bluuebunny/crossref_metadata_2025 huggingface dataset:
Time‐Dependent Interaction Between Lopinavir/Ritonavir and Fexofenadine
Authors: Rolf P. G. , Heeswijk van , Bourbeau Marc , Campbell Pearl , Seguin Isabelle , Chauhan Bobby M. , Foster Brian C. , Cameron D. William
Published: June 2006

This study investigated the effect of single‐dose and steady‐state lopinavir/ritonavir on the exposure to fexofenadine, as a measure of P‐glycoprotein activity. Sixteen volunteers (8 women) received single‐dose oral fexofenadine 120 mg alone, in combination with single‐dose ritonavir 100 mg or lopinavir/ritonavir 400/100 mg (randomized 1:1, stratified by sex), and in combination with steady‐state lopinavir/ritonavir 400/100 mg twice daily. Single‐dose ritonavir and lopinavir/ritonavir increased the area under the fexofenadine plasma concentration‐time curve from 0 to infinity (AUC∞) by 2.2‐ and 4.0‐fold, respectively (P< .02). Steady‐state lopinavir/ritonavir increased the fexofenadine AUC∞by 2.9‐fold. No changes were observed in the fexofenadine elimination half‐life (P> .12). The fexofenadine AUC∞was increased by lopinavir/ritonavir, likely due to increased bioavailability secondary to P‐glycoprotein inhibition. After repeated administration of lopinavir/ritonavir, the interaction was attenuated compared to the single‐dose effect, although a net inhibitory effect was maintained. Time‐dependent inhibition of P‐glycoprotein by lopinavir/ritonavir should be considered when P‐glycoprotein substrates are coadministered.
Lack of Effect of Aprepitant on Hydrodolasetron Pharmacokinetics in CYP2D6 Extensive and Poor Metabolizers
Authors: Li Susie Xiujiang , Pequignot Edward , Panebianco Deborah , Lupinacci Paul , Majumdar Anup , Rosen Laura , Ahmed Tuli , Royalty Jane E. , Rushmore Thomas H. , Murphy M. Gail , Petty Kevin J.
Published: June 2006

To prevent chemotherapy‐induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5‐hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open‐label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2–3). For hydrodolasetron area under the concentration‐versus‐time curve (AUC0‐∞) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (≤2.0) for clinical significance (AUC0‐∞, 1.09 [90% CI, 1.01–1.18], Cmax, 1.08 [90% CI, 0.94–1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.
Study of the Pharmacokinetic Interaction Between Simvastatin and Prescription Omega‐3‐Acid Ethyl Esters
Authors: McKenney J. M. , Swearingen D. , Spirito M. Di , Doyle R. , Pantaleon C. , Kling D. , Shalwitz R. A.
Published: June 2006

The coadministration of prescription omega‐3‐acid ethyl esters (P‐OM3) with a statin may present a treatment option for patients with mixed hyperlipidemia. This open‐label, randomized, 2‐way crossover, drug‐drug interaction study evaluated the impact of P‐OM3 capsules on plasma simvastatin pharmacokinetics in 24 healthy volunteers. Under fasted conditions, 80 mg simvastatin was administered with or without 4 g P‐OM3 for two 14‐day periods. After 14 days of dosing to achieve steady state, no significant differences were found in either the extent (AUCτ) or rate (Cmax) of exposure to simvastatin or its major β‐hydroxy metabolite after coadministration of P‐OM3 with simvastatin compared with administration of simvastatin alone. At steady state, the coadministration of P‐OM3 capsules did not appear to affect the pharmacokinetics of simvastatin tablets. The combination of P‐OM3 capsules and simvastatin appeared to be well tolerated.
An Administrator's Challenge: Encouraging Teachers to Be Leaders
Authors: Birky Virginia Davidhizar , Shelton Marc , Headley Scot
Published: June 2006

This article examines how high school administrators influence teacher leadership in both positive and negative ways, particularly in an educational reform environment. It specifically looks at how they encourage, discourage, and motivate involvement in teacher leadership activities. Data from two studies were collected from teacher leaders through individual interviews and multiple surveys. The findings provide additional evidence that when teacher leaders function within a collaborative leadership model, teachers find more meaning and are motivated to continue in their leadership roles.
Catastrophic Cervical Spine Injuries in High School and College Football Players
Authors: Boden Barry P. , Tacchetti Robin L. , Cantu Robert C. , Knowles Sarah B. , Mueller Frederick O.
Published: July 2006

Background

Catastrophic cervical spine injuries in football are rare but tragic events.

Purpose

To update the incidence of catastrophic cervical injuries in scholastic football players and identify new injury patterns.

Study Design

Descriptive epidemiology study.

Methods

The authors retrospectively reviewed 196 incidents of catastrophic high school and collegiate football injuries reported to the National Center for Catastrophic Sports Injury Research during 13 academic years (September 1989 through June 2002).

Results

There were 15.08 direct catastrophic cervical spine injuries in scholastic football participants per year, an incidence of 1.10 and 4.72 injuries per 100 000 high school and 100 000 college participants, respectively. Seventy-six athletes had quadriplegia (5.85 per year), 0.50 per 100 000 high school players and 0.82 per 100 000 college players. Spear tackling by players on defense continued to be the predominant mechanism of injury causing quadriplegia. Five athletes had a Brown-Séquard–like syndrome; only 1 made a full recovery. One athlete with Brown-Séquard–like syndrome and permanent neurologic symptoms reported a cervical cord neurapraxia event before the study period. Forty-three athletes (3.31 per year) had diagnosed cervical cord neurapraxia. In addition to hyperflexion and hyperextension injuries, axial forces were found to cause cervical cord neurapraxia. Sixteen of the 43 athletes returned to football after a cervical cord neurapraxia episode, and none of the 16 suffered a permanent quadriplegic event. Nine athletes sustained an isolated injury at the C1 or C2 level, and 7 sustained a combined injury at the C1, or C2 level and at a subaxial level.

Conclusion

The total number of quadriplegic events for high school and college football players is approximately 6 per year, with a higher incidence at the college level. Cervical cord neurapraxia can be caused by hyperflexion, hyperextension, and axial compression forces. Upper level cervical injuries involving the atlas and axis can occur in football players and may be associated with noncontiguous subaxial injuries.
Translation and Validation of the Dutch Version of the International Knee Documentation Committee Subjective Knee Form
Authors: Haverkamp Daniël , Sierevelt Inger N. , Breugem Stefan J. M. , Lohuis Kim , Blankevoort Leendert , van Dijk C. Niek
Published: July 2006

Background

For knee-related surgery, there is a great demand for internationally useable subjective scoring systems. Before such measurements can be used, they should be translated and validated for the population they are used on. For the Dutch population, only the Western Ontario and McMaster Universities Osteoarthritis Index and Oxford 12 Questionnaire have been validated. However, these scores can only be used regarding osteoarthritis of the knee. In 2001, the International Knee Documentation Committee presented the Subjective Knee Form, which is a knee-specific rather than a disease-specific questionnaire.

Study Design

Cohort study (diagnosis/symptom prevalence); Level of evidence, 2.

Methods

The authors describe the translation procedure and validation of the Dutch Subjective Knee Form. After a forward backward translation protocol, the reliability, validity, and content validity were tested. The responses of 145 consecutive knee patients on 2 questionnaires containing the Short Form–36, Western Ontario and McMaster Universities Osteoarthritis Index, Oxford 12 Questionnaire score, a visual analog scale, and the Dutch International Knee Documentation Committee Subjective Knee Form were used. Reliability was tested by measuring the test-retest reliability and internal consistency. Validity was tested by correlating the questionnaire to the other outcome measurements, and content validity was tested by measuring the floor and ceiling effects.

Results

The reliability proved excellent with an intraclass coefficient of 0.96 for test-retest. Internal consistency was strong (Cronbach [.alpha],. 92). The construct, convergent, and divergent validities were good. The content validity was good; no floor or ceiling effect occurred.

Conclusion

The validation procedure shows that the Dutch International Knee Documentation Committee Subjective Knee Form is an excellent evaluation instrument for Dutch patients with knee-related injuries.
The Role of the Medial Collateral Ligament and Posteromedial Capsule in Controlling Knee Laxity
Authors: Robinson James R. , Bull Anthony M. J. , deW. Thomas Rhidian R. , Amis Andrew A.
Published: July 2006

Background

The medial aspect of the knee has a complex capsular structure; the biomechanical roles of specific structures are not well understood.

Hypothesis

The 3 strong stabilizing structures, the superficial and deep medial collateral ligaments and the posteromedial capsule, make distinct contributions to controlling tibiofemoral laxity.

Study Design

Controlled laboratory study.

Methods

Changes in knee laxity under anterior-posterior drawer, valgus, and internal-external rotation loads were found by sequential cutting in 18 cadaveric knees. Three cutting sequences allowed the roles of the 3 structures to be seen in isolation and in combination. Some force contributions were also calculated.

Results

The posteromedial capsule controlled valgus, internal rotation, and posterior drawer in extension, resisting 42% of a 150-N drawer force when the tibia was in internal rotation. The superficial collateral ligament controlled valgus at all angles and was dominant from 30° to 90° of flexion, plus internal rotation in flexion. The deep collateral ligament controlled tibial anterior drawer of the flexed and externally rotated knee and was a secondary restraint to valgus.

Conclusion

Distinct roles in controlling tibiofemoral laxity have been found for these structures that vary according to knee flexion and tibial rotation.

Clinical Relevance

The restraining functions demonstrated provide new information about knee stabilization, which may allow better evaluation of structural damage at the medial aspect of the knee.
Race, Gender, and the Wage Gap
Authors: Renzulli Linda A. , Grant Linda , Kathuria Sheetija
Published: July 2006

Using the Integrated Postsecondary Education Data System, the authors compare the gender pay gap at predominantly white institutions (PWIs) with the gap at historically Black colleges and universities (HBCUs). Also, within the HBCU milieu, they examine how class of the institution has an impact on pay gaps. First, they find that HBCUs do seem to have a smaller gap but that pay for all faculty at HBCUs is lower than in PWIs. Second, the gap is only significantly smaller in the rank of associates. Third, the gap is smaller at the associate rank because men make less money in HBCUs than they do in PWIs. Fourth, elite HBCUs are more similar to PWIs than to HBCUs in terms of their gender pay gap. Race, class, and gender effects must be taken into account to understand patterns of wage equity across these institutions. The greater gender equity at HBCUs is apparent because of the absence of the “men's bonus, ” which is prevalent in PWIs and elite HBCUs.
Gender, Race, and Urban Policing
Authors: Brunson Rod K. , Miller Jody
Published: July 2006

Proactive policing strategies produce a range of harms to African Americans in poor urban communities. We know little, however, about how aggressive policing is experienced across gender by adolescents in these neighborhoods. The authors argue that important insights can be gained by examining the perspectives of African American youths and draw from in-depth interviews with youths in St. Louis, Missouri, to investigate how gender shapes interactions with the police. The comparative analysis reveals important gendered facets of African American adolescents' experiences with and expectations of law enforcement. Young men described being treated routinely as suspects regardless of their involvement in delinquency and also reported police violence. Young women typically described being stopped for curfew violations but also expressed concerns about police sexual misconduct. This study highlights the differential harms of urban policing for African American young women and men and highlights the need for systematic attention to the intersections of race and gender in research on criminal justice practices.
Ibuprofen-Associated Aseptic Meningitis
Authors: Meier Joanna E. , Smith Katherine P.
Published: June 2006

Aseptic meningitis is a rare condition associated with ibuprofen use. It is a diagnosis of exclusion and should be considered only after all infectious and most well-known noninfectious causes have been ruled out. The mechanism of ibuprofen-induced aseptic meningitis is not fully understood; however, most believe it is caused by a hypersensitivity-related reaction. Common symptoms of aseptic meningitis include headache, fever, nuchal rigidity, and confusion. Cerebral spinal fluid analysis generally reveals pleocytosis (the predominant white blood cell varies), with high protein concentrations and normal to low glucose concentrations. Autoimmune diseases and connective tissue diseases may predispose an individual to this condition. It is treated solely by withdrawal of the medication, although supportive treatment is often necessary. It is important that health care practitioners recognize this condition so that they are able to treat and prevent recurrence through patient education.
Reporting Participants in Research Studies to Child Protective Services: Limited Risk to Attrition
Authors: Knight Elizabeth Dawes , Smith Jamie B. , Dubowitz Howard , Litrownik Alan J. , Kotch Jonathan B. , English Diana , Everson Mark D. , Runyan Desmond K.
Published: July 2006

This study examines the impact of Child Protective Services (CPS) reports made by research study staff on participant retention and discusses human subjects protocols that may minimize either the need to make such reports or the negative impact of reporting on participants and on participant retention. Among 1, 354 primary caregiver-child pairs in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) studies, a total of 15 were reported to CPS by study staff. Within this group, rates of study-generated reports and study participation subsequent to having been reported by researchers were examined. There was an overall retention rate of 93% across a minimum of three interview waves in this sample. Reporting research participants to CPS may have little impact on attrition.
Creating and Field-Testing Child Maltreatment Definitions: Improving the Reliability of Substantiation Determinations
Authors: Slep Amy M. Smith , Heyman Richard E.
Published: July 2006

The decision to substantiate a case of maltreatment is pivotal to myriad stakeholders; however, the reliability (and therefore, accuracy) of substantiation determinations is suspect. The authors tested if (a) they could develop more reliable substantiation definitions and processes and (b) case workers would be comfortable with and accepting of a new approach. Determinations from five field sites were compared with those of master reviewers (made while listening to the field sites' case presentations). Agreement, sensitivity, specificity, positive predictive values, and negative predictive values were high overall (.87, .96, .97, .89, and .97, respectively) and for each form of maltreatment. Agreement was substantially improved. The definitions and the determination process were well liked by case workers and other stakeholders. Clearly, implementing standardized definitions in a typical child protective environment would pose myriad political challenges. However, our results suggest achieving reliable substantiation determinations may be a feasible goal.
Childhood Sexual Abuse Among Black Women and White Women From Two-Parent Families
Authors: Amodeo Maryann , Griffin Margaret L. , Fassler Irene R. , Clay Cassandra M. , Ellis Michael A.
Published: July 2006

Differences in childhood sexual abuse (CSA) between Black women and White women are explored in a community sample of 290 women raised in two-parent families.A selfadministered questionnaire and a face-to-face interview assessed CSA characteristics, aftermath, and prevalence as well as family structure and other childhood variables. Siblings served as collateral informants for the occurrence of CSA. Overall, comparisons of the nature, severity, and aftermath of CSA showed similarities by race; some differences, for example, in age of onset, are potentially relevant for the planning of prevention programs. Logistic regression models examined effects of childhood variables on CSA prevalence. Initial analyses showed a higher CSA prevalence among Black women (34.1% [45] of Black women vs. 22.8% [36] of White women) that was attenuated when family structure (e.g., living with two biological parents throughout childhood or not) and social class were considered. Of interest, differences in family structure remained important even among these two-parent families. Understanding the dynamics of abuse by race and family structure will facilitate the design of more targeted CSA prevention programs.
Understanding the Ecology of Child Maltreatment: A Review of the Literature and Directions for Future Research
Authors: Freisthler Bridget , Merritt Darcey H. , LaScala Elizabeth A.
Published: July 2006

Studies examining neighborhood characteristics in relation to social problems, including child maltreatment, have proliferated in the past 25 years. This article reviews the current state of knowledge of ecological studies of child maltreatment. Taken as a whole, these 18 studies document a stable ecological relationship among neighborhood impoverishment, housing stress, and rates of child maltreatment, as well as some evidence that unemployment, child care burden, and alcohol availability may contribute to child abuse and neglect. The authors include a discussion of methodological difficulties in conducting research at the neighborhood level and present a set of recommendations for future research that emphasizes movement from a simple examination of neighborhood-level characteristics toward a theoretically driven explication of processes and mechanisms supported by appropriate multilevel modeling techniques. The final goal of such efforts would be to enable practitioners to develop evidence-based neighborhood interventions that would prevent and reduce child abuse and neglect.
Child Protective Services Referrals in Cases of Sudden Infant Death: A 10-Year, Population-Based Analysis in San Diego County, California
Authors: Krous Henry F. , Haas Elisabeth A. , Manning Julie M. , Deeds Anita , Silva Patricia D. , Chadwick Amy E. , Stanley Christina
Published: July 2006

The potential diagnostic significance of prior family referral to Child Protective Services (CPS) in cases of sudden infant death is unknown. Therefore, the authors retrospectively searched for CPS data for the 5-year referral history on all 533 families whose infants died suddenly from Sudden Infant Death Syndrome (SIDS), other natural diseases, accidents, or inflicted injuries and underwent postmortem examination by the medical examiner during a 10-year period. No family had more than one infant death. At least 27% of the families in each group had at least one CPS referral. The data suggest that a family's referral to CPS prior to their sudden death of their infant does not increase the likelihood that it was caused by inflicted injuries, and prior referral should not preclude a diagnosis of SIDS. The authors recommend future prospective studies that include refined exposure histories and that are large enough to have sufficient statistical power to compare family CPS referrals and outcomes in groups of infants who died suddenly with a matched group of living infants.
What Is the Functional Significance of Chronic Stress-Induced CA3 Dendritic Retraction Within the Hippocampus?
Authors: Conrad Cheryl D.
Published: June 2006

Chronic stress produces consistent and reversible changes within the dendritic arbors of CA3 hippocampal neurons, characterized by decreased dendritic length and reduced branch number. This chronic stress-induced dendritic retraction has traditionally corresponded to hippocampus-dependent spatial memory deficits. However, anomalous findings have raised doubts as to whether a CA3 dendritic retraction is sufficient to compromise hippocampal function. The purpose of this review is to outline the mechanism underlying chronic stress-induced CA3 dendritic retraction and to explain why CA3 dendritic retraction has been thought to mediate spatial memory. The anomalous findings provide support for a modified hypothesis, in which chronic stress is proposed to induce CA3 dendritic retraction, which then disrupts hypothalamic-pituitary-adrenal axis activity, leading to dysregulated glucocorticoid release. The combination of hippocampal CA3 dendritic retraction and elevated glucocorticoid release contributes to impaired spatial memory. These findings are presented in the context of clinical conditions associated with elevated glucocorticoids.
Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors
Authors: Marodon Gilles , Fisson Sylvain , Levacher Béatrice , Fabre Monique , Salomon Benoît L. , Klatzmann David
Published: June 2006

Immune tolerance to self-antigens is established during lymphocyte differentiation in the thymus, but a simple means to induce antigen-specific tolerance in the thymus is still elusive. We show here that intrathymic injection of a lentiviral vector expressing the hemagglutinin antigen (HA) in TCR-HA transgenic mice resulted in negative selection of HA-specific effector T cells and sustained positive selection of HA-specific regulatory T cells (Tregs). This positive selection increased the number of HA-specific Tregs 10-fold and was comparable with the one observed in TCR-HA transgenic mice crossed with transgenic mice expressing HA under the control of the insulin promoter (Ins-HA). HA expression by radioresistant thymic epithelial cells was sufficient to drive Treg generation. Intrathymic injection of the lentiviral vector also resulted in an enrichment of HA-specific Tregs in peripheral lymphoid organs, which prevented diabetes induced in Ins-HA mice by transfer of HA-specific effector T cells. In this model, HA-specific Tregs inhibited effector T-cell division in pancreatic lymph nodes. Finally, we show that intrathymic injection of a lentiviral vector expressing preproinsulin-2 could reduce the occurrence of spontaneous diabetes in nonobese diabetic mice. Intrathymic gene transfer using lentiviral vectors thus offers new means to manipulate antigen-specific tolerance.
Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery
Authors: Dou Huanyu , Destache Christopher J. , Morehead Justin R. , Mosley R. Lee , Boska Michael D. , Kingsley Jeffrey , Gorantla Santhi , Poluektova Larisa , Nelson Jay A. , Chaubal Mahesh , Werling Jane , Kipp James , Rabinow Barrett E. , Gendelman Howard E.
Published: June 2006

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 μM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4+ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.
BCL11B participates in the activation of IL2 gene expression in CD4+ T lymphocytes
Authors: Cismasiu Valeriu B. , Ghanta Sailaja , Duque Javier , Albu Diana I. , Chen Hong-Mei , Kasturi Rohini , Avram Dorina
Published: June 2006

BCL11A and BCL11B are transcriptional regulators important for lymphopoiesis and previously associated with hematopoietic malignancies. Ablation of the mouse Bcl11b locus results in failure to generate double-positive thymocytes, implicating a critical role of Bcl11b in T-cell development. However, BCL11B is also expressed in CD4+ T lymphocytes, both in resting and activated states. Here we show both in transformed and primary CD4+ T cells that BCL11B participates in the control of the interleukin-2 (IL2) gene expression following activation through T-cell receptor (TCR). BCL11B augments expression from the IL2 promoter through direct binding to the US1 site. In addition, BCL11B associates with the p300 coactivator in CD4+ T cells activated through TCR, which may account for its transcriptional activation function. These results provide the first evidence that BCL11B, originally described as a transcriptional repressor, activates transcription of a target gene in the context of T-cell activation.
Dyspnoea and hypoxaemia after lung surgery: the role of interatrial right-to-left shunt
Authors: Marini C. , Miniati M. , Ambrosino N. , Formichi B. , Tonelli L. , Di Ricco G. , Michelassi C. , Giusti S. , Spadoni I.
Published: July 2006

After lung surgery, some patients complain of unexplained increased dyspnoea associated with hypoxaemia. This clinical presentation may be due to an interatrial right-to-left shunt despite normal right heart pressure. Some of these patients show postural dependency of hypoxaemia, whereas others do not.

In this article, the pathogenesis and mechanisms involved in this post-surgical complication are discussed, and the techniques used for confirmation and localisation of shunt are reported.

An invasive technique, such as right heart catheterisation with angiography, was often used in the past as the diagnostic procedure for the visualisation of interatrial shunt. As to noninvasive techniques, a perfusion lung scan may be used as the first approach as it may detect the effect of the right-to-left shunt by visualising an extrapulmonary distribution of the radioactive tracer. The 100% oxygen breathing test could also be used to quantify the amount of right-to-left shunt. Particular emphasis is given to newer imaging modalities, such as transoesophageal echocardiography, which is minimally invasive but highly sensitive in clearly visualising the atrial septum anatomy.

Finally, the approch to closure of the foramen ovale or atrial septal defect is discussed. Open thoracotomy was the traditional approach in the past. Percutaneous closure has now become the most used and effective technique for the repair of the interatrial anatomical malformation.
Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers
Authors: Vergnon J-M. , Huber R. M. , Moghissi K.
Published: July 2006

Cryotherapy, brachytherapy and photodynamic therapy (PDT) are three different methods proposed in the endoluminal treatment of lung cancers. The current article presents an overview of the specific indications and limits of each technique.

These three methods were first proposed with palliative intent in inoperable patients with centrally located lung cancers. Now, the best indication is a curative intent in early stage lung cancers.

Of the three, cryotherapy is the cheapest method. It induces cell necrosis in a 3-mm radius around the probe, and is suitable for treatment of superficial tumours. However, clinical trials are limited. In contrast, many clinical studies have confirmed the efficacy of PDT in treatment of superficial lung cancers. Brachytherapy can cure more aggressive tumours with deeper invasion into the bronchial wall. Unfortunately, no comparative studies have been published. Each of these methods induces a delayed tumour necrosis, and thus neither is indicated in the treatment of obstructive tumours with acute dyspnoea. In many situations, these methods should be complementary, particularly cryotherapy and brachytherapy or PDT and brachytherapy.

The combination of these endoscopic methods with chemotherapy should be widely tested to promote the adjuvant role of the endoscopic methods in the treatment of lung cancers.
Oxidative stress and redox regulation of lung inflammation in COPD
Authors: Rahman I. , Adcock I. M.
Published: July 2006

Reactive oxygen species, either directly orviathe formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (c-Jun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-κB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-κB-mediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of κB-α kinase or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-κB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression.

Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity.

The antioxidant/anti-inflammatory effects of thiol molecules (glutathione,N-acetyl-L-cysteine andN-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/quercetin and reserveratol), specific spin traps, such as α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-κB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells.

Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.
Positional hyperventilation-induced hypoxaemia in pectus excavatum
Authors: Wallaert B. , Cavestri B. , Fournier C. , Nevière R. , Aguilaniu B.
Published: July 2006

The presented case is of a young male (aged 19 yrs) with a pectus excavatum who showed significant exercise intolerance, despite normal pulmonary function at rest, including carbon monoxide diffusing capacity. Clinical exercise testing led to a strong suspicion of a right-to-left shunt due to an abnormally wide alveolo–arterial oxygen gradient (26.4 kPa) at peak oxygen uptake, with severe arterial hypoxaemia (arterial oxygen tension 12.54 kPa).

A right-to-left shunt was confirmed by transoesophageal echocardiography demonstrating a permeable foramen ovale, despite normal right heart pressures. The right-to-left venous flow was mainly dependent on the upright body position and the deep inspiration. Indeed,i.v.dobutamine infusion to selectively affect cardiac output and hyperventilation induced by tidal volume expansion at constant breathing rate in the supine position did not result in arterial oxygen desaturation or shunting. Closure of the foramen ovale through atrial umbrella placement dramatically improved clinical and physiological abnormalities.

This observation demonstrates that a hyperventilatory manoeuvre in the upright position is able to detect a permeable foramen ovale favouring flow in the inferior vena cava in the direction of the abnormal pre-existing atrial channel in a patient with a pectus excavatum.
Cough: what's in a name?
Authors: Widdicombe J. , Fontana G.
Published: July 2006

The cough reflex (CR) and the expiration reflex (ER) are two defensive reflexes from the respiratory tract, the latter mainly from the larynx. Both are elicited by mechanical and chemical irritation of the airway mucosa, and are a characteristic of airway diseases, but they have different functions. The CR first draws air into the lungs, to accentuate the subsequent expulsive phase; the ER consists of a strong expiration, to prevent aspiration of material into the lungs. They have different sensory pathways, central nervous circuits, and physiological and pharmacological modulations. In practice, coughing often consists of a combination of the two reflexes, a cough bout, epoch or attack. Articles on cough usually do not distinguish between the two reflexes, or whether the coughs are single events or epochs; they usually only measure frequency of expiratory efforts, and neglect other aspects. Current methods for measuring and assessing cough are described, with indications of when the use of these methods may be important.
Pharmacological strategies for self-management of asthma exacerbations: Table 1—
Authors: Reddel H. K. , Barnes D. J.
Published: July 2006

Written action plans are effective within asthma self-management, but there are few guidelines about the specific medication adjustments which can be recommended for self-treatment of exacerbations.

This review examines pharmacological strategies for self-management of asthma exacerbations in adults, including those for inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) users.

Oral corticosteroids are well-established in clinical practice and clinical trials for the treatment of severe exacerbations, including during combination therapy. Evidence supports 7–10 days treatment, with no need to taper except to reduce side-effects. Doubling the dose of ICS is not effective. Several studies have shown benefit from high-dose ICS (2,400–4,000 µg beclomethasone equivalent) for 1–2 weeks. This may be achieved by adding a high-dose ICS inhaler to maintenance ICS or ICS/LABA therapy. There is inconclusive evidence about acutely increasing the dose of maintenance budesonide/formoterol for exacerbations, and no studies of this approach with fluticasone/salmeterol. For patients taking maintenance budesonide/formoterol, use of the same medication as-needed reduces exacerbations. Short-acting β2-agonists are still effective in producing bronchodilation during combination therapy; however, a higher dose may be required.

There is a need for further studies to clarify remaining issues about self-management of asthma exacerbations, particularly with regard to side-effects of treatment and patient acceptability.
Dendritic cell derived-exosomes: biology and clinical implementations
Authors: Chaput Nathalie , Flament Caroline , Viaud Sophie , Taieb Julien , Roux Stephan , Spatz Alain , André Fabrice , LePecq Jean-Bernard , Boussac Muriel , Garin Jérôme , Amigorena Sebastian , Théry Clotilde , Zitvogel Laurence
Published: June 2006

Exosomes are nanometer-sized membrane vesicles invaginating from multivesicular bodies and secreted from different cell types. They represent an “in vitro” discovery, but vesicles with the hallmarks of exosomes are present in vivo in germinal centers and biological fluids. Their protein and lipid composition is unique and could account for their expanding functions such as eradication of obsolete proteins, antigen presentation, or “Trojan horses” for viruses or prions. The potential of dendritic cell-derived exosomes (Dex) as cell-free cancer vaccines is addressed in this review. Lessons learned from the pioneering clinical trials allowed reassessment of the priming capacities of Dex in preclinical models, optimizing clinical protocols, and delineating novel, biological features of Dex in cancer patients.
Differential infection of mononuclear phagocytes by Francisella tularensis: role of the macrophage mannose receptor
Authors: Schulert Grant S , Allen Lee-Ann H
Published: July 2006

Francisella tularensis (Ft) is a Gram-negative bacterium and the causative agent of tularemia. It is well established that this organism replicates inside macrophages, but we are only beginning to understand this interface at the molecular level. Herein, we compared directly the ability of Ft subspecies holarctica live-vaccine strain to infect freshly isolated human peripheral blood monocytes, monocyte-derived macrophages (MDM), and cells of the murine macrophage cell line J774A.1 (J774). We now show that unopsonized bacteria infected human MDM fivefold more efficiently than monocytes or J774 cells in standard media. Moreover, enhanced infection of MDM was mediated, in part, by te macrophage mannose receptor (MR). Forming Ft phagosomes accumulated MR, and infection was inhibited by MR-blocking antibody or soluble mannan but not by the dectin-1 ligand laminarin. Up-regulation of MR in MDM (by exposure to interleukin-4) increased Ft phagocytosis, as did expression of MR in J774 cells. Conversely, opsonized Ft were ingested readily by monocytes and MDM. Medium supplementation with 2.5% fresh autologous serum was sufficient to confer opsonophagocytosis and CD11b accumulated in the membrane at sites of Ft engulfment. Infection of monocytes by opsonized Ft was nearly ablated by complement receptor 3 (CR3) blockade. Conversely, MDM used MR and CD11b/CD18 to ingest opsonized organisms. Altogether, our data demonstrate differential infection of mononuclear phagocytes by Ft and define distinct roles for MR and CR3 in phagocytosis.
Carbamazepine-responsive paroxysmal nausea and vomiting in a patient with meningeal carcinomatosis
Authors: Strohscheer Imke , Borasio Gian Domenico
Published: June 2006

In neurology, paroxysmal syndromes are well-known, eg, as manifestations of multiple sclerosis. We report a patient with meningeal carcinomatosis, who presented with therapyrefractory nausea and vomiting. The clinical suspicion of a paroxysmal syndrome prompted a trial of carbamazepine, which resulted in complete cessation of the symptoms. In cancer patients with central nervous system (CNS) involvement and therapy-refractory symptoms with sudden onset, carbamazepine treatment should be considered.
Doctors' understanding of palliative care
Authors: Hanratty Barbara , Hibbert Derek , Mair Frances , May Carl , Ward Chris , Corcoran Ged , Capewell Simon , Litva Andrea
Published: June 2006

Palliative care has been challenged to share its message with a wider audience, and for many years it has been articulating an approach that is suitable for all patients. However, it is not clear how widely this message has been accepted. As part of a study into end-of-life care for heart failure, we conducted seven focus groups with doctors in general practice, palliative medicine, cardiology, geriatrics and general medicine. In these, we explored doctors' understanding of palliative care. Participants displayed a reasonable grasp of the wider concept of palliative care, but the specialists' role was ill-defined, reflected in scepticism about their place outside of cancer. Perceptions of palliative care fell into three broad areas: it was more than a service, about managing dying, and the concern of nurses, rather than doctors. Palliative care was welcomed as providing permission to fail, whilst representing a dilemma between quantity and quality of life for the interviewees. Our work suggests that specialist palliative care has been partially successful in getting their message across, and poor understanding or receptivity are not major barriers to implementing palliative care. Educational or other interventions to implement change in palliative care need to acknowledge the complex interaction of factors influencing physicians' behaviour.
Qualitative study of Chinese widows in Hong Kong: insights for psycho-social care in hospice settings
Authors: Chow Amy YM , Chan Cecilia LW , Ho Samuel MY , Tse Doris MW , Suen Margaret HP , Yuen Karen FK
Published: June 2006

In an exploratory, phenomenological study of seven Chinese widows in Hong Kong, five major themes are identified: relationship with the deceased, relationship with others, grief reactions, coping and emotional expression. This paper focuses on the first theme: the widows' relationship with the deceased husband along a timeline from the time of diagnosis to after death. The experiences in the final days with the deceased were frequently referred to when the informants talked about this theme. This paper aims to give added voice, based on the experience of Chinese widows, to the possible role of hospice and palliative care on influencing the bereavement experience. Issues of awareness and acceptance of death, the supportive environment and support for family carers, the moment of death, creation of legacies, and sensitivity towards cultural embedded practices, are discussed. It is hoped that the experiences of these bereaved widows will stimulate new research to elucidate and verify the findings reported in this paper.
Improving standards in clinical record-keeping
Authors: Pullen Ian , Loudon John
Published: June 2006

Clinical records are the most basic of clinical tools. Aggregated, they form a permanent account of individual considerations and the reasons for decisions. Essential for effective communication and good clinical care, they are often accorded low priority, are poorly maintained and not readily available. Independent inquiries, health ombudsmen's reports and the courts have repeatedly criticised the quality of records and the resulting failings of care. Most advice from professional bodies, indemnity organisations and the General Medical Council is extremely brief and confined to individual entries in the record. Patient safety and the demands of clinical governance make change essential. This article draws together standards and concludes with some good practice points for a fit-for-purpose, structured, multidisciplinary record to support good care and protect the interests of patients and clinicians. These principles should be equally applicable to electronic records.
Personality disorders as disorganisation of attachment and affect regulation
Authors: Sarkar Jaydip , Adshead Gwen
Published: June 2006

If personality disorder is no longer to be a diagnosis of exclusion it needs a conceptual framework that fits both the symptoms of the illness and the behavioural problems that constitute its current diagnostic criteria. In this article, we suggest that personality disorder is best understood as disorganisation of the capacity for affect regulation, mediated by early attachments. We present evidence for this argument based on both developmental and neurobiological research.
Outcomes of an effectiveness trial of cognitive–behavioural intervention by mental health nurses in schizophrenia
Authors: Turkington Douglas , Kingdon David , Rathod Shanaya , Hammond Katie , Pelton Jeremy , Mehta Raj
Published: July 2006

Background

Little is known about the medium-term durability of cognitive–behavioural therapy (CBT) in a community sample of people with schizophrenia.

Aims

To investigate whether brief CBT produces clinically important outcomes in relation to recovery, symptom burden and readmission to hospital in people with schizophrenia at 1-year follow-up.

Method

Participants (336 of 422 randomised at baseline) were followed up at a mean of 388 days (s.d. =53) by raters masked to treatment allocation (CBT or usual care).

Results

At 1-year follow-up, participants who received CBT had significantly more insight (P=0.021) and significantly fewer negative symptoms (P=0.002). Brief therapy protected against depression with improving insight and against relapse; significantly reduced time spent in hospital for those who did relapse and delayed time to admission. It did not improve psychotic symptoms or occupational recovery, nor have a lasting effect on overall symptoms or depression at follow-up.

Conclusions

Mental health nurses should be trained in brief CBT for schizophrenia to supplement case management, family interventions and expert therapy for treatment resistance.
Cost-effectiveness of referral for generic care or problem-solving treatment from community mental health nurses, compared with usual general practitioner care for common mental disorders
Authors: Kendrick Tony , Simons Lucy , Mynors-Wallis Laurence , Gray Alastair , Lathlean Judith , Pickering Ruth , Harris Scott , Rivero-Arias Oliver , Gerard Karen , Thompson Chris
Published: July 2006

Background

UK general practitioners (GPs) refer patients with common mental disorders to community mental health nurses.

Aims

To determine the effectiveness and cost-effectiveness of this practice.

Method

Randomised trial with three arms: usual GP care, generic mental health nurse care, and care from nurses trained in problem-solving treatment; 98 GPs in 62 practices referred 247 adult patients with new episodes of anxiety, depression and life difficulties, to 37 nurses.

Results

There were 212 (86%) and 190 (77%) patients followed up at 8 and 26 weeks respectively. No significant differences between groups were found in effectiveness at either point. Mean differences in Clinical Interview Schedule – Revised scores at 26 weeks compared with GP care were –1.4 (95% Cl –5.5 to 2.8) for generic nurse care, and 1.1 (–2.9 to 5.1) for nurse problem-solving. Satisfaction was significantly higher in both nurse-treated groups. Mean extra costs per patient were £283 (95% Cl 154–411) for generic nurse care, and £315 (183–481) for nurse problem-solving treatment.

Conclusions

GPs should not refer unselected patients with common mental disorders to specialist nurses. Problem-solving should be reserved for patients who have not responded to initial GP care.