bluuebunny/crossref_metadata_2025 huggingface dataset:
Sciatica due to extrapelvic heterotopic ossification: A case report
Authors: Panagiotopoulos Elias C , Syggelos Spyros A , Plotas Athanasios , Tsigkas Gregorios , Dimopoulos Panagiotis
Published: September 2008

Introduction

Sciatica is a common problem, usually caused by disc herniation or spinal stenosis. Low back pain is also present in most cases. When sciatica is the unique clinical finding, especially in young patients, extraspinal pathology should be investigated.

Case presentation

We describe a rare case of sciatica in a 32-year-old man, which was developed as a complication of post-traumatic pelvic heterotopic ossification. During the operation, the sciatic nerve was found to be bluish, distorted and compressed in an hourglass fashion around a heterotopic bone mass. The heterotopic bone tissue, 4 cm in diameter, was removed and the patient had fully recovered 3 months after the operation.

Conclusion

In cases of sciatica without back pain, the possibility of direct pressure of the sciatic nerve from cysts, tumours or bone, as in the present case, should be considered.
Primary osteogenic sarcoma of the breast: A case report
Authors: Khan Shabuddin , Griffiths Ewen A , Shah Nigam , Ravi Srinivasan
Published: September 2008

Introduction

Primary osteosarcoma of the breast is a rare malignant tumour. It is typically a poor prognosis tumour, which has some interesting features worthy of discussion. We report a case of primary osteosarcoma of the breast and summarise the previous medical literature to highlight several details of this unusual tumour.

Case presentation

A 66-year-old Caucasian lady presented with painless lump in her right breast. Mammography showed features of fibroadenoma with calcification and fine needle aspiration cytology was reported as showing malignant cells (C5). Wide local excision was performed and histological features were consistent with primary osteosarcoma with predominance of osteoclastic activity. Subsequent completion mastectomy was performed because of suspicion of incomplete excision. She remains disease free 8 years from her initial surgery.
Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity
Authors: Wither Joan , Cai Yong-chun , Lim Sooyeol , McKenzie Tamara , Roslin Nicole , Claudio Jaime O , Cooper Glinda S , Hudson Thomas J , Paterson Andrew D , Greenwood Celia MT , Gladman Dafna , Pope Janet , Pineau Christian A , Smith C Douglas , Hanly John G , Peschken Christine , Boire Gilles ,   CaNIOS Investigators, Fortin Paul R
Published: September 2008

Introduction

Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives.

Methods

Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.

Results

We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait.

Conclusions

The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.
The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas
Authors: Herschkowitz Jason I , He Xiaping , Fan Cheng , Perou Charles M
Published: September 2008

Introduction

Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in prognosis. One of these groups, the basal-like subtype, is poorly differentiated, highly metastatic, genomically unstable, and contains specific genetic alterations such as the loss of tumour protein 53 (TP53). The loss of the retinoblastoma tumour suppressor encoded by the RB1 locus is a well-characterised occurrence in many tumour types; however, its role in breast cancer is less clear with many reports demonstrating a loss of heterozygosity that does not correlate with a loss of RB1 protein expression.

Methods

We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples.

Results

RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy.

Conclusions

These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses.
Effects of inhaled iloprost on right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence: a randomized placebo-controlled trial in an experimental model of acute pulmonary hypertension
Authors: Rex Steffen , Missant Carlo , Claus Piet , Buhre Wolfgang , Wouters Patrick F
Published: September 2008

Introduction

Prostacyclin inhalation is increasingly used to treat acute pulmonary hypertension and right ventricular failure, although its pharmacodynamic properties remain controversial. Prostacyclins not only affect vasomotor tone but may also have cAMP-mediated positive inotropic effects and modulate autonomic nervous system tone. We studied the role of these different mechanisms in the overall haemodynamic effects produced by iloprost inhalation in an experimental model of acute pulmonary hypertension.

Methods

In this prospective, randomized, placebo-controlled animal study, twenty-six pigs (mean weight 35 ± 2 kg) were instrumented with biventricular conductance catheters, a pulmonary artery flow probe and a high-fidelity pulmonary artery pressure catheter. The effects of inhaled iloprost (50 μg) were studied in the following groups: animals with acute hypoxia-induced pulmonary hypertension, and healthy animals with and without blockade of the autonomic nervous system.

Results

During pulmonary hypertension, inhalation of iloprost resulted in a 51% increase in cardiac output compared with placebo (5.6 ± 0.7 versus 3.7 ± 0.8 l/minute;P= 0.0013), a selective reduction in right ventricular afterload (effective pulmonary arterial elastance: 0.6 ± 0.3 versus 1.2 ± 0.5 mmHg/ml;P= 0.0005) and a significant increase in left ventricular end-diastolic volume (91 ± 12 versus 70 ± 20 ml;P= 0.006). Interestingly, right ventricular contractility was reduced after iloprost-treatment (slope of preload recruitable stroke work: 2.2 ± 0.5 versus 3.4 ± 0.8 mWatt·s/ml;P= 0.0002), whereas ventriculo-vascular coupling remained essentially preserved (ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance: 0.97 ± 0.33 versus 1.03 ± 0.15). In healthy animals, inhaled iloprost had only minimal haemodynamic effects and produced no direct effects on myocardial contractility, even after pharmacological blockade of the autonomic nervous system.

Conclusions

In animals with acute pulmonary hypertension, inhaled iloprost improved global haemodynamics primarily via selective pulmonary vasodilatation and restoration of left ventricular preload. The reduction in right ventricular afterload is associated with a paradoxical decrease in right ventricular contractility. Our data suggest that this reflects an indirect mechanism by which ventriculo-vascular coupling is maintained at the lowest possible energetic cost. We found no evidence for a direct negative inotropic effect of iloprost.
Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo
Authors: Bosisio Daniela , Vulcano Marisa , Del Prete Annalisa , Sironi Marina , Salvi Valentina , Salogni Laura , Riboldi Elena , Leoni Flavio , Dinarello Charles A , Girolomoni Giampiero , Sozzani Silvano
Published: September 2008

Histone deacetylase (HDAC) inhibitors are small molecules inducing cell-cycle arrest, differentiation, and apoptosis, currently undergoing clinical trials as anticancer drugs. In addition, emerging evidence suggests HDAC inhibitors may have anti-inflammatory and immunomodulatory properties as well, although the molecular mechanisms remain poorly defined. Given the central role of dendritic cells (DC) in the induction and maintenance of the inflammatory and immune response, we investigated the effects of HDAC inhibitors on the maturation and activation of human monocyte-derived DC in the presence of LPS and IFN-γ. Our results show that the production of TH1- and TH17-inducing cytokines, namely IL-12 and IL-23, was inhibited by trichostatin A (72% and 52%, respectively) and suberoylanilide hydroxamic acid (86% and 83%). Strikingly, HDAC inhibitors were effective if added simultaneously as well as after the proinflammatory challenge, and their effect was not associated to a reduction of expression or function of LPS/IFN-γ receptors. These findings were confirmed in two different murine models. In addition, HDAC inhibitors selectively blocked the production of TH1-attracting chemokines CXCL9, CXCL10, and CXCL11. The reduction of TH1- and TH17-inducing cytokines as well as TH1-attracting chemokines may represent relevant mechanisms through which HDAC inhibitors at nonproapoptotic doses exert their immunomodulatory properties.
The frequency of regulatory CD3+CD8+CD28−CD25+ T lymphocytes in human peripheral blood increases with age
Authors: Simone Rita , Zicca Anna , Saverino Daniele
Published: September 2008

Aging is commonly associated with immune deficiency and dysregulation. The aging of the immune system involves a progressive reduction in naïve T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells. We have investigated frequency, phenotype, and function of CD3+CD8+CD28−CD25+ T cells in healthy volunteers over a wide age range. We demonstrate that the frequency of CD3+CD8+CD28−CD25+ T cells in healthy volunteers increases with age. Peripheral CD3+CD8+CD28−CD25+ T cells share phenotypic and functional features with CD3+CD4+CD25+ regulatory T cells (Tregs): In particular, they strongly express CTLA-4 and forkhead box P3. We observed that in vitro, functional titration assays of CD3+CD8+CD28−CD25+ T cells show equivalent regulatory function in young and elderly donors, with suppression of proliferation and cytokine production in response to polyclonal T cell stimulation. Finally, CD3+CD8+CD28−CD25+ T cells seem to specifically express the CD122 receptor. Altogether, these observations demonstrate an increase in peripheral blood CD8+ Tregs associated with aging.
Prevention and Treatment of Pediatric Obesity: An Endocrine Society Clinical Practice Guideline Based on Expert Opinion
Authors: August Gilbert P. , Caprio Sonia , Fennoy Ilene , Freemark Michael , Kaufman Francine R. , Lustig Robert H. , Silverstein Janet H. , Speiser Phyllis W. , Styne Dennis M. , Montori Victor M.
Published: September 2008

Objective: Our objective was to formulate practice guidelines for the treatment and prevention of pediatric obesity.

Conclusions: We recommend defining overweight as body mass index (BMI) in at least the 85th percentile but < the 95th percentile and obesity as BMI in at least the 95th percentile against routine endocrine studies unless the height velocity is attenuated or inappropriate for the family background or stage of puberty; referring patients to a geneticist if there is evidence of a genetic syndrome; evaluating for obesity-associated comorbidities in children with BMI in at least the 85th percentile; and prescribing and supporting intensive lifestyle (dietary, physical activity, and behavioral) modification as the prerequisite for any treatment. We suggest that pharmacotherapy (in combination with lifestyle modification) be considered in: 1) obese children only after failure of a formal program of intensive lifestyle modification; and 2) overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history of type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions. We suggest bariatric surgery for adolescents with BMI above 50 kg/m2, or BMI above 40 kg/m2 with severe comorbidities in whom lifestyle modifications and/or pharmacotherapy have failed. Candidates for surgery and their families must be psychologically stable and capable of adhering to lifestyle modifications. Access to experienced surgeons and sophisticated multidisciplinary teams who assess the benefits and risks of surgery is obligatory. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. We suggest that clinicians educate children and parents through anticipatory guidance about healthy dietary and activity habits, and we advocate for restricting the availability of unhealthy food choices in schools, policies to ban advertising unhealthy food choices to children, and community redesign to maximize opportunities for safe walking and bike riding to school, athletic activities, and neighborhood shopping.
Influences of Gender on the Interaction between Sympathetic Nerve Traffic and Central Adiposity
Authors: Tank Jens , Heusser Karsten , Diedrich Andre , Hering Dagmara , Luft Friedrich C. , Busjahn Andreas , Narkiewicz Krzysztof , Jordan Jens
Published: September 2008

Context: Sympathetic activation promotes insulin resistance and arterial hypertension with increasing adiposity. A difference in the relationship between adiposity and sympathetic activity between women and men could contribute to the known gender difference in cardiovascular disease risk.

Objective: We tested whether muscle sympathetic nerve activity (MSNA) is correlated differently with waist circumference, waist to hip ratio (WHR), and body mass index (BMI) in women and men.

Design and Setting: We pooled data from two microneurography centers (Berlin, Germany; Gdansk, Poland) for a cross-sectional study.

Participants: We studied 111 normotensive, healthy Caucasian subjects (70 males and 41 females). Age ranged between 19 and 62 yr and BMI ranged between 18 and 40 kg/m2.

Intervention: No intervention was applied during the study.

Measurements: Supine heart rate, blood pressure, and MSNA were recorded after at least 30 min rest.

Results: MSNA in bursts per minute was age dependent in both sexes [r (male) = 0.56, r (female) = 0.34, P < 0.01]. Controlling for waist and hip circumferences, age dependence remained highly significant in men (r = 0.43) and women (r = 0.43). Adjusting for age, in men, waist circumference (r = 0.29), WHR (r = 0.39), and BMI (r = 0.31) were predictive for MSNA and directly correlated (P < 0.01) but not in women. Adjusting for BMI, in men, only WHR (r = 0.40) remained predictive for MSNA.

Conclusion: These data support the hypothesis of a gender difference in the regulation of the sympathetic nervous system, in which MSNA mainly relates to WHR in men but not women. The phenomenon may contribute to the sexual dimorphism in cardiovascular disease risk.
Changes in Adenosine 5′-Monophosphate-Activated Protein Kinase as a Mechanism of Visceral Obesity in Cushing’s Syndrome
Authors: Kola Blerina , Christ-Crain Mirjam , Lolli Francesca , Arnaldi Giorgio , Giacchetti Gilberta , Boscaro Marco , Grossman Ashley B. , Korbonits Márta
Published: September 2008

Objective: Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushing’s syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushing’s syndrome.

Methods: AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushing’s syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery.

Results: The patients with Cushing’s syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P < 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushing’s syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol.

Conclusions: Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing’s syndrome.
BLACK ATLANTIC, QUEER ATLANTIC
Authors: Tinsley Omise'eke Natasha
Published: September 2008

What would it mean for both queer and African diaspora studies to theorize that the black Atlantic has always been a queer Atlantic? What new geography—or better, oceanography—of sexual, gendered, transnational, and racial identities might emerge through a queer reading of transoceanic dislocations between Africa and the Caribbean? This article examines canonical African diaspora and queer theoretical texts in dialogue with recently published creative texts that imagine queer relationships between African kidnapees in slave ships' holds. These creative texts, I argue, more expansively theorize conceptual space both to rethink submerged sexual, racial histories and to comment on the intersections between African diaspora and queer experiences in a contemporary era of Haitian refugees, transnational Dominican laborers, and international West Indian “gay” activists. Texts examined include Paul Gilroy's Black Atlantic (1993), Judith Butler's Gender Trouble (1990), Ana-Maurine Lara's Erzulie's Skirt (2006), and Dionne Brand's Map to the Door of No Return (2001).
A POLITICAL ECOLOGY OF “UNNATURAL OFFENCES”
Authors: Weston Kath
Published: September 2008

What is the relationship between forced migration and queerness, especially migration that takes the form of transportation to an offshore detention facility under the auspices of a state security regime? How could an obsession with same-sex eroticism on the part of a prison administration affect the political ecology of an entire archipelago? What insights can be gained by opening a dialogue between the interdisciplinary fields of political ecology and LGBTQ studies? This essay examines such questions through a late-nineteenth-century crackdown on “unnatural offences” at the British penal colony in the Andaman and Nicobar Islands. The prosecution of same-sex eroticism among forced migrants at the colony turns out to be intimately entangled with prison labor, discourses of visibility, recontoured landscapes, criminalization of everyday activities, and a politics of surmise. The essay argues for a more capacious and historically contextualized understanding of embodiment on the part of queer theory, one that can go beyond the suffering, labors, and desires of queered yet still visibly bounded bodies to take into account the “somaeconomic” extension of those bodies into the environments they shape.
TACIT SUBJECTS
Authors: Decena Carlos Ulises
Published: September 2008

Privileging the disclosure of a homosexual identity, or “coming out,” blinds researchers to negotiations of the closet that do not resort to the confession. Drawing from Spanish grammar and from ethnographic research among Dominican immigrant homosexual men living in New York City, this article proposes the concept of tacit subjects to suggest that gay men and those close to them may be complicit in relegating information about a person's sexuality to the realm of what is tacit and/or understood. By stressing the structural and relational variables that people negotiate as they sustain their family and other kin networks, the concept of tacit subjects underlines the collaborative nature of identity negotiation and the forms of knowledge that make social collectivities viable.
Is Global Governance Bad for East Asian Queers?
Authors: Ho Josephine
Published: September 2008

The rise of transnational systems and networks of governance and norms since the 1990s and the emergence of the so-called global civil society hold out promises of equity for LGBT advocates and marginal groups in East Asia as pride marches, lesbian and gay cultural events, and booming queer Internet communities corroborate the impression that queer Asia may be much more than a concept. Yet there is a growing retrenchment in the same region as various states take up measures quite inhospitable to queer existence. Christian NGOs in particular are aggressively raising social discontent and mobilizing opposition against the growing visibility of gay lifestyles and the equity demands launched by queer activism. The present essay analyzes this new “reign of civility” and its construction of “child protection” as a universal imperative; it also demonstrates how developments in juridification are suturing up global governance, East Asia's liberal states, and conservative NGOs into a new power bloc that fosters antiqueer and antisex climates in the region.
Transnational Discourses and Circuits of Queer Knowledge in Indonesia
Authors: Blackwood Evelyn
Published: September 2008

This article examines the circulation of “global queer discourse” in Indonesia to interrogate the processes by which queer knowledge is received and appropriated. While Western-oriented queer discourse articulated by international LGBT organizations promote a “modern ideal” of lesbian and gay identities, individual female subjectivities are much more complex and layered. In Padang, West Sumatra tombois and their girlfriends, who identify themselves as masculine and feminine, access global circuits of queer knowledge and see themselves as part of a global community, but maintain subject positions that are distinct from the identities promoted and encouraged by activist lesbian organizations in Indonesia. In this article I examine the ways both lesbian activists in Jakarta and individuals in Padang selectively appropriate circuits of queer knowledge to make sense of their own subjectivities and negotiate their places in the “lesbian” world. I offer insights into the asymmetries of reception and the consequent multiplicity of desires and subjectivities as a way to incorporate the diversity of queer subjectivities within a “global gay” ecumene.
THE VIEW FROM THE SHORTBUS, OR ALL THOSE FUCKING MOVIES
Authors: Davis Nick
Published: September 2008

This article takes the recent success and notoriety of John Cameron Mitchell's Shortbus (2006) as the occasion for an overview of “real” sex as a recurring motif and practice of commercial, nonpornographic cinema of recent years. Diverse in their generic modalities and, even more crucially, in their national and cultural origins, these films constitute a cinematic “counterpublic” along the lines Michael Warner prescribes for human and textual communities, recalibrating the relations among sexuality, visuality, and representation as they play out for public audiences and in the emphatically public, innately collaborative medium of cinema. “Counterpublic” also emerges as an apt descriptor of the New Queer Cinema of the 1990s, and indeed, Shortbus owes much of its uniqueness to its overt (indeed, explicit) interbraiding of New Queer tropes and intertexts with the formal and political dispositions of other “real sex” films. If, however, the film's felicitous coalition of these two lineages accounts for part of its utopian merriment and subversive zeal, Shortbus also reprises some of the cultural and political myopias (particularly in relation to gender and race) that the New Queer movement often had trouble transcending. The complex reflections and critiques of an American public that are embedded in the film's script, mise-en-scène, and processes of production are essential to the film's compatibility with other “real sex” films, where the invocation and interrogation of the “real” so often bears national and social as well as sexual weight. At the same time, in its very internationalism and stylistic heterogeneity, this cinematic counterpublic refuses any single model of the public, the political, the sexual, or the real, and sets ever-new horizons for the subversive potential of sexual images in cinema.
Dynein drives nuclear rotation during forward progression of motile fibroblasts
Authors: Levy Jennifer R. , Holzbaur Erika L. F.
Published: September 2008

During directed cell migration, the movement of the nucleus is coupled to the forward progression of the cell. The microtubule motor cytoplasmic dynein is required for both cell polarization and cell motility. Here, we investigate the mechanism by which dynein contributes to directed migration. Knockdown of dynein slows protrusion of the leading edge and causes defects in nuclear movements. The velocity of nuclear migration was decreased in dynein knockdown cells, and nuclei were mislocalized to the rear of motile cells. In control cells, we observed that wounding the monolayer stimulated a dramatic induction of nuclear rotations at the wound edge, reaching velocities up to 8.5 degrees/minute. These nuclear rotations were significantly inhibited in dynein knockdown cells. Surprisingly, centrosomes do not rotate in concert with the nucleus; instead, the centrosome remains stably positioned between the nucleus and the leading edge. Together, these results suggest that dynein contributes to migration in two ways: (1) maintaining centrosome centrality by tethering microtubule plus ends at the cortex; and (2) maintaining nuclear centrality by asserting force directly on the nucleus.
Quantifying the Long-Term Impact of Negative Word of Mouth on Cash Flows and Stock Prices
Authors: Luo Xueming
Published: September 2008

This paper seeks to quantify the long-term financial impact of negative word of mouth (NWOM), an issue that has long challenged extant research. We do so with real-world data on firm security prices. The developed time-series models innovatively uncover (1) short- and long-term effects of NWOM on cash flows, stock returns, and stock volatilities, and (2) NWOM's “wear-in” effects (i.e., it takes a number of months before the stock price impact of NWOM reaches the peak point) and “wear-out” effects (i.e., it takes several months after the peak before the stock price impact of NWOM dies out completely). In addition, the results related to endogeneity and feedback effects from the stock market are also interesting, supporting the idea that historical underperformance in stock prices may breed more harmful future buzz in a “vicious” cycle of NWOM. After controlling for competition, NWOM's long-term financial harm becomes more destructive in magnitude, kicks in more quickly, and haunts investors longer. Overall, these findings offer some unique implications for buzz management, time-series models quantifying the financial impact of word of mouth, and the marketing-finance interface.
Effects of Information Disclosure Under First- and Second-Price Auctions in a Supply Chain Setting
Authors: Chen Ying-Ju , Vulcano Gustavo
Published: September 2008

We study a supply chain where an upstream supplier auctions his inventory or capacity as a bundle. The importance of this setting is twofold: From a practical point of view, there are several examples, both in manufacturing (e.g., auctioning the capacity of a wafer fabrication facility) and service industries (e.g., auctioning the sponsorship of a website), where a supplier's capacity is sold as a single piece; from a theoretical side, it highlights the information asymmetry introduced on the downstream supply chain parties when the auction result is disclosed.

We formulate the problem as a two-stage supply chain comprising a single supplier and two resellers. Each reseller receives a signal of the consumer demand and bids for the capacity of the supplier. The supplier announces the winner as well as the auction price. Both resellers can get additional units in a procurement market and then engage in Cournot competition in the consumer market.

We analyze the impact of the information elicited by the supplier in the early stage of the game. We characterize sufficient conditions for the existence of equilibrium behavior, derive the equilibrium bidding functions under both first- and second-price auctions, and show that the bidding functions are lower than the corresponding ones for a single-shot auction without resale. Our computational experiments indicate that both the supplier and resellers are better off running a second-price auction and that consumers benefit if the resellers have very different signals on the total demand. Overall, our results suggest that traditional auctions may have a profound impact in the context of a supply chain because of the information disclosure in the upstream stages.
Dexmedetomidine Infusion as Adjunctive Therapy to Benzodiazepines for Acute Alcohol Withdrawal
Authors: Darrouj Jamil , Puri Nitin , Prince Erin , Lomonaco Anthony , Spevetz Antoinette , Gerber David R
Published: September 2008

Objective:

To report a case of alcohol withdrawal and delirium tremens successfully treated with adjunctive dexmedetomidine.

Case Summary:

A 30–year-old man with a history of alcohol abuse was admitted to the general medical unit because of altered mental status and agitation. He was initially treated for alcohol withdrawal with benzodiazepines; his condition then deteriorated and he was transferred to the intensive care unit. Because of the patient's poor response to benzodiazepines (oxazepam and lorazepam, with midazolam the last one used), intravenous dexmedetomidine was started at an initial dose of 0.2 µg/kg/h and titrated to 0.7 µg/kg/h to the patient's comfort. Midazolam was subsequently tapered to discontinuation due to excessive sedation. In the intensive care unit, the patient's symptoms remained controlled with use of dexmedetomidine alone. He remained in the intensive care unit for 40 hours; dexmedetomidine was then tapered to discontinuation and the patient was transferred back to the general medical unit on oral oxazepam and thiamine, which had been started in the emergency department. He was discharged after 5 days.

Discussion:

A review of the PubMed database (1989-2007} failed to identify any other instances of dexmedetomidine having been used as the principal agent to treat alcohol withdrawal. The use of sedative to treat delirium tremens Is well documented, with benzodiazepines being the agents of choice. The clinical utility of benzodiazepines is limited by their stimulation of the γ-aminobutyric acid receptors, an effect not shared by dexmedetomidine, a central α2-receptor agonist that induces a state of cooperative sedation and does not suppress respiratory drive.

Conclusions:

In patients with delirium tremens, dexmedetomidine should be considered as an option for primary treatment. This case illustrates the need for further studies to investigate other potential uses for dexmedetomidine.
Sustained-Release Fampridine for Symptomatic Treatment of Multiple Sclerosis
Authors: Korenke Anne R , Rivey Michael P , Allington Douglas R
Published: September 2008

Objective:

To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of sustained-release (SR) fampridine in patients with multiple sclerosis (MS).

Data Sources:

An English-language human data search was done using PubMed/MEDLINE (1966-August 2008) to retrieve relevant material using the search terms fampridine-SR, 4-aminopyridine. and multiple sclerosis. References of selected articles and information from the drug developer were used to further identify pertinent trials.

Study Selection and Data Extraction:

Article selection was based primarily on studies that evaluated the pharmacokinetics, safety, and efficacy of fampridine-SR in patients with MS. Relevant meeting abstracts were also included as part of the analysis.

Data Synthesis:

Fampridine-SR is a sustained-release, orally administered potassium-channel blocker acting in the central nervous system to enhance conduction in demyelinated axons Several small trials have evaluated the safety and efficacy of fampridine-SR in patients with MS to improve their walking ability. Data from a recent large Phase 3 trial indicated that walking speed improved in 42.9% of patients with MS who were treated with fampridine-SR compared with 9.3% of those who received placebo (p < 0.001), Treatment-related adverse events associated with the use of fampridine-SR include dizziness, insomnia, nausea, and paresthesia. More severe adverse events, such as seizure, have occurred in patients receiving doses higher than those currently recommended.

Conclusions:

Positive results from 2 Phase 3 clinical trials have put fampridine-SR on the path toward approval as a medication for improving walking speed and tower extremity strength in patients with MS.
Efficacy of an Adverse Drug Reaction Electronic Reporting System Integrated into a Hospital Information System
Authors: Ortega Ana , Aguinagalde Aránzazu , Lacasa Carlos , Aquerreta Irene , Fernández-Benítez Margarita , Fernández Luis M
Published: September 2008

Background:

Adverse drug reaction (ADR) spontaneous reporting is the primary method of postmarketing drug surveillance: although it is an important part of postmarketing drug surveillance, it is underused. Before 2004, almost no ADRs were reported in our 400-bed hospital. As an electronic hospital information system was available in our hospital, we developed a tool (ADR-RS-IHIS) for ADR reporting integrated into the hospital information system to facilitate reporting through easy use, automatic input of certain information, increased accessibility, real-time review, and intervention.

Objective:

To analyze the efficacy of the ADR-RS-IHIS in increasing ADR reporting to the national drug surveillance system, propose and implement improvements to increase ADR reporting, and evaluate the impact of these improvements,

Methods:

Every ADR reported through the ADR-RS-IHIS was evaluated retrospectively. Two study phases for evaluating ADR-RS-IHIS efficacy were identified. Phase I took place April 2004-August 2006; in April 2006, an interim analysis was performed to propose improvements. Phase II took place September 2006-April 2007 for evaluation of the impact made by the proposed improvements. Efficacy in the phase I and improvement impact on phase II were measured as the number of ADRs reported to the national drug surveillance system

Results:

The rate of ADRs reported per month to the national system increased from 0 before 2004 to 0.91 in phase I and 1.62 in phase II (2.25 if delayed reporting was considered). Improvement measures included: allowing nurses to report ADRs in the same way as physicians and pharmacists, automatic form filling of certain information from the electronic hospital information system, easier ADR report analysis, and automatic notification to the allergy department regarding suspected allergies.

Conclusions:

An ADR reporting system integrated into the electronic hospital information system is effective for increasing the number of ADRs reported to the national drug surveillance system. Allowing nurses to report ADRs in a manner similar to that of physicians and pharmacists, as well as automatic entry of certain data into the form, contributes to the improvement of the system.
Incremental Drug Treatment Cost in HIV-Positive Patients in Industry-Sponsored Clinical Trials
Authors: Perrín Rosario Santolaya , López Fernando J García
Published: September 2008

Background:

Drugs used in clinical trials supported by the pharmaceutical industry are supplied free of charge by the companies. However, maintenance of treatment with those drugs when the trials have finished can generate extra cost for patients who participated in the trials.

Objective:

To assess whether HIV-infected patients' participation in clinical trials results in drug cost savings or increases.

Methods:

An analysis of alt antiretrovirals dispensed to HIV-infected outpatients prior to, during, and after their participation in clinical trials in a university hospital during a 2-year period was conducted. Only patients who completed the trial during the study period were included. The following outcomes were measured: (1) cost saved (difference between cost per day during the trial and cost per day before study entry), (2) cost generated (difference between cost per day at the end of the trial and cost per day before study entry), (3) balance between cost saved and cost generated, and (4) number of days that a patient received a drug once the trial was finished to generate cost, considering costs saved. All data were extracted from the hospital pharmacy database. A stratified analysis by type of clinical trial (ordinary or expanded use) was undertaken.

Results:

Data from 61 patients were analyzed. The cost of drug therapy during patient participation in a clinical trial was lower than the cost prior to inclusion. Therefore, mean drug savings of $10.38 (US) per patient day resulted (95% CI –5.9 to 14.84), The mean cost generated was $8.74 per patient day (95% CI 3.95 to 13.52).

Conclusions:

A patient's participation in a clinical trial or expanded-access clinical trial generated extra cost once the trial had finished because the cost of drug therapy was higher at the end of the study. In our study, the daily drug costs saved during the trial were similar to the daily drug costs generated.
Trastuzumab-Induced Hepatotoxicity
Authors: Srinivasan Sridhar , Parsa Venkata , Liu Chin Y , Fontana Joseph A
Published: September 2008

Objective:

To report a case of probable trastuzumab-induced hepatotoxicity.

Case Summary:

A 54-yoar-old African American woman presented with locally advanced right-sided breast cancer that was found to be strongly positive for human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization. She was treated with neoadjuvant chemotherapy with 4 cycles of dose-dense doxorubicin and cyclophosphamide. Laboratory test results, including liver function tests (LFTs), were normal at that time. Therapy consisting of weekly doses of paditaxel 80 mg/m2 and a loading dose of trastuzumab 4 mg/kg for the first week and 2 mg/kg weekly thereafter was started. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels began to increase after the initial dose; the levels were significantly elevated after the fifth cycle. Paclitaxel was withheld, and trastuzumab was continued, as there were no prior reported cases of trastuzumab-induced hepatotoxicity at that time. Other possible etiologies for the elevated enzyme levels, including metastasis to the liver, were excluded. The patient continued to receive trastuzumab for a total of 8 weeks; it was discontinued at that time because enzyme levels continued to increase. When trastuzumab was discontinued, enzyme levels returned to normal. Subsequently, surgical resection of the cancer was performed. The patient's lymph nodes wore found to be involved and, because of the high risk of disease recurrence, she was re-challenged with trastuzumab, LFTs showed enzyme levels rising again and trastuzumab was discontinued after 2 cycles, with subsequent normalization of the levels. She was then treated with weekly paclitaxel and her LFT values continued to be in the near-normal range.

Discussion:

There were no comorbidities in this patient and, on initiation of trastuzumab, her liver enzyme levels were normal. The levels became elevated after initiation of trastuzumab, normalized after its discontinuation, and increased upon rechallenge. According to a validated drug-induced hepatotoxicity scale, trastuzumab was the probable cause of hepatotoxicity in this patient.

Conclusions:

Livor enzyme levels must be closely monitored in patients receiving trastuzumab. To our knowledge, this is the first report of trastuzumab-induced hepatotoxicity requiring discontinuation of the drug.
Compatibility and Aerosol Characteristic of Formoterol Fumarate Mixed with Other Nebulizing Solutions
Authors: Akapo Samuel , Gupta June , Martinez Eloisa , McCrea Chithra , Ye Liwen , Roach Mark
Published: September 2008

Background:

Patients with chronic obstructive pulmonary disease (COPO) are often given admixtures of nebulizable drugs to minimize the time of administration in treatment regimens.

Objective:

To evaluate the physicochemical compatibility and aerodynamic characteristics of formoterol fumarate 20 μg/2 mL when mixed or sequentially nebulized with budesonide inhalation suspension 0.5 mg/2 mL, ipratropium bromide 0.5 mg/2.5 mL, cromolyn sodium 20 mg/2 mL, or acetylcysteine 10% (100 mg/mL).

Methods:

The admixtures were prepared in triplicate and analyzed for physicochemical compatibility at 0, 15, 30, and 60 minutes after mixing at room temperature. Physical compatibility was determined by visual examination and measurements of pH, osmolality, and turbidity. Chemical stability was evaluated using compendial or in-house-validated high-performance liquid chromatography (HPLC) assay methods. The aerodynamic characteristics of the admixtures or sequentially nebulized drugs were determined from aerosols generated from a Pari LC Plus nebulizer, using an 8-stage cascade impactor followed by HPLC analysis of the deposited drug.

Results:

The admixtures remained clear, colorless solutions with no precipitation. except for cloudiness observed in the formoterol/budesonide combination due to budesonide suspension. The pH, osmolality, and turbidity for all admixtures were within the initial values (=3%), and there were no significant changes (=2%) in potency of the active components throughout the 1-hour study period. Due to increased drug volume or reconcentration in the nebulizer cup, the respirable fraction/delivered dose increased significantly (p < 0.05) for the mixed or sequentially nebulized drug Howover, the fine particle fraction (FPF), mass median aerodynamic diameter, and geometric standard deviation generally remained unchanged for all admixtures, with the exception of FPF for the formoterol/budesonide combination.

Conclusions:

Our results indicate that admixtures of formoterol with budesonide, ipratropium, cromolyn, or acetylcysteine are physically and chemically compatible. However, admixing or sequential nebulization significantly increased the amount of drug delivered compared with single drug nebulization. The clinical implications of the in vitro data in patients with COPD have not been determined.
Presynaptic Type III Neuregulin 1 Is Required for Sustained Enhancement of Hippocampal Transmission by Nicotine and for Axonal Targeting of α7 Nicotinic Acetylcholine Receptors
Authors: Zhong Chongbo , Du Chuang , Hancock Melissa , Mertz Marjolijn , Talmage David A. , Role Lorna W.
Published: September 2008

Both the neuregulin 1 (Nrg1) and α7 nicotinic acetylcholine receptor (α7*nAChRs) genes have been linked to schizophrenia and associated sensory–motor gating deficits. The prominence of nicotine addiction in schizophrenic patients is reflected in the normalization of gating deficits by nicotine self-administration. To assess the role of presynaptic type III Nrg1 at hippocampal–accumbens synapses, an important relay in sensory–motor gating, we developed a specialized preparation of chimeric circuitsin vitro. Synaptic relays fromNrg1tm1Lwrheterozygote ventral hippocampal slices to wild-type (WT) nucleus accumbens neurons (1) lack a sustained, α7*nAChRs-mediated phase of synaptic potentiation seen in comparable WT/WT circuits and (2) are deficient in targeting α7*nAChRs to presynaptic sites. Thus, selective alteration of the level of presynaptic type III Nrg1 dramatically affects the modulation of glutamatergic transmission at ventral hippocampal to nucleus accumbens synapses.
Mechanism and Time Course of Cocaine-Induced Long-Term Potentiation in the Ventral Tegmental Area
Authors: Argilli Emanuela , Sibley David R. , Malenka Robert C. , England Pamela M. , Bonci Antonello
Published: September 2008

Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activity-dependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D5receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaine-induced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spike-timing-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocainein vivoorin vitro.