bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycobacterium avium-intracellulare associated with tracheobronchopathia osteochondroplastica
Authors: Baugnee PE , Delaunois LM
Published: September 2003

A previously healthy woman aged 53 years presented with cough, night sweats and weakness. Chest roentgenogram revealed a reticulonodular infiltrate of the right upper lung. Multiple sputum cultures were positive for Mycobacterium avium-intracellulare, with no immunodeficiency disease. Fibreoptic endoscopy showed multiple tracheal cartilaginous knobs from a tracheobronchopathia osteochondroplastica. The infiltrate improved after chest physiotherapy, but sputum cultures remained positive. Despite its low incidence, tracheobronchopathia osteochondroplastica can be associated with atypical mycobacterial disease.
Production of granulocyte colony-stimulating factor by malignant mesothelioma
Authors: Rikimaru T , Ichikawa Y , Ogawa Y , Higuchi E , Kinosita M , Oizumi K , Shima I
Published: September 2003

We present the case of a male patient, aged 45 yrs, with malignant mesothelioma producing granulocyte colony-stimulating factor (G-CSF). The diagnosis was established by histopathological examination of the autopsied pleural tissues. Production of G-CSF was confirmed by immunoperoxidase staining, using a specific monoclonal antibody against recombinant G-CSF (rhG-CSF).
Combined occurrence of chyloperitoneum and chylothorax after retroperitoneal surgery
Authors: Muns G , Rennard SI , Floreani AA
Published: September 2003

Chyloperitoneum is a rare complication of abdominal or retroperitoneal surgery, and the combined occurrence of chylothorax and chyloperitoneum has been reported in only a few cases. We describe a case of this complication, which became clinically apparent 20 days after a Warren shunt operation. The large chylous effusion compromised breathing and required chest tube drainage, pleurodesis, medium chain triglyceride (MCT) diet, and, later, total parenteral nutrition (TPN). The patient made a full recovery on TPN for 5 weeks.
Difference in end-tidal CO2 between asphyxia cardiac arrest and ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest in the prehospital setting
Authors: Grmec Štefek , Lah Katja , Tušek-Bunc Ksenija
Published: September 2003

Introduction

There has been increased interest in the use of capnometry in recent years. During cardiopulmonary resuscitation (CPR), the partial pressure of end-tidal carbon dioxide (PetCO2) correlates with cardiac output and, consequently, it has a prognostic value in CPR. This study was undertaken to compare the initial PetCO2 and the PetCO2 after 1 min during CPR in asphyxial cardiac arrest versus primary cardiac arrest.

Methods

The prospective observational study included two groups of patients: cardiac arrest due to asphyxia with initial rhythm asystole or pulseless electrical activity, and cardiac arrest due to acute myocardial infarction or malignant arrhythmias with initial rhythm ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT). The PetCO2 was measured for both groups immediately after intubation and then repeatedly every minute, both for patients with and without return of spontaneous circulation (ROSC).

Results

We analyzed 44 patients with asphyxial cardiac arrest and 141 patients with primary cardiac arrest. The first group showed no significant difference in the initial value of the PetCO2, even when we compared those with and without ROSC. There was a significant difference in the PetCO2 after 1 min of CPR between those patients with ROSC and those without ROSC. The mean value for all patients was significantly higher in the group with asphyxial arrest. In the group with VF/VT arrest there was a significant difference in the initial PetCO2 between patients without and with ROSC. In all patients with ROSC the initial PetCO2 was higher than 10 mmHg.

Conclusions

The initial PetCO2 is significantly higher in asphyxial arrest than in VT/VF cardiac arrest. Regarding asphyxial arrest there is also no difference in values of initial PetCO2 between patients with and without ROSC. On the contrary, there is a significant difference in values of the initial PetCO2 in the VF/VT cardiac arrest between patients with and without ROSC. This difference could prove to be useful as one of the methods in prehospital diagnostic procedures and attendance of cardiac arrest. For this reason we should always include other clinical and laboratory tests.
Jaspers was right after all – delusions are distinct from normal beliefs
Authors: Jones Hugh , Delespaul Philippe , van Os Jim
Published: September 2003

Jaspers' textbook General Psychopathology has in the past been described as the ‘most important single book on the aims and logic of psychological medicine’ (Shepherd, 1990). In recent years it seems to have rather fallen off the psychiatric syllabus. Its diminished importance is exemplified by changing opinions about delusions. Nowadays, delusions are considered by many to lie on a continuum with normal beliefs, and this model underpins modern cognitive therapy for psychosis (Kingdon & Turkington, 1994). Jaspers, in contrast, considered that delusions were distinct from normal beliefs. This required him to formulate a distinct mechanism of delusions that resembles, to large extent, the concepts of ‘modularity’ proposed by Fodor (Fodor, 1983) (who has not yet entered the psychiatric syllabus!). The continuum model suggests that delusions ought to be treatable. However, trials of cognitive-behavioural therapy for psychosis suggest significant benefit in only about half of patients treated (see Turkington & McKenna, 2003). What prevents therapeutic change along the dimensions of belief in non-responsive patients? One possibility is that Jaspers was right after all. In this month's debate the modular view of delusions is taken by Dr Hugh Jones and the case for a continuum model is argued by Professors Philippe Delespaul and Jim van Os.
Defining thought broadcast
Authors: Pawar Ajaykumar V. , Spence Sean A.
Published: September 2003

Background

The symptom of thought broadcast may have diagnostic significance but its definition varies.

Aims

To examine multiple definitions of thought broadcast in differenttexts, to synthesise their common features and to undertake local and national surveys of psychiatrists to determine which definitions they endorse.

Method

A semi-structured literature review of electronic databases, supplemented by a manual search of psychiatric textbooks, conceptual analyses and postal surveys of clinicians in NorthTrent (58 trainees and 70 consultants) and throughout the UK (49 professors of general adult psychiatry).

Results

Thought broadcast is susceptible to multiple definitions: three exemplars were identified in the literature, each endorsed by influential authors. Among those psychiatrists responding to the survey (approximately 59%), some endorsed each definition of thought broadcast.

Conclusions

Thought broadcast means different things to different people. Inconsistent terminology might impair communication in clinical and research contexts.
Functional health status, chronic medical conditions and disorders of mood
Authors: Surtees Paul G. , Wainwright Nicholas W. J. , Khaw Kay-Tee , Day Nicholas E.
Published: September 2003

Background

Understanding of the impact of depressive and anxiety disorders on functional health status in the context of chronic medical illness has been gained almost exclusively from the study of patient populations.

Aims

To compare the impact of major depressive and generalised anxiety disorder with that of chronic medical conditions on functional health in a UK resident population.

Method

The functional health of 20 921 study participants was assessed using the Medical Outcomes Study Short Form 36 questionnaire. Depressive and anxiety disorder episode histories and chronic medical conditions were assessed using independent self-completed questionnaires.

Results

The degree of physical functional impairment associated with mood disorders was of equivalent magnitude to that associated with the presence of chronic medical conditions or with being some 12 years older.

Conclusions

Depressive and anxiety disorders have a profound impact on functional health that is independent of chronic medical illness. Chronic anxiety is associated with physical health limitations in excess of those associated with chronic depression or any of the physical health conditions considered, except for stroke.
Comorbidity of substance misuse and mental illness in community mental health and substance misuse services
Authors: Weaver T. , Madden P. , Charles V. , Stimson G. , Renton A. , Tyrer P. , Barnes T. , Bench C. , Middleton H. , Wright N. , Paterson S. , Shanahan W. , Seivewright N. , Ford C. ,   Comorbidity of Substance Misuse and Mental Illness Collaborative (Cosmic) Study Team
Published: September 2003

Background

Improved management of mental illness and substance misuse comorbidity is a National Health Service priority, but little is known about its prevalence and current management.

Aims

To measure the prevalence of comorbidity among patients of community mental health teams (CMHTs) and substance misuse services, and to assess the potential for joint management.

Method

Cross-sectional prevalence survey in four urban UK centres.

Results

Of CMHT patients, 44% (95% CI 38.1-49.9) reported past-year problem drug use and/or harmful alcohol use; 75% (95% CI 68.2-80.2) of drug service and 85% of alcohol service patients (95% CI 74.2-931) had a past-year psychiatric disorder. Most comorbidity patients appear ineligible for cross-referral between services. Large proportions are not identified by services and receive no specialist intervention.

Conclusions

Comorbidity is highly prevalent in CMHT, drug and alcohol treatment populations, but may be difficult to manage by cross-referral psychiatric and substance misuse services as currently configured and resourced.
Stability of recall of military hazards over time
Authors: Wessely S. , Unwin C. , Hotopf M. , Hull L. , Ismail K. , Nicolaou V. , David A.
Published: September 2003

Background

Wartime traumatic events are related to subsequent psychological and physical health, but quantifying the association is problematic. Memory changes over time and is influenced by psychological status.

Aims

To use a large, two-stage cohort study of members of the UK armed forces to study changes in recall of both traumatic and ‘toxic’ hazards.

Method

A questionnaire-based follow-up study assessed 2370 UK military personnel, repeating earlier questions about exposure to military hazards.

Results

The κ statistics for reporting of hazards were good for some exposures, but very low for others. Gulf veterans reported more exposures over time (no significant rise in the Bosnia cohort). In the Gulf cohort only, reporting new exposures was associated with worsening health perception, and forgetting previously reported exposures with improved perception. We found no association between physical health, psychological morbidity or post-traumatic stress disorder symptoms and endorsement or non-endorsement of exposures.

Conclusions

Reporting of military hazards after a conflict is not static, and is associated with current self-rated perception of health. Self-report of exposures associated with media publicity needs to be treated with caution.
Estimating psychological treatment effects from a randomised controlled trial with both non-compliance and loss to follow-up
Authors: Dunn G. , Maracy M. , Dowrick C. , Ayuso-Mateos J. L. , Dalgard O. S. , Page H. , Lehtinen V. , Casey P. , Wilkinson C. , Vázquez-Barquero J. L. , Wilkinson G. ,   Odin Group
Published: September 2003

Background

The Outcomes of Depression International Network (ODIN) trial evaluated the effect of two psychological interventions for the treatment of depression in primary care. Only about half of the patients in the treatment arm complied with the offer of treatment, prompting the question: ‘what was the effect of treatment in those patients who actually received it?’

Aims

To illustrate the estimation of the effect of receipt of treatment in a randomised controlled trial subject to non-compliance and loss to follow-up.

Method

We estimated the complier average causal effect (CACE) of treatment.

Results

In the ODIN trial the effect of receipt of psychological intervention (an average of about 4 points on the Beck Depression Inventory) is about twice that of offering it.

Conclusions

The statistical analysis of the results of a clinical trial subject to noncompliance to allocated treatment is now reasonably straightforward through estimation of a CACE and investigators should be encouraged to present the results of analyses of this type as a routine component of a trial report.
Abusive experiences and psychiatric morbidity in women primary care attenders
Authors: Coid Jeremy , Petruckevitch Ann , Chung Wai-Shan , Richardson Jo , Moorey Stirling , Feder Gene
Published: September 2003

Background

Abusive experiences in childhood and adulthood increase risks of psychiatric morbidity in women and independently increase risks of further abuse over the lifetime. It is unclear which experiences are most damaging.

Aims

To measure lifetime prevalence of abusive experiences and psychiatric morbidity, and to analyse associations in women primary care attenders.

Method

A cross-sectional, self-report survey of 1207 women attending 13 surgeries in the London borough of Hackney, UK. Independent associations between demographic measures, abusive experiences and psychiatric outcome were established using logistic regression.

Results

Childhood sexual abuse had few associations with adult mental health measures, in contrast to physical abuse. Sexual assault in adulthood was associated with substance misuse; rape with anxiety, depression and post-traumatic stress disorder but not substance misuse. Domestic violence showed strongest associations with most mental health measures, increased for experiences in the past year.

Conclusions

Abuse in childhood and adulthood have differential effects on mental health; effects are increased by recency and severity. Women should be routinely questioned about ongoing and recent experiences as well as childhood.
Maternal depression and child behaviour problems
Authors: Verduyn Chrissie , Barrowclough Christine , Roberts Janine , Tarrier Nicholas , Harrington Richard
Published: September 2003

Background

Despite the frequently reported association between maternal depression and childhood psychopathological disorder, few studies have attempted to intervene with both conditions.

Aims

To evaluate the effect of group cognitive-behavioural therapy (CBT) on child behaviour problems and maternal depression in a group of women with young children.

Method

An assessor-masked, randomised placebo-controlled trial compared three treatments: CBT for depression and parenting skills enhancement; a mothers' support group; and no intervention. An epidemiological (general population) sample was recruited.

Results

Analysis showed no significant difference between the groups. Within-group comparison suggested that at the end of treatment and at 6-month and 12-month follow-up, child problems and maternal depression had improved significantly in the CBT group.

Conclusions

There was no statistically significant difference between groups. Both contact interventions seemed to provide some benefits to mothers with depression, with a possibly improved outcome resulting from CBT for children with behavioural problems. The results must be treated with caution.
Common mental disorders among those attending primary health clinics and traditional healers in urban Tanzania
Authors: Ngoma Mdimu Charua , Prince Martin , Mann Anthony
Published: September 2003

Background

Traditional healers provide a popular and accessible service across the African continent. Little is known of the characteristics or mental health status of those using these services.

Aims

To determine and compare the prevalence of common mental disorder among, and the characteristics of, those attending primary health care clinics (PHCs) and traditional healer centres (THCs) in Dar-es-Salaam.

Method

The Clinical Interview Schedule – Revised was used to determine the prevalence of mental disorders in 178 patients from PHCs and 176 from THCs, aged 16–65 years.

Results

The prevalence of common mental disorders among THC patients (48%) was double that of PHC patients (24%). Being older, Christian, better educated, and divorced, separated or widowed were independently associated with THC attendance. None of these factors explained the excess of mental disorder among THC attenders.

Conclusions

The high prevalence of mental disorders among THC attenders may reflect the failure of primary health care services adequately to detect and treat these common and disabling disorders. Traditional healers should be involved in planning comprehensive mental health care.
Consultant child and adolescent psychiatrists' knowledge of and attitude to the use of legislation concerning young people with psychiatric disorder
Authors: Mears Alex , White Richard , Lelliott Paul
Published: September 2003

Aims and Method

This study aimed to examine in-patient child and adolescent consultant psychiatrists' knowledge of and attitude to the Mental Health Act 1983 (MHA), the Children Act 1989 and issues around consent. A questionnaire form was sent to all in-patient consultants in England and Wales.

Results

The consultants who responded (n=51, 67%) reported a desire for more training in legal issues. Knowledge of the MHA was better than for the Children Act 1989; those who used the MHA at least once every 6 months scored more correct answers to questions about the MHA than did those who used it less frequently or never.

Clinical Implications

Although the study indicates specific gaps in knowledge, the main message is that training should consider the legal framework as a whole, with an emphasis on practical issues about its application in the in-patient setting.
Setting up clinical audit in a psychodynamic psychotherapy service: a pilot study
Authors: Adelman Simon , Ward Anne , Davison Sue
Published: September 2003

Aims and Method

Clinical governance implies a need to engage in a demonstrable form of clinical audit. We decided to pilot a pre–post-therapy questionnaire study, involving both therapists and patients, with the aim of assessing its feasibility as a routine measure of outcome in our service. Questionnaires were chosen to reflect both the symptom profile Clinical Outcomes in Routine Evaluation (CORE) and the general level of functioning Global Assessment of Functioning Scale (GAF). The patients were also questioned about their satisfaction with the therapy.

Results

Of 53 eligible patient–therapist pairs, 26 patients and 19 therapists responded pre-treatment (overall 51% response rate). The mean (s.d.) CORE score per item was 1.93 (0.78), whereas the GAF score was 55 (15.2), somewhat belying the idea that psychotherapists only treat the ‘worried well’. The post-therapy response rate was poorer, rendering statistical analysis of change difficult to perform. The trend, however, was towards an improvement in both symptoms and level of functioning over the course of therapy.

Clinical Implications

Our patient group presents with a considerable degree of impairment. Although the response rates in this pilot study were poor, the data trend suggests that patients do benefit from the treatment offered. The aims of the study were met in that implementation of a clinical audit process within our department is feasible and the data are obtainable. The main interest, however, lies in what we learned from the process. We offer a dynamic and practical assessment of the impediments encountered, with implications for how these might be confronted.
Clinical activity within a specialist mental health service for deaf people: comparison with a general psychiatric service
Authors: Appleford Jim
Published: September 2003

Aims and Method

This paper compares the case mix and clinical activity in a specialist mental health service for deaf people within a general psychiatric population, using ICD–10 diagnostic criteria.

Results

Out-patient and in-patient caseloads differ between the two services: 27% of the deaf out-patient caseload have schizophrenia, schizotypal and delusional disorders (compared with 19% of hearing patients) and 19% have neurotic, stress-related and somatoform disorders (compared with 8% of hearing patients). The general psychiatric service out-patient case-load had rates of 8% and 43% for bipolar affective disorder and unipolar depression, respectively, compared with 3% and 17% in the deaf group. Deaf patients have a mean length of stay of 59 days, compared with 30 days for the hearing group. In-patient treatment accounts for 89% of the annual treatment cost for the deaf patient population.

Clinical Implications

Expansion of community services for deaf people as recommended by a recent Health Advisory Service report could reduce admission rates for deaf patients, delivering treatment benefits and cost savings.
Out-of-area placements: implications of psychiatric services in learning disability
Authors: Mitra Ipsita , Alexander Regi
Published: September 2003

Aims and Method

With an absence of appropriate residential services, people with learning disabilities are often placed outside their local areas and there is regularly no dialogue between the relevant health authorities prior to a placement being made. This survey from Leicestershire explored this issue by focusing on the catchment area covered by one consultant psychiatrist. Practice standards were formulated and compliance with these was examined.

Results

A total of 29 patients were identified as ‘out-of-area’ placements. They had high psychiatric morbidity, exhibited significant degrees of aggression and needed a high level of professional input. The suggested practice standards were met by less than 10%.

Clinical Implications

In parts of the country where a large number of ‘specialist’ residential homes have opened, there has been an unplanned increase in the workload of local learning disability/ mental health services. This can compromise patient care and there is an urgent need for health authorities to address this issue.
Military psychiatry – a Jordanian experience
Authors: Shuriquie Nasser
Published: September 2003

Jordan is a Middle-Eastern country, located North West of Saudia Arabia. The total area is 93 300 sqkm. Jordan has borders with Iraq, Israel, Saudi Arabia, Syria and the West Bank. Regarding ethnic groups, about 98% of population are Arabs, 1% Circassian and 1% Armenian. Moslems make up around 94% of the population and the remaining 6% are Christians. Jordan is a constitutional Monarchy that became independent from British administration in 1946. The population of Jordan is 5 307 740 (July 2002 estimate), the capital is Amman and the language is Arabic.
The new MRCPsych Part II exam – golden tips on how to pass
Authors: Naeem Asim , Rutherford Joan , Kenn Chris
Published: September 2003

“Examinations are formidable even to the best prepared, for the greatest fool may ask more than the wisest man can answer!” (Charles Kaleb Cotton)

The MRCPsych Part II examination remains an important milestone (or barrier) for those wishing to pursue higher specialist training in psychiatry. There have been significant changes to the structure of this complex exam, with modification of the multiple choice question (MCQ) and essay papers and the introduction of the critical review paper. With pass rates varying from 39–49% over recent years, it clearly represents a significant hurdle for psychiatric trainees. This article aims to provide specific advice on how best to approach and tackle each of the components of the exam.
High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin’s Lymphoma: Results From the Randomized European CUP Trial
Authors: Schouten Harry C. , Qian Wendi , Kvaloy Stein , Porcellini Adolfo , Hagberg Hans , Johnsen Hans Erik , Doorduijn Jeanette K. , Sydes Matthew R. , Kvalheim Gunnar
Published: September 2003

Purpose: To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkin’s lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS.

Patients and Methods: Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P).

Results: Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were .0037 and .079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively.

Conclusion: HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.
Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With Paclitaxel
Authors: Leyland-Jones Brian , Gelmon Karen , Ayoub Jean-Pierre , Arnold Andrew , Verma Shail , Dias Reg , Ghahramani Parviz
Published: September 2003

Purpose: This phase II study evaluated the pharmacokinetics and safety of trastuzumab and paclitaxel given every 3 weeks to women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer.

Patients and Methods: Thirty-two patients received a loading dose of trastuzumab 8 mg/kg intravenously (day 1) and paclitaxel 175 mg/m2 (day 0). Thereafter, trastuzumab 6 mg/kg was administered on the same day as paclitaxel 175 mg/m2 every 3 weeks for seven cycles. In responding patients, trastuzumab monotherapy every 3 weeks was then continued until disease progression or patient withdrawal.

Results: Trastuzumab trough levels were more than 20 μg/mL by the end of cycle 1. The half-life of trastuzumab was estimated to be 18 to 27 days, although this may be an underestimate. The combination of paclitaxel and trastuzumab was generally well tolerated, with no unexpected toxicities and no pharmacokinetic interaction. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue. Events associated with trastuzumab included infusion-related reactions and cardiac dysfunction. Ten patients had a ≥ 15% decrease in ejection fraction, but only one had symptomatic heart failure. The investigator-assessed objective response rate was 59% (four complete and 15 partial responses) and seven patients (22%) had stable disease. The median duration of response was 10.5 months and median time to progression was 12.2 months.

Conclusion: Additional investigation of trastuzumab administered every 3 weeks is warranted. In combination with paclitaxel, it is generally well tolerated. Plasma trastuzumab trough levels and clinical response rates compare favorably with those achieved with the standard weekly trastuzumab regimen plus chemotherapy. The presence of trastuzumab does not alter exposure to paclitaxel.
Membrane Estrogen Receptor-Dependent Extracellular Signal-Regulated Kinase Pathway Mediates Acute Activation of Endothelial Nitric Oxide Synthase by Estrogen in Uterine Artery Endothelial Cells
Authors: Chen Dong-bao , Bird Ian M. , Zheng Jing , Magness Ronald R.
Published: September 2003

Rapid uterine vasodilatation after estrogen administration is believed to be mediated by endothelial production of nitric oxide (NO) via endothelial NO synthase (eNOS). However, the mechanism(s) by which estrogen activates eNOS in uterine artery endothelial cells (UAEC) is unknown. In this study, we observed that estradiol-17β (E2) and E2-BSA rapidly (<2 min) increased total NOx production in UAEC in vitro. This was associated with rapid eNOS phosphorylation and activation but was unaltered by pretreatment with actinomycin-D. estrogen receptor-α protein was detectable in isolated plasma membrane proteins by immunoblotting, and E2-BSA-fluorescein isothiocyanate binding was evident on the plasma membrane of UAEC. E2 did not mobilize intracellular Ca2+, but E2 and ionomycin in combination induced greater eNOS phosphorylation than either E2 or ionomycin alone. E2 did not stimulate rapid Akt phosphorylation. E2 stimulated rapid ERK2/1 activation in a time- and dose-dependent manner, with maximal responses observed at 5–10 min with E2 (10 nm to 1 μm) treatment. Acute activation of eNOS and NOx production by E2 could be inhibited by PD98059 but not by LY294002. When E2-BSA was applied, similar responses in NOx production, eNOS, and ERK2/1 activation to those of E2 were achieved. In addition, E2 and E2-BSA-induced ERK2/1 activation and ICI 182,780 could inhibit NOx production by E2. Thus, acute activation of eNOS to produce NO in UAEC by estrogen is at least partially through an ERK pathway, possibly via estrogen receptor localized on the plasma membrane. This pathway may provide a novel mechanism for NO-mediated rapid uterine vasodilatation by estrogen.
Hypothalamic-Pituitary Cytokine Network
Authors: Kariagina Anastasia , Romanenko Dmitry , Ren Song-Guang , Chesnokova Vera
Published: September 2003

Cytokines expressed in the brain and involved in regulating the hypothalamus-pituitary-adrenal (HPA) axis contribute to the neuroendocrine interface. Leukemia inhibitory factor (LIF) and LIF receptors are expressed in human pituitary cells and murine hypothalamus and pituitary. LIF potently induces pituitary proopiomelanocortin (POMC) gene transcription and ACTH secretion and potentiates CRH induction of POMC. In vivo, LIF, along with CRH, enhances POMC expression and ACTH secretion in response to emotional and inflammatory stress. To further elucidate specific roles for both CRH and LIF in activating the inflammatory HPA response, double-knockout mice (CRH/LIFKO) were generated by breeding the null mutants for each respective single gene. Inflammation produced by ip injection of lipopolysaccharide (1 μg/mouse) to double CRH and LIF-deficient mice elicited pituitary POMC induction similar to wild type and markedly higher than in single null animals (P < 0.0.01). Double-knockout mice also demonstrated robust corticosterone response to inflammation. High pituitary POMC mRNA levels may reflect abundant TNFα, IL-1β, and IL-6 activation observed in the hypothalamus and pituitary of these animals. Our results suggest that increased central proinflammatory cytokine expression can compensate for the impaired HPA axis function and activates inflammatory ACTH and corticosterone responses in mice-deficient in both CRH and LIF.
Influence of traditional Chinese anti-inflammatory medicinal plants on leukocyte and platelet functions
Authors: Prieto J M , Recio M C , Giner R M , Máñez S , Giner-Larza E M , Ríos J L
Published: September 2003

The enzymes 5-lipoxygenase and elastase are therapeutic targets in dermatological disorders such as psoriasis. Fifteen extracts from traditional Chinese medicinal plants used to treat topical inflammations were screened for their inhibitory effect on lipoxygenase, cyclooxygenase and elastase activity in intact leukocytes and platelets. Astragalus membranaceus, Forsythia suspensa and Poria cocos inhibited 5-lipoxygenase, with IC50 values of 141, 80 and 141 μg mL−1, respectively. The latter two species, along with Angelica dahurica and Angelica pubescens, also inhibited elastase (IC50 values of 80, 123, 68 and 93 μg mL−1, respectively), while A. pubescens, Atractylodes macrocephala, Lentinus edodes, Rehmannia glutinosa and Paeonia lactiflora selectively inhibited 12-(S)-HHTrE production, a valid marker of cyclooxygenase activity. The inhibition of phospholipase A2 activity by P. cocos is discussed. Dehydrotumulosic and pachymic acids, which have been isolated from P. cocos, were shown to inhibit leukotriene B4 release. The results indicate that both P. cocos and F. suspensa are potentially valuable species in the management of skin pathologies involving chronic inflammation.
Pharmacokinetic interaction between oltipraz and dimethyl-4,4‘-dimethoxy-5,6,5′,6’-dimethylene dioxybiphenyl-2,2′-dicarboxylate (DDB) after single intravenous and oral administration to rats
Authors: Bae Soo Kyung , Kim Eun Jung , Chung Suk Jae , Kim Sang Geon , Lee Myung Gull
Published: September 2003

The aim of this study was to report the pharmacokinetic interaction between oltipraz (50 mg kg−1) and dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate (DDB, 10 mg kg−1) after single intravenous and oral administration to rats. After intravenous administration of oltipraz plus DDB, the area under the plasma concentration–time curve from time zero to time infinity (AUC) of oltipraz was significantly greater (1440 vs 1740 μg min mL−1) than that after oltipraz alone. This was not due to slower clearances of oltipraz after oltipraz plus DDB since the total body, renal and nonrenal clearances were comparable between the two groups of rats. It could be due to a decrease in tissue binding of oltipraz by DDB. The apparent volume of distribution at steady state (Vdss) of DDB was significantly smaller (7060 vs 4650 mL kg−1) than after oltipraz alone. After oral administration of oltipraz plus DDB, the AUC of olitpraz was also significantly greater (479 vs 583 μg min mL−1) than that after oltipraz alone. This was not due to increased absorption of oltipraz from the rat gastrointestinal tract after oltipraz plus DDB but again could be due to a decrease in Vdss of oltipraz by DDB. However, after both intravenous and oral administration, the pharmacokinetic parameters of DDB were comparable between DDB alone and DDB plus oltipraz, indicating that oltipraz did not greatly affect the pharmacokinetics of DDB in rats.
Effect of bupropion on CYP2B6 and CYP3A4 catalytic activity, immunoreactive protein and mRNA levels in primary human hepatocytes: comparison with rifampicin
Authors: Hesse Leah M , Sakai Yumiko , Vishnuvardhan Daesety , Li Albert P , von Moltke Lisa L , Greenblatt David J
Published: September 2003

Animals treated with multiple doses of bupropion have had increased bupropion clearance or increased liver weight, suggesting induction of drug-metabolizing activity. The possibility of cytochrome p450 (CYP) induction by bupropion (10 μM) was evaluated in-vitro by comparing catalytic activity, immunoreactive protein and CYP mRNA levels from human hepatocytes in primary culture versus cells treated with vehicle (0.5% methanol) and with rifampicin (rifampin) as a positive control. mRNA levels were analysed using a branched DNA luminescent assay. CYP2B6 activity, protein and mRNA levels were increased by 2.5, 1.5 and 2.1 fold, respectively, by 20 μM rifampicin. However, 10 μM bupropion minimally altered CYP2B6 (1.4, 1.1, 0.8 fold). Although CYP3A4 activity, protein, and mRNA levels were increased by 4.0, 2.3, and 14.0 fold, respectively, by 20 μM rifampicin, 10 μM bupropion minimally altered CYP3A4 (1.4, 1.0, 0.8 fold). Rifampicin (20 μM) increased CYP2E1 protein by 2.1 fold, while 10 μM bupropion minimally altered CYP2E1 protein (1.2 fold). Overall, results of this study suggest that multiple doses of bupropion are not likely to induce CYP2B6, 3A4 or 2E1 in-vivo in man.
Quantitative evaluation of isothiocyanates as substrates and inhibitors of P-glycoprotein
Authors: Barecki-Roach Mary , Wang Er-jia , Johnson William W
Published: September 2003

The ATP-binding cassette transporter P-glycoprotein (P-gp) exerts a critical role in the systemic disposition of, and exposure to, lipophilic and amphipathic drugs, carcinogens, toxins and other xenobiotics. The ability of P-gp to transfer a wide variety of structurally unrelated compounds from the cell interior across the membrane bilayer remains intriguing. Since dietary chemicals in cruciferous and several other foods appear to exert anticarcinogenic effects by inducing phase II enzymes and inhibiting some phase I enzymes, the isothiocyanate constituents are frequently studied for interactions with various biomacromolecules as well as cytotoxins or isolated cells. Several prominent dietary isothiocyanates were characterized for their interaction with P-gp and their specific effects on the P-gp export activity of several marker substrates. Some of these compounds inhibit the active P-gp-mediated efflux of the fluorescent markers LDS-751 and daunorubicin with low potency, with the most potent among them, phenethyl isothiocyanate, inhibiting transport of the LDS-751 substrate with an IC50 of ˜240 μM. Overall, these isothiocyanates are unlikely to impede the xenobiotic defence function of P-gp even in the intestine where the concentrations are potentially high.
Quantification of crystalline forms in active pharmaceutical ingredient and tablets by X-ray powder diffraction
Authors: Cooper V Brett , Pearce Gareth E S , Petts Catherine R
Published: September 2003

A Merck development compound was known to exist in several polymorphic forms, hydrates and solvates. The polymorphic forms were characterized and the most thermodynamically stable form at room temperature was identified and taken into development. During routine stability analysis it became apparent that the crystalline form of the compound was converting from one form to another in tablets that were stored at 40° C/75% relative humidity in open containers. This form conversion did not occur when the active pharmaceutical ingredient (API) alone was stored under these conditions. This paper describes the development and application of an X-ray powder diffraction method for the determination of the relative content of the two crystalline forms in API and within the final formulation. Results of monitoring the crystalline form conversion are reported and a possible mechanism of conversion is postulated.
Effects of surface roughness and chrome plating of punch tips on the sticking tendencies of model ibuprofen formulations
Authors: Roberts Matthew , Ford James L , MacLeod Graeme S , Fell John T , Smith George W , Rowe Philip H
Published: September 2003

The sticking of three model ibuprofen–lactose formulations with respect to compaction force and the surface quality of the upper punch were assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Two sets of 12.5-mm flat-faced punches were used to evaluate the influence of surface quality. A third set of chrome-plated tooling was also used. Surface profiles (Taylor Hobson Talysurf 120) of the normal tooling upper punches indicated a large difference in quality. The punches were subsequently classified as old (Ra = 0.33 μm) or new (Ra = 0.04 μm) where Ra is the mean of all positive deviations from zero. Surface profiles of sample tablets were also obtained. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. Punch surface roughness, compaction force and the blend composition were all significant factors contributing to sticking. Chrome plating of punch faces increased sticking at a low compaction force but decreased sticking at higher forces. Surface roughness of the tablets did not correlate with the corresponding data for sticking, indicating that this is not a suitable method of quantifying sticking.
Comparative study of eight well-known polyphenolic antioxidants
Authors: Cos P , Hermans N , Calomme M , Maes L , De Bruyne T , Pieters L , Vlietinck A J , Berghe D Vanden
Published: September 2003

Eight antioxidants from five different polyphenolic classes (cinnamic acids, benzoic acids, flavonoids, proanthocyanidins and stilbenes), and the water-soluble vitamin E derivative trolox were examined for their antioxidant activity in-vitro. In addition, the compounds were tested for their cytotoxicity on growing fibroblasts and their inhibition of the classical pathway of the complement system. Procyanidin C1 was shown to be a good scavenger of both DPPH* and HO*, and a strong inhibitor of lipid peroxidation and the classical pathway of the complement system. Consequently, procyanidin C1 was classified as the most promising antioxidant in-vitro of all compounds tested. In contrast, genistein exhibited a very low antioxidant activity in both the lipid peroxidation and the DPPH* scavenging assay, a high cytotoxicity and a low complement-inhibiting activity.
Influences of a light–dark profile and the pineal gland on the hypnotic activity of melatonin in mice and rats
Authors: Wang Fang , Li Jing Cai , Wu Chun Fu , Yang Jing Yu , Zhang Ruo Ming , Chai Hui Fang
Published: September 2003

We have investigated the influences of the light–dark cycle and the pineal gland on the hypnotic activity of melatonin in rats and mice. The results showed that melatonin significantly shortened time to sleep onset and wakefulness time, increased slow wave sleep, paradoxical sleep, and total sleep time in rats during the light phase of a 12-h light: 12-h dark cycle, by electroencephalogram recording. However, during the dark phase it had almost no significant sleep-promoting effect except shortened time to sleep onset. Melatonin exhibited more potent sleep-promoting effect in rats exposed to constant light compared with rats exposed to 12:12-h light:dark at 2000 h. Melatonin markedly prolonged sleeping time in the mice exposed to constant illumination. It was found that pinealectomy was an important factor that influenced the hypnotic activity of melatonin. When melatonin was administered to pinealectomized mice, the hypnotic activity of melatonin was more intense compared with sham-operated mice. These results demonstrated that the hypnotic activity of melatonin displayed a light-dependence manner. These results suggested that light exposure and the functional state of the pineal gland could substantially impact the hypnotic activity of melatonin at pharmacological dosage.
Enhancement of radiation-induced apoptosis by Podophyllum hexandrum
Authors: Kumar I Prem , Rana S V S , Samanta N , Goel H C
Published: September 2003

The aqueous extract of Podophyllum hexandrum (RP-1), which has been recently reported to manifest radioprotective and anti-tumour properties, has been investigated for its mode of action. RP-1, under in-vitro conditions dose-dependently chelated metal ions, inhibited radiation or metal ion-induced hydroxyl radicals and lipid peroxidation and scavenged superoxide anions. Intraperitoneal administration of RP-1 to mice pre-irradiation (10 Gy) induced more DNA fragmentation and lipid peroxidation in thymocytes maximally at 4 and 8 h, respectively, in comparison with RP-1 treatment or irradiation. Flow-cytometric quantification of sub-diploid peak, oligonucleosomal cleavage assay (ladder) and depletion of total thiols also corroborated the ability of RP-1 to enhance radiation-induced apoptosis. RP-1 in presence of 100 μM CuSO4 induced strand breaks in plasmid DNA and addition of metal chelators (EDTA and deferoxamine) inhibited the strand scission. Treatment with a major constituent of RP-1, podophyllin, did not cause strand breaks, but isolated constituents of RP-1, quercetin or podophyllotoxin, induced strand breaks. Depending on its concentration in the milieu, RP-1 acted as a pro- or antioxidant modifying the radiation-induced apoptosis and therefore could be exploited for cancer management.
A new chloroquinolinyl chalcone derivative as inhibitor of inflammatory and immune response in mice and rats
Authors: De León E J , Alcaraz M J , Dominguez J N , Charris J , Terencio M C
Published: September 2003

The synthetic chalcone derivative 1-(2,4-dichlorophenyl)-3-(3-(6,7-dimethoxy-2-chloroquinolinyl))-2-propen-1-one (CIDQ) was evaluated for its anti-inflammatory, analgesic and immunomodulatory efficacy in-vitro and in-vivo. CIDQ concentration-dependently inhibited the production of nitric oxide (NO) (IC50 4.3 μM) and prostaglandin E2 (PGE2) (IC50 1.8 μM) in RAW 264.7 macrophages stimulated with lipopolysaccharide. Human mononuclear cell proliferation was significantly inhibited by 10 μM CIDQ. Oral administration of CIDQ (10–30 mg kg−1) in the 24-h zymosan-stimulated mouse air-pouch model produced a dose-dependent reduction of cell migration as well as NO and PGE2 levels in exudates. CIDQ (20 mg kg−1, p.o.) inhibited ear swelling and leucocyte infiltration in the delayed-type hypersensitivity response to 2,4-dinitrofluorobenzene in mice. In the rat adjuvant-arthritis model, this compound reduced joint inflammation as well as PGE2 and cytokine levels. In addition, CIDQ displayed analgesic effects in the phenylbenzoquinone-induced abdominal constriction model in mice and in the late phase of the nociceptive response to formalin. Our findings indicated the potential interest of CIDQ in the modulation of some immune and inflammatory conditions.
The role of neurotrophin receptors in female germ-cell survival in mouse and human
Authors: Spears Norah , Molinek Michael D. , Robinson Lynne L. L. , Fulton Norma , Cameron Helen , Shimoda Kohji , Telfer Evelyn E. , Anderson Richard A. , Price David J.
Published: September 2003

During mammalian ovary formation, the production of ovarian follicles is accompanied by an enormous loss of germ cells. It is not known how this loss is regulated. We have investigated the role of the Trk tyrosine kinase receptors, primarily TrkB, in this process. The ovaries of TrkB–/– and TrkC–/– mice with a mixed (129Sv ×C57BL/6) genetic background were examined shortly after birth. Around 50% of TrkB–/– mice had grossly abnormal ovaries that contained greatly reduced numbers of follicles. No defects were found in the ovaries of TrkC–/– mice. Congenic TrkB–/– mice were generated on 129Sv and C57BL/6 backgrounds: whereas the former had a mixed ovarian phenotype similar to that of the original colony of mice, the ovaries of all offspring of the C57BL/6 congenic line contained reduced numbers of follicles. RT-PCR showed that mRNA encoding TrkB and its two ligands, neurotrophin 4 (NT4) and brain-derived neurotrophic factor (BDNF), were present throughout the period of follicle formation in the mouse. In situ hybridisation showed that TrkB was expressed primarily in the germ cells before and after follicle formation. Mouse neonatal and fetal ovaries and human fetal ovaries were cultured in the presence of K252a, a potent inhibitor of all Trk receptors. In mice, K252a inhibited the survival of germ cells in newly formed(primordial) follicles. This effect was rescued by the addition of basic fibroblast growth factor (bFGF) to the culture medium. Combined addition of both BDNF and NT4 blocking antibodies lowered germ-cell survival, indicating that these TrkB ligands are required in this process. The results indicate that signalling through TrkB is an important component of the mechanism that regulates the early survival of female germ cells.