following traumatic brain injury: A single case and review of the literature

A 27-year-old patient with traumatic brain injury and neuropsychiatric symptoms fitting the obsessive-compulsive disorder was investigated. Brain CT-scan revealed left temporal and bilateral fronto-basal parenchymal contusions. Main Outcome Measure was the Yale-Brown Obsessive Compulsive Scale at pre- and post-treatment and at 6 months follow-up. The combination of pharmacotherapy and psychotherapy resulted in lower intensity and frequency of symptoms. Our case illustrates the importance of a detailed diagnostic procedure in order to provide appropriate therapeutic interventions. Further studies are needed to guide the clinician in determining which patients are likely to benefit from a psychotherapeutic intervention in combination with pharmacotherapy.

Antinociceptive activity of pre- versus post-operative intra-articular bupivacaine in goats undergoing stifle arthrotomy

OBJECTIVE: To evaluate the peri-operative analgesic efficacy of intra-articular bupivacaine administered before or after stifle arthrotomy. STUDY DESIGN: Prospective, randomized, blind, placebo-controlled experimental trial. ANIMALS: Thirty-nine healthy goats. METHODS: The goats were allocated randomly to one of three intra-articular treatment groups: group PRE (bupivacaine before and saline after surgery), group POST (saline before and bupivacaine after surgery) and group CON (saline before and after surgery). Anaesthesia was maintained with a constant end-tidal sevoflurane of 2.5%. Intra-operatively heart rate (HR), respiratory rate and mean arterial blood pressure (MAP) after critical surgical events (CSE) were recorded and compared with pre-incision values. Propofol requirements to maintain surgical anaesthesia were recorded. Flunixin was administered for 5 days. Post-operative pain assessment at 20 minutes, 2 hours, 4 hours after recovery and on day 2 and 3 included a multidimensional pain score (MPS), a lameness score and mechanical nociceptive threshold (MNT) testing. Rescue analgesia consisted of systemic opioids. Data were analysed using Kruskal-Wallis, Mann-Whitney, Friedman or chi-square tests as appropriate. RESULTS: Intra-operatively, group PRE had lower HR and MAP at several CSEs than groups POST/CON and required less propofol [0 mg kg(-1) (0-0 mg kg(-1))] than group POST/CON [0.3 mg kg(-1) (0-0.6 mg kg(-1))]. Post-operatively, group POST had significantly higher peri-articular MNTs than groups PRE and CON up to 4 hours after recovery. No treatment effect was detected for MPS, lameness scores and rescue analgesic consumption at any time point. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-operative intra-articular bupivacaine provided notable intra-operative analgesia in goats undergoing stifle arthrotomy but did not reduce post-operative pain. Post-operative intra-articular bupivacaine provided a short lasting reduction of peri-articular hyperalgesia without affecting the requirements for systemic analgesia. Multimodal perioperative pain therapy is recommended to provide adequate analgesia for stifle arthrotomy in goats.

Coping personality type and environmental enrichment affect aggression at weaning in pigs

This study investigated the effects of different environmental treatments and personality types on aggression at mixing of newly weaned domestic piglets. From birth to weaning, 16 litters were housed with their dams in either barren (B) or larger, substrate-enriched (E) environments. At 15 days old, piglets were classified as 'high' (HR) or low resistant' (LR) in a manual restraint test (backtest), which is thought to identify proactive (HR) and reactive (LR) stress coping strategies that may reflect different personality types. At 30 days old, 128 piglets were weaned, relocated and mixed into 32 pens comprising two HR and two LR unfamiliar pigs, balanced for sex and weaning weight. Eight B and eight E groups changed environmental condition whereas the others remained in the same type of environment. Number and duration of fights. fight outcomes and unilateral fighting were scored for 5 h post-mixing and skin lesions were counted before and 5 h, 1 day and 2 days after mixing. On the day following weaning, fighting and also exploratory and oral manipulative behaviours were measured for 6 h. Generalized Linear Mixed Model analyses suggested interactions between pre-weaning environment, post-weaning environment and personality type. Overall, pre-weaning E pigs had longer fights at weaning and mixing (P=0.01) and fought for longer on the next day (P=0.02) than pre-weaning B pigs, and inflicted more skin lesions (P=0.02). Post-weaning enrichment did not affect fighting at mixing but reduced the time spent fighting the next day (P=0.03). Personality had subtle and environment-dependent effects on fighting, and influenced the "structure" rather than the amount of aggressive behaviour. HR pigs, for instance, bullied (i.e. chased surrendering pigs) more often (P=0.009) and their fighting behaviour was less affected by their relative body weight than that of LR pigs. Post-weaning E pigs showed relatively higher levels of exploratory behaviour (P=0.02) and less oral manipulative behaviour (P=0.04) than post-weaning B pigs. In particular, switching from a good quality environment (E) to a worse quality one (B) at weaning decreased exploratory behaviour on the next day, especially for LR pigs, who also tended to fight with and orally manipulate their pen mates more in that condition, and seemed to be more affected by a deterioration of the environment. Overall, pre-weaning enrichment increased aggression after weaning whereas post-weaning enrichment reduced it, and personality type related to some aspects of fighting behaviour. (C) 2011 Elsevier B.V. All rights reserved.

Harry Potter and the Theory of Things

This thesis investigates the boundaries between body and object in J.K. Rowling’s Harry Potter series, seven children’s literature novels published between 1997 and 2007. Lord Voldemort, Rowling’s villain, creates Horcruxes—objects that contain fragments of his soul—in order to ensure his immortality. As vessels for human soul, these objects rupture the boundaries between body and object and become “things.” Using contemporary thing theorists including John Plotz and materialists Jean Baudrillard and Walter Benjamin, I look at Voldemort’s Horcruxes as transgressive, liminal, unclassifiable entities in the first chapter. If objects can occupy the juncture between body and object, then bodies can as well. Dementors and Inferi, dark creatures that Rowling introduces throughout the series, live devoid of soul. Voldemort, too, becomes a thing as he splits his soul and creates Horcruxes. These soulless bodies are uncanny entities, provoking fear, revulsion, nausea, and the loss of language. In the second chapter, I use Sigmund Freud’s theorization of the uncanny as well as literary critic Kelly Hurley to investigate how Dementors, Inferi, and Voldemort exist as body-turned-object things at the juncture between life and death. As Voldemort increasingly invests his immaterial soul into material objects, he physically and spiritually degenerates, transforming from the young, handsome Tom Marvolo Riddle into the snake-like villain that murdered Harry’s parents and countless others. During his quest to find and destroy Voldemort’s Horcruxes, Harry encounters a different type of object, the Deathly Hallows. Although similarly accessing boundaries between body/object, life/death, and materiality/immateriality, the three Deathly Hallows do not transgress these boundaries. Through the Deathly Hallows, Rowling provides an alternative to thingification: objects that enable boundaries to fluctuate, but not breakdown. In the third chapter, I return to thing theorists, Baudrillard, and Benjamin to study how the Deathly Hallows resist thingification by not transgressing the boundaries between body and object.

Motor symptoms and schizophrenia

Classical schizophrenia literature reports motor symptoms as characteristic of the disorder. After the introduction of neuroleptic drugs, the existence of genuine motor disorders was challenged. Renewed interest arose as symptoms were found in never-medicated patients. Reports focused on abnormal involuntary movements, parkinsonism, neurological soft signs, catatonia, negative symptoms, or psychomotor slowing. Since these syndromes refer to different concepts, however, the definitions are not congruent and the symptoms overlap. The prevalence rates of motor symptoms in schizophrenia are surprisingly high, and recent studies indicate a possible pathobiology. In particular, the development and maturation of the human motor system appears to be closely linked to the emergence of motor symptoms observed in schizophrenia. Post-mortem and neuroimaging results demonstrated aberrant structure and function of premotor and motor cortices, basal ganglia, thalamus, and the connecting white matter tracts. Animal models have focused on aberrant neurotransmission and genetic contributions. Findings of localized abnormal oligodendrocyte function and myelination point to the special role of the white matter in schizophrenia, and recent studies specifically found an association between motor abnormalities and white matter structure in schizophrenia. This review of the literature supports the idea that motor symptoms are closely related to the neurodevelopmental disturbances of schizophrenia and a distinct syndromal dimension with its own pathophysiology.

Bacchus and Civic Order: The Culture of Drink in Early Modern Germany / Bacchus und die bürgerliche Ordnung. Die Kultur des Trinkens im frühneuzeitlichen Augsburg

Lining the streets inside the city's gates, clustered in its center, and thinly scattered among its back quarters were Augsburg's taverns and drinking rooms. These institutions ranged from the poorly lit rooms of backstreet wine sellers to the elaborate marble halls frequented by society's most privileged members. Urban drinking rooms provided more than food, drink, and lodging for their guests. They also conferred upon their visitors a sense of social identity commensurate with their status. Like all German cities, Augsburg during the sixteenth and seventeenth centuries had a history shaped by the political events attending the Reformation, the post-Reformation, and the Thirty Years' War; its social and political character was also reflected and supported by its public and private drinking rooms. In Bacchus and Civic Order: The Culture of Drink in Early Modern Germany, Ann Tlusty examines the social and cultural functions served by drinking and tavern life in Germany between 1500 and 1700, and challenges existing theories about urban identity, sociability, and power. Through her reconstruction of the social history of Augsburg, from beggars to council members, Tlusty also sheds light on such diverse topics as social ritual, gender and household relations, medical practice, and the concerns of civic leaders with public health and poverty. Drunkenness, dueling, and other forms of tavern comportment that may appear "disorderly" to us today turn out to be the inevitable, even desirable result of a society functioning according to its own rules.

Expression and diversity of Echinococcus multilocularis AgB genes in secondarily infected mice: evaluating the influence of T-cell immune selection on antigenic variation

The T-cell-mediated immune response exhibits a crucial function in the control of the intrahepatic proliferation of Echinococcus multilocularis larvae in mice and humans, both being natural intermediate hosts of the parasite. Antigen B (AgB), a metabolized Echinococcus spp. lipoprotein, contributes to the modulation of the T-cell immune response, and distinct sites of the corresponding AgB1, AgB3 and AgB4 genes were shown to be under positive selection pressure. Since several AgB gene variants are present in a single Echinococcus metacestode, we used secondary E. multilocularis infections in BALB/c and in athymic nude mice (devoid of T-cell responses) to analyze the effect of the cellular immune response on the expression and diversity of EmAgB1-EmAgB4 genes. We demonstrated hereby that EmAgB transcripts were less abundant in nude mice during the early phase of infection (at one month post-infection), and that EmAgB2 is simultaneously down-regulated when compared to the other three genes. A negative relationship exists between the level of transcription and diversity of EmAgB genes. Moreover, no excess of non-synonymous substitutions was found among the distinct EmAgB alleles from a single host. Together, these results pointed to the effect of purifying selection, which seemed to eliminate the detrimental AgB variants generated during the development of the metacestode within the peritoneal cavity of its intermediate host.

Responsiveness and habituation of soluble icam-1 to acute psychosocial stress in men: determinants and efect of stress-hemoconcentration

We studied the psychophysiology of soluble intercellular adhesion molecule-1 (sICAM-1) in 25 apparently healthy middle-aged men who underwent an acute psychosocial stressor three times with one week apart. Measures of the biological stress response were obtained at week one and three. The magnitude of the sICAM-1 stress response showed no habituation between visits. At week one, cognitive stress appraisal independently predicted integrated sICAM-1 area under the curve (AUC) between rest, immediately post-stress, and 45 min and 105 min post-stress (beta=.67, p=.012, deltaR(2)=.41). Diastolic blood pressure AUC (beta=-.45, p=.048, deltaR(2)=.21) and heart rate (AUC) (beta=.44, p=.055, deltaR(2)=.21) were independent predictors of sICAM-1 (AUC) at week three. Adjustment for hemoconcentration yielded a decrease in sICAM-1 levels from rest to post-stress (p<.001). Stress responsiveness of plasma sICAM-1 was predicted by stress perception and hemodynamic reactivity and affected by stress-hemoconcentration but unrelated to cortisol reactivity and not readily adapting to stress repeats.

Pain management and the effect of guidelines in neonatal units in Austria, Germany and Switzerland

BACKGROUND: Painful invasive procedures are frequently performed on preterm infants admitted to a neonatal intensive care unit (NICU). The aim of the present study was to investigate current pain management in Austrian, German and Swiss NICU and to identify factors associated with improved pain management in preterm infants. METHODS: A questionnaire was sent to all Austrian, German and Swiss pediatric hospitals with an NICU (n = 370). Pain assessment and documentation, use of analgesics for 13 painful procedures, presence of written guidelines for pain management and the use of 12 analgesics and sedatives were examined. RESULTS: A total of 225 units responded (61%). Pain assessment and documentation and frequent analgesic therapy for painful procedures were performed more often in units using written guidelines for pain management and in those treating >50 preterm infants at <32 weeks of gestation per year. This was also the case for the use of opioid analgesics and sucrose solution. Non-opioid analgesics were used more often in smaller units and in units with written guidelines. There was a broad variation in dosage of analgesics and sedatives within all groups. CONCLUSION: Pain assessment, documentation of pain and analgesic therapy are more frequently performed in NICU with written guidelines for pain management and in larger units with more than 50 preterm infants at <32 weeks of gestation per year.

Lack of concordance between subjective improvement and symptom change in psychotic episodes

OBJECTIVES: Subjective, self-rated improvement in patients with schizophrenia spectrum disorders can carry significance as a first-person account of treatment outcome, and can be of importance for the individual patient's acceptance of further treatment, including psychological treatments. This study assessed the concordance between post-treatment subjective improvement and the observed symptom change after a psychotic episode. DESIGN: Longitudinal study based on daily symptom ratings. METHOD: The study sample consisted of 43 younger, primarily first- or second-episode patients. Observed symptom change was calculated as both pre-post differences and symptom trajectories. Subjective improvement was assessed at the end of treatment by using the 'Emotional and Behavioural Changes in Psychotherapy Questionnaire' (VEV), a retrospective measure of subjective change. RESULTS: The findings indicated no significant concordance between pre-post differences in symptoms and self-rated improvement, nor were final levels of symptoms related to subjective improvement. Higher initial and mean symptom levels for positive symptoms were related to a lower degree of subjective improvement. A shorter duration of an initial trend-like improvement in psychosis was shown to be associated with greater subjective improvement. CONCLUSIONS: Subjective assessment of improvement may differ markedly from symptom change. In psychotic episodes, more severe initial positive symptoms as well as a delayed improvement of positive symptoms may be related to a reduced subjective experience of improvement for the duration of the entire episode. The treatment of psychosis should take a possible discordance between subjective and objective change into account.

Stratification of cumulative antibiograms in hospitals for hospital unit, specimen type, isolate sequence and duration of hospital stay

BACKGROUND: Empirical antibiotic therapy is based on patients' characteristics and antimicrobial susceptibility data. Hospital-wide cumulative antibiograms may not sufficiently support informed decision-making for optimal treatment of hospitalized patients. METHODS: We studied different approaches to analysing antimicrobial susceptibility rates (SRs) of all diagnostic bacterial isolates collected from patients hospitalized between July 2005 and June 2007 at the University Hospital in Zurich, Switzerland. We compared stratification for unit-specific, specimen type-specific (blood, urinary, respiratory versus all specimens) and isolate sequence-specific (first, follow-up versus all isolates) data with hospital-wide cumulative antibiograms, and studied changes of mean SR during the course of hospitalization. RESULTS: A total of 16 281 isolates (7965 first, 1201 follow-up and 7115 repeat isolates) were tested. We found relevant differences in SRs across different hospital departments. Mean SRs of Escherichia coli to ciprofloxacin ranged between 64.5% and 95.1% in various departments, and mean SRs of Pseudomonas aeruginosa to imipenem and meropenem ranged from 54.2% to 100% and 80.4% to 100%, respectively. Compared with hospital cumulative antibiograms, lower SRs were observed in intensive care unit specimens, follow-up isolates and isolates causing nosocomial infections (except for Staphylococcus aureus). Decreasing SRs were observed in first isolates of coagulase-negative staphylococci with increasing interval between hospital admission and specimen collection. Isolates from different anatomical sites showed variations in SRs. CONCLUSIONS: We recommend the reporting of unit-specific rather than hospital-wide cumulative antibiograms. Decreasing antimicrobial susceptibility during hospitalization and variations in SRs in isolates from different anatomical sites should be taken into account when selecting empirical antibiotic treatment.

Preparing writing centers and tutors for literacy mediation for working class campus-staff

Writing centers work with writers; traditionally services have been focused on undergraduates taking composition classes. More recently, centers have started to attract a wider client base including: students taking labs that require writing; graduate students; and ESL students learning the conventions of U.S. communication. There are very few centers, however, which identify themselves as open to working with all members of the campus-community. Michigan Technological University has one such center. In the Michigan Tech writing center, doors are open to “all students, faculty and staff.” While graduate students, post docs, and professors preparing articles for publication have used the center, for the first time in the collective memory of the center UAW staff members requested center appointments in the summer of 2008. These working class employees were in the process of filling out a work related document, the UAW Position Audit, an approximately seven-page form. This form was their one avenue for requesting a review of the job they were doing; the review was the first step in requesting a raise in job level and pay. This study grew out of the realization that implicit literacy expectations between working class United Auto Workers (UAW) staff and professional class staff were complicating the filling out and filing of the position audit form. Professional class supervisors had designed the form as a measure of fairness, in that each UAW employee on campus was responding to the same set of questions about their work. However, the implicit literacy expectations of supervisors were different from those of many of the employees who were to fill out the form. As a result, questions that were meant to be straightforward to answer were in the eyes of the employees filling out the form, complex. Before coming to the writing center UAW staff had spent months writing out responses to the form; they expressed concerns that their responses still would not meet audience expectations. These writers recognized that they did not yet know exactly what the audience was expecting. The results of this study include a framework for planning writing center sessions that facilitate the acquisition of literacy practices which are new to the user. One important realization from this dissertation is that the social nature of literacy must be kept in the forefront when both planning sessions and when educating tutors to lead these sessions. Literacy scholars such as James Paul Gee, Brian Street, and Shirley Brice Heath are used to show that a person can only know those literacy practices that they have previously acquired. In order to acquire new literacy practices, a person must have social opportunities for hands-on practice and mentoring from someone with experience. The writing center can adapt theory and practices from this dissertation that will facilitate sessions for a range of writers wishing to learn “new” literacy practices. This study also calls for specific changes to writing center tutor education.