bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of HIV/AIDS on care and outcomes of severe sepsis
Authors: Mrus Joseph M , Braun LeeAnn , Yi Michael S , Linde-Zwirble Walter T , Johnston Joseph A
Published: September 2005

Introduction

There has been dramatic improvement in survival for patients with HIV/AIDS; however, some studies on patients with HIV/AIDS and serious illness have reported continued low rates of intensive care. The purpose of this study was to examine patterns of care and outcomes for patients with severe sepsis and HIV/AIDS and compare them with those of patients with severe sepsis without HIV/AIDS.

Methods

We assessed data from all 1999 discharge abstracts from all non-federal hospitals in six US states. Patient demographic characteristics, discharge diagnoses, resource use, and outcomes were extracted. Analyses were performed using chi-square, Wilcoxon rank sum, or regression techniques, as appropriate.

Results

We identified 74,020 patients with severe sepsis (7,638 (10.3%) had HIV/AIDS) using ICD-9-CM codes. Patients with severe sepsis and HIV/AIDS had a similar mean length of stay (16.9 days versus 17.7 days; p = 0.0669), had lower mean hospitalization cost ($24,382 versus $30,537; p < 0.0001), were less likely to be admitted to the intensive care unit (37% versus 56%; p < 0.0001), and had a greater mortality (29% versus 20%; p < 0.0001) than those without HIV/AIDS. After adjustment for cohort differences, patients with severe sepsis and HIV/AIDS had increased likelihood of death (OR (95% CI) = 2.41 (2.23–2.61)) and were substantially less likely to be admitted to the intensive care unit (OR (95% CI) = 0.54 (0.51–0.59)). When compared with those with severe sepsis and HIV/AIDS, patients with severe sepsis without HIV/AIDS were universally more likely to be admitted to the intensive care unit, even when they had comorbid illnesses with equal or worse expected in-hospital mortality (e.g., metastatic cancer).

Conclusion

For patients with severe sepsis, there are differences in care and outcomes for those with HIV/AIDS. Further research is needed to examine the delivery of care for patients with severe sepsis and HIV/AIDS.
Postnatal stem cell survival: does the niche, a rare harbor where to resist the ebb tide of differentiation, also provide lineage-specific instructions?
Authors: Kindler Vincent
Published: September 2005

Postnatal stem cells regulate the homeostasis of the majority of our tissues. They continuously generate new progenitors and mature, functional cells to replace old cells, which cannot assume the tissue function anymore and are eliminated. Blood, skin, gut mucosa, muscle, cartilage, nerves, cornea, retina, liver, and many other structures are regulated by stem cells. As a result of their ability to produce large numbers of functionally mature cells, postnatal stem cells represent a promising tool for regenerative therapy. Indeed, unmanipulated stem cells or their progeny amplified in vitro are already used in some clinical applications to restore the function of injured or genetically deficient tissues. However, despite our cumulating understanding concerning postnatal stem cells, many aspects of their functionality remain unclear. For instance, in most tissues, we cannot reliably define the phenotype of the postnatal stem cells sustaining its survival. We do not know to which extent the environment surrounding the stem cell—the niche—which is a key actor insuring stem cell self-maintenance, is also implicated in the maintenance of stem cell lineage specificity. Moreover, we have to clarify whether postnatal stem cells are capable of undertaking “transdifferentiation”, that is, the conversion of one cell type into another under physiological conditions. Answering these questions should help us to draw a more accurate picture of postnatal stem cell biology and should lead to the design of safe, effective therapies.
Cultural economy: a critical review
Authors: Gibson Chris , Kong Lily
Published: September 2005

This article reviews work on `cultural economy', particularly from within geography, and from other disciplines, where there are links to overtly geographical debates. We seek to clarify different interpretations of the term and to steer a course through this multivalency to suggest productive new research agendas. We review and critique work on cultural economy that represents a relatively straightforward economic geography, based on empirical observation while theoretically informed and driven by debates about Fordism and post-Fordism, agglomeration and cluster theory. Some of these ideas about cultural economy have proven attractive to policy-makers and we map a normative script of cultural economy, with its prescriptive recommendations for economic development, which we then critique. Turning from this normative cultural economy, we move to a more theoretical discussion which reinterprets the cultural economy in light of debates on the culturization of `the economic' in research praxis. We conclude that better acknowledgement is needed of the contradictory uses of `cultural economy', but point nevertheless value of this multivalency as long as we reflect on the multiple contradictions and interpretations. With many current absences in work on cultural economy, we suggest various agendas waiting to be addressed.
Peripheral arterial disease symptom subtype and walking impairment
Authors: Collins Tracie C , Petersen Nancy J , Suarez-Almazor Maria
Published: September 2005

Walking impairment is common in patients with peripheral arterial disease (PAD). The purpose of this study was to compare specific leg symptoms and walking impairment in a racially diverse cohort of patients with PAD. Patients who were receiving care at the Michael E DeBakey Veterans Affairs Medical Center or in the Harris County Hospital District were screened for PAD, which was diagnosed in the office setting by blood pressure measurements that were used to calculate the ankle-brachial index (a level <0.90 was defined as disease). To define leg symptoms, we asked patients to complete the San Diego Claudication Questionnaire. Based on the questionnaire results, leg symptoms were categorized as: asymptomatic, atypical, and intermittent claudication. The patients also completed the Walking Impairment Questionnaire. Among 403 patients screened (136 Caucasians, 136 African Americans and 131 Latinos), 67 were found to have PAD (18 Caucasians, 31 African Americans and 18 Latinos). The mean age of the cohort was 63.8 years (standard deviation (SD) 7.3). Walking distance, speed and stair climbing scores were lower (p < 0.0001) for patients with PAD and leg pain on exertion or at rest when compared with patients with PAD without leg symptoms or with symptoms of intermittent claudication. For patients with PAD and leg pain on exertion and at rest, the walking distance score was 27.1 ± SD 37.7 compared with 41.0 ± 38.4 for those with asymptomatic disease who were inactive, and with 38.5 ± 42.7 for those with intermittent claudication ( p = 0.02).

In an ethnically diverse primary care clinic population, patients with PAD and leg pain on exertion and at rest had greater compromise in their walking ability when compared with patients with intermittent claudication. The reasons for the significant impairment in walking among patients with PAD and these atypical leg symptoms may stem from coexisting illnesses or other as yet undefined factors. Future research should focus on methods to improve daily walking in patients with PAD and atypical leg symptoms.
Inflammatory markers and IL-6 polymorphism in peripheral arterial disease with and without diabetes mellitus
Authors: Danielsson P , Truedsson L , Eriksson K-F , Norgren L
Published: September 2005

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis, recognized as an inflammatory disease of the vessel wall, probably accelerated by diabetes mellitus (DM). Elevated interleukin (IL)-6 levels have been associated with increased cardiovascular morbidity and a common polymorphism has been identified in the promoter region of the IL-6 gene. The aim of this prospective study was to investigate inflammatory mediators in PAD patients (±DM) and to investigate a possible relationship to the IL-6 gene polymorphism. Five groups of patients (DM, intermittent claudication ±DM, critical limb ischemia (CLI) ±DM) and a control group of 20 individuals each were included. Hemoglobin, high sensitive C-reactive protein (hsCRP), creatinine, blood lipids, white blood cells (WBC); CD11b/CD18; vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, sP-selectin; IL-6, IL-8, tumour necrosis factor (TNF)α, sTNFα-R1 and sTNFα-R2 were analysed. The IL-6 gene polymorphism was determined in all groups and also compared with 200 healthy controls from a larger study of blood donors. In a multiple regression analysis, adjusted for gender, smoking and age, the effect of CLI was significantly ( p < 0.05) associated with elevated levels of the WBC count, hsCRP, proinflammatory cytokines (IL-6, TNFα-R1-2) and endothelial (sICAM, sVCAM) and WBC (CD11b gran) markers. The effect of less advanced PAD (intermittent claudication) was related to an increased concentration of sVCAM-1 and the number of monocytes and granulocytes. DM or leg ulcers were not significantly related to any of the markers. No significant difference in frequency of the various IL-6 genotypes was found between the groups or when compared with the group of 200 blood donors ( p > 0.3). Activation of cytokines, endothelial cells and WBC was related to the Fontaine stage of PAD but not to the presence of DM or ulcers. No association was found between the polymorphism in the IL-6 promoter region and PAD.
Relationship of sonographic wall components of the brachial artery to hypertension and coronary atherosclerosis
Authors: Frick Matthias , Alber Hannes F , Rinner Alexander , Suessenbacher Alois , Ulmer Hanno , Schwarzacher Severin P , Pachinger Otmar , Weidinger Franz
Published: September 2005

The aim of this study was to determine whether sonographically assessed intimal (echodense, ED) or medial (echolucent, EL) thickening of the brachial artery is associated with coronary artery disease (CAD) and/or arterial hypertension (HT). In 201 patients the ED and EL wall components, as well as the total wall thickness of the brachial artery, were measured with high-resolution ultrasound (13 MHz). According to the presence or absence of CAD and HT, the patients were divided into four groups: no HT and no CAD (n = 26, group 1), CAD (≥30% diameter stenosis in ≥1 major branch) only (n = 63, group 2), HT only (n = 34, group 3), and HT and CAD (n = 78, group 4). EL ( p < 0.001) and combined wall thickness ( p < 0.001), but not the ED wall component, were significantly different between the groups, with the highest values occurring in group 4. On logistic regression analyses adjusting for age, coronary risk factors and body mass index, EL, but not ED, thickness correlated independently with the presence of CAD (p = 0.04) and HT ( p < 0.001). High-resolution ultrasound examination of the brachial artery wall structure may contribute to the noninvasive assessment of early atherosclerosis.
Association of anger proneness, depression and low social support with peripheral arterial disease: the Atherosclerosis Risk in Communities Study
Authors: Wattanakit Keattiyoat , Williams Janice E , Schreiner Pamela J , Hirsch Alan T , Folsom Aaron R
Published: September 2005

There is mounting evidence to suggest that psychosocial factors, including anger proneness, depression and social isolation, are risk factors for cardiovascular disease. Nevertheless, evidence relating these factors to peripheral arterial disease (PAD) and intermittent claudication remains sparse. Using data from the Atherosclerosis Risk in Communities Study, we analyzed the relationship of psychosocial variables (Spielberger anger score, depression score from the Maastricht questionnaire, and a perceived social support scale) at study visit 2 with incident PAD (ankle-brachial index ≤0.9; a hospital discharge diagnosis of PAD, leg amputation, or leg revascularization procedures; or intermittent claudication). In 12 965 middle-aged adults with no prior history of PAD, 854 developed PAD over a mean follow-up time of 9.7 years, yielding an incidence rate of 6.8 per 1000 person years. A modest, monotonic dose-response, positive association between anger proneness and incident PAD was observed in a multivariable model: relative risk (RR) = 1.15 (95% confidence interval (CI) 0.99-1.38) in the moderate anger group and RR = 1.38 (95% CI 1.08-1.76) in the high anger group, compared with the low anger group. When compared with a low level of depressive symptoms, moderate and high levels of depressive symptoms were also associated with greater incident PAD, with multivariable RRs of 1.20 (95% CI 0.99-1.45) and 1.44 (95% CI 1.19-1.74) respectively. There was no association of perceived level of social support with the occurrence of PAD. Anger proneness and depressive symptoms may be associated with the occur-rence of PAD, as for other atherosclerotic syndromes. These findings may warrant confirmation in further studies and, if causal, could serve as a unique target for a PAD prevention trial.
Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor
Authors: Qureshi Irfan , Chen Hongjiang , Brown Aliza T , Fitzgerald Ryan , Zhang Xingjian , Breckenridge Julie , Kazi Rafi , Crocker Amy J , Stühlingexsr Markus C , Lin Kenneth , Cooke John P , Eidt John F , Moursi Mohammed M
Published: September 2005

Elevated plasma homocysteine accelerates myointimal hyperplasia and luminal narrowing after carotid endarterectomy. N-methyl D aspartate receptors (NMDAr) in rat cerebrovascular cells are involved in homocysteine uptake and receptor-mediated stimulation. In the vasculature, NMDAr subunits (NR1, 2A-2D) have been identified by sequence homology in rat aortic endothelial cells. Exposure of these cells to homocysteine increased expression of receptor subunits, an effect that was attenuated by dizocilpine (MK801), a noncompetitive NMDA inhibitor. The objective of this study was to investigate the existence of an NMDAr in rat vascular smooth muscle (A7r5) cells, and also the effect of homocysteine on vascular dysregulation as mediated by this receptor. Subunits of the NMDAr (NR1, 2A-2D) were detected in the A7r5 cells by using the reverse transcriptase polymerase chain reaction and Western blotting. Homocysteine induced an increase in A7r5 cell proliferation, which was blocked by MK801. Homocysteine, in a dose and time dependent manner, increased expression of matrix metallinoproteinase-9 and interleukin-1beta, which have been implicated in vascular smooth muscle cell migration and/or proliferation. Homocysteine reduced the vascular elaboration of nitric oxide and increased the elaboration of the nitric oxide synthase inhibitor, asymmetric dimethylarginine. All of these homocysteine mediated effects were inhibited by MK801. NMDAr exist in vascular smooth muscle cells and appear to mediate, at least in part, homocysteine-induced dysregulation of vascular smooth muscle cell functions.
Quality of the assessment of primary and secondary endpoints in claudication and critical leg ischemia trials
Authors: Hiatt William R , Cox Lisa , Greenwalt Marilyn , Griffin Ali , Schechter Cynthia
Published: September 2005

Clinical trials in peripheral arterial disease (PAD) require an accurate definition of the disease for inclusion; they typically use treadmill testing, questionnaires and hemodynamic measures as primary and secondary endpoints. Trials of new pharmacologic therapies for PAD often employ multiple clinical sites with presumed expertise in the diagnosis and management of PAD as well as in clinical trials. However, considerable variability has been observed in the assessment of endpoints used in PAD trials, as well as a marked placebo response with treadmill testing. This variability and placebo response impact adversely on overall trial integrity, necessitate an inflated sample size, and may contribute to the large number of recently negative claudication trials. We hypothesized that site monitoring visits for evaluating testing methods would identify and characterize several critical issues that would contribute to poor testing quality. One hundred sites participating in three claudication trials for which peak walking time on the treadmill was the primary endpoint, and 16 sites participating in a critical leg ischemia study for which transcutaneous oxygen tension (TcPO2) was the primary endpoint were evaluated. Each site was visited one or more times by a clinical monitor trained in conducting a ‘site endpoint evaluation visit’ focusing on equipment, physical set-up of the room in which testing was to be conducted, and the site staff’s ability to conduct each of the specific measurements. Full reports were generated that covered a number of technical issues for each measurement and data were extracted from these reports to summarize the testing problems encountered at each site. Problems with treadmill testing were common. For example, 92% of sites had problems with their treadmill equipment, 58% did not perform proper treadmill familiarization, 24% did not start the treadmill test appropriately, 24% did not conduct the test properly, and 15% did not properly conclude the test to determine the peak walking time of the participant. Similar problems were encountered with the ankle-brachial index test, the administration of questionnaires and measurement of the TcPO2. Major deficiencies were identified at the majority of sites in the assessment of primary and secondary endpoints in PAD trials. These errors and improper testing provide a potential explanation for the wide variability and placebo responses observed in claudication and critical leg ischemia trials. Site interventions need to address these deficiencies in measurement to improve the quality of PAD trials.
Chronic pain following trauma
Authors: Curran N , Brandner B
Published: September 2005

Trauma is increasingly recognized as a factor in the development of chronic pain. Complex regional pain syndrome (CRPS) and phantom limb pain are distinct chronic conditions associated with trauma; they are also a challenge to treat and can lead to life-long suffering with a significant drain on healthcare resources. This review explores the underlying pathophysiology of acute pain after trauma and its transition to become chronic. In doing so it will provide a better understanding of treatment options. The evidence is increasing that treating injury well in the acute phase can prevent chronic pain from developing (Katz et al., 1996). Once chronic pain has developed it is more difficult to treat.
Trauma and critical care III: chest trauma
Authors: Shirley Peter J
Published: September 2005

Patients requiring intensive care for chest trauma are often severely injured and may have suffered trauma elsewhere. The single largest cause of significant blunt chest trauma is road traffic accidents (RTAs). RTAs account for 70-80% of such injuries. Falls and acts of violence are other causative mechanisms. Blast injuries can also result in significant blunt thoracic trauma. Penetrating chest trauma comprises a broad spectrum of injuries and severity. Particular challenges occur in patients with associated polytrauma, as well as those with a combination of blunt and penetrating chest trauma. Chest injury is the most important injury in polytrauma patients with reported incidences of 45-65% and an associated mortality of up to 60%. The treatment of these patients can be prolonged and the initial injury may become of secondary importance to the effects of systemic inflammatory response syndrome, acute lung injury (ALI), nosocomial infection and intercurrent multiorgan dysfunction syndrome (MODS). Multiply-injured patients with thoracic injuries require significantly longer periods of mechanical ventilation and longer intensive care unit lengths of stay compared with nonthoracic injury trauma patients. The use of a variety of therapeutic interventions may have to be considered during management of the disease process.
Trauma in the anticoagulated patient
Authors: Guly HR , Jones LO , Nokes TJC
Published: September 2005

An increasing number of people are taking anticoagulants for the prophylaxis of thromboembolic disease. This may cause problems when they attend hospital following trauma. Patients may also develop spontaneous bleeding that may have similar effects to bleeding after an injury.

This article discusses the risks of bleeding (especially in head injury); the risks of stopping anticoagulation; how anticoagulation should be reversed and how anticoagulation should affect the approach to the head-injured patient.
The early hospital management of gunshot wounds. Part 1: head, neck and thorax
Authors: Garner Jeff
Published: September 2005

The management of gunshot wounds is an increasing problem for UK emergency doctors, but not to an extent where it has become routine or allowed individuals to gain significant experience in their treatment. This article reviews the pathophysiology of gunshot injury in general before examining the evidence available concerning the management of gunshot wounds to the head neck and thorax.
Prefrontal white matter in pathological liars
Authors: Yang Yaling , Raine Adrian , Lencz Todd , Bihrle Susan , Lacasse Lori , Colletti Patrick
Published: September 2005

Background

Studies have shown increased bilateral activation in the prefrontal cortex when normal individuals lie, but there have been no structural imaging studies of deceitful individuals.

Aims

To assess whether deceitful individuals show structural abnormalities in prefrontal grey and white matter volume.

Method

Prefrontal grey and white matter volumes were assessed using structural magnetic resonance imaging in 12 individuals who pathologically lie, cheat and deceive (‘liars’), 16 antisocial controls and 21 normal controls.

Results

Liars showed a 22–26% increase in prefrontal white matter and a 36–42% reduction in prefrontal grey/white ratios compared with both antisocial controls and normal controls.

Conclusions

These findings provide the first evidence of a structural brain deficit in liars, they implicate the prefrontal cortex as an important (but not sole) component in the neural circuitry underlying lying and provide an initial neurobiological correlate of a deceitful personality.
Schizophrenia and cancer: an epidemiological study
Authors: Goldacre Michael J. , Kurina Lianne M. , Wotton Clare J. , Yeates David , Seagroatt Valerie
Published: September 2005

Background

For decades there has been interest in the possibility that people with schizophrenia might have some protection against cancer, and that, if this were so, it might hold clues about aetiological mechanisms in schizophrenia.

Aims

To study cancer incidence in schizophrenia.

Method

Cohort analysis of linked hospital and death records was used to compare cancer rates in people with schizophrenia with a reference cohort.

Results

We did not find a reduced risk for cancer overall (rate ratio 0.99, 95% CI 0.90–1.08) or for most individual cancers. There was, however, a significantly low rate ratio for skin cancer (0.56, 95% CI 0.36–0.83)

Conclusions

We found no evidence that schizophrenia confers protection against cancer in general. Low rates of skin cancer are consistent with the hypothesis that sun exposure may influence the development of schizophrenia, although other explanations are also possible.
Family education for people with schizophrenia in Beijing, China
Authors: Li Zheng , Arthur David
Published: September 2005

Background

Much of China lacks well-developed services for people with schizophrenia and their families, and most of the existing services focus on hospitals. There is a need for culturally sensitive family treatments offered by nurses.

Aims

To conduct a longitudinal experimental study examining the effect of patient and family education in a sample of Chinese people with schizophrenia.

Method

A randomised controlled trial was conducted in a large hospital with a sample of 101 patients with schizophrenia and their families. Data were collected at admission and at discharge, and then at 3 and 9 months after discharge. The intervention group received family education, and data on their knowledge about schizophrenia, symptoms, functioning, psychosocial behaviour, relapse and medication adherence were collected and compared with the control group.

Results

There was a significant improvement in knowledge about schizophrenia in the experimental group and a significant difference in symptom scores and functioning at 9 months after discharge. Patients who were non-adherent to medication regimens were more likely to relapse.

Conclusions

Family education on schizophrenia by nurses in China was effective in improving knowledge and promoting improvement in patients' symptoms.
In-patient treatment of opiate dependence: medium-term follow-up outcomes
Authors: Smyth Bobby P. , Barry Joe , Lane Alison , Cotter Mary , O'Neill Mary , Quinn Caroline , Keenan Eamon
Published: September 2005

Background

The outcome for opiate-dependent patients seeking abstinence is unclear in this era of improved access to methadone maintenance.

Aims

To measure the outcome 2–3 years after in-patient treatment.

Method

Opiate-dependent patients admitted with a goal of abstinence were followed-up. A structured interview examined drug use and treatment in the preceding month.

Results

Five patients had died and 109 (76%) of the remaining 144 were interviewed. Fifty per cent (54 patients) reported recent opiate misuse and 57% (62) were on methadone maintenance. Twenty-three per cent (25 patients) were abstinent (i.e. neither using opiates nor on methadone maintenance). Abstinence was significantly associated with completion of the 6-week in-patient treatment programme and attendance at out-patient after-care, and negatively associated with a family history of substance misuse.

Conclusions

Abstinence remains an attainable goal. As the principal influence on outcome was treatment adherence, inpatient services should seek to enhance rates of programme completion. Aftercare should be provided to patients. We caution against use of pre-treatment patient characteristics as criteria for prioritising access to in-patient treatment.
Clinical implications of Brief Psychiatric Rating Scale scores
Authors: Leucht Stefan , Kane John M. , Kissling Werner , Hamann Johannes , Etschel Eva , Engel Rolf
Published: September 2005

Background

Despite the widespread use of the Brief Psychiatric Rating Scale (BPRS), the clinical meaning of its total score and cut-off values used to define treatment response are unclear.

Aims

To link the BPRS to Clinical Global Impression (CGI) ratings.

Method

Equipercentile linking of BPRS and CGI ratings from seven drug trials in acutely ill patients with schizophrenia (n=1979).

Results

‘Mildly ill’ according to the CGI approximately corresponded to a BPRS total score of 31, ‘moderately ill’ to a BPRS score of 41 and ‘markedly ill’ to a BPRS score of 53. ‘Minimally improved’ according to the CGI score was associated with percentage BPRS reductions of 24, 27 and 30% at weeks 1, 2 and 4, respectively. The corresponding numbers for a CGI rating of ‘much improved’ were 44, 53 and 58%

Conclusions

The results provide a clearer understanding of how to interpret BPRS total and percentage reduction scores in clinical trials with patients acutely ill with schizophrenia who are experiencing positive symptoms.
Prevalence and predictors of mental incapacity in psychiatric in-patients
Authors: Cairns Ruth , Maddock Clementine , Buchanan Alec , David Anthony S. , Hayward Peter , Richardson Genevra , Szmukler George , Hotopf Matthew
Published: September 2005

Background

Little is known about the proportion of psychiatric in-patients who lack capacity to make treatment decisions, or the associations of lack of capacity.

Aims

To determine the prevalence of psychiatric in-patients who lack capacity to make decisions about current treatment and to identify demographic and clinical associations with lack of mental capacity.

Method

Patients (n=112) were interviewed soon after admission to hospital and a binary judgement of capacity was made, guided by the MacArthur Competence Tool for Treatment. Demographic and clinical information was collected from an interview and case notes.

Results

Of the 112 participants, 49 (43.8%) lacked treatment-related decisional capacity Mania and psychosis, poor insight, delusions and Black and minority ethnic group were associated with mental incapacity. Of the 49 patients lacking capacity, 30 (61%) were detained under the Mental Health Act 1983. Of the 63 with capacity, 6 (9.5%) were detained.

Conclusions

Lack of treatment-related decisional capacity is a common but by no means inevitable correlate of admission to a psychiatric in-patient unit.
Transcriptional Characterizations of Differences between Eutopic and Ectopic Endometrium
Authors: Wu Yan , Kajdacsy-Balla André , Strawn Estil , Basir Zainab , Halverson Gloria , Jailwala Parthav , Wang Yuedong , Wang Xujing , Ghosh Soumitra , Guo Sun-Wei
Published: September 2005

Endometriosis, defined as the presence of endometrial glandular and stromal cells outside the uterine cavity, is a common gynecological disease with poorly understood pathogenesis. Using laser capture microdissection and a cDNA microarray with 9600 genes/expressed sequence tags (ESTs), we have conducted a comprehensive profiling of gene expression differences between the ectopic and eutopic endometrium taken from 12 women with endometriosis adjusted for menstrual phase and the location of the lesions. With dye-swapping and replicated arrays, we found 904 genes/ESTs that are differentially expressed. We validated the gene expression using real-time RT-PCR. We found that the expression patterns of these genes/ESTs correctly classified the 12 patients into ovarian and nonovarian endometriosis. We identified gene clusters that are location-specific. In addition, we identified several biological themes using Expression Analysis Systematic Explorer. Finally, we identified 79 pathways with over 100 genes with known functions, which include oxidative stress, focal adhesion, Wnt signaling, and MAPK signaling. The identification of these genes and their associated pathways provides new insight. Our findings will stimulate future investigations on molecular genetic mechanisms underlying the pathogenesis of endometriosis.
Rapid Control of Brain Aromatase Activity by Glutamatergic Inputs
Authors: Balthazart Jacques , Baillien Michelle , Ball Gregory F.
Published: September 2005

Estrogens derived from the neural aromatization of testosterone play a key role in the activation of male sexual behavior in many vertebrates and have now been recognized to have rapid membrane effects on brain function. Such changes in aromatase activity and hence in local estrogen concentrations could rapidly modulate behavioral responses. We show here that there is a very rapid (within minutes) decrease in aromatase activity in quail hypothalamic explants exposed to treatments affecting intracellular Ca2+ concentrations, such as the addition of glutamate agonists (kainate, α-amino-3-hydroxymethyl-4-isoxazole propionic acid, and, to a much lesser extent, N-methyl-d-aspartate), but not of γ-aminobutyric acid. The kainate effects, which reduce aromatase activity by 25–50%, are observed within 5 min, are completely blocked in explants exposed to specific kainate antagonists (6-cyano-7-nitroquinoxaline-2,3-dione disodium or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium), and are also rapidly reversible when effectors are washed out. Together, these data support the idea that the synthesis of estrogen can be rapidly regulated in the brain, thus producing rapid changes in local estrogen bioavailability that could rapidly modify brain function with a time course similar to what has previously been described for neurotransmitters and neuromodulators.
LS14: A Novel Human Adipocyte Cell Line that Produces Prolactin
Authors: Hugo Eric R. , Brandebourg Terry D. , Comstock Clay E. S. , Gersin Keith S. , Sussman Jeffrey J. , Ben-Jonathan Nira
Published: September 2005

Adipose tissue is an integral component within the endocrine system. Adipocytes produce numerous bioactive substances, and their dysregulation has serious pathophysiological consequences. We previously reported that human adipose tissue from several depots produces significant amounts of prolactin (PRL). To study locally produced PRL, we sought an acceptable in vitro model. Consequently, we developed an adipocyte cell line derived from a metastatic liposarcoma. The cell line, designated LS14, has been in continuous culture for 2 yr. These cells exhibit many properties of primary preadipocytes, including the ability to undergo terminal differentiation, as judged by morphological alterations, lipid accumulation, and increase in glycerol-3-phosphate dehydrogenase. LS14 cells express many adipose-associated genes, such as adipocyte fatty acid-binding protein (aP2), hormone-sensitive lipase, lipoprotein lipase, preadipocyte factor 1, adiponectin, leptin, and IL-6. Similar to primary adipocytes, LS14 cells also produce and respond to PRL, thus making them an attractive model to study adipose PRL production and function. The expression of PRL was confirmed at the transcriptional level by RT-PCR, and PRL secretion was determined by the Nb2 bioassay. Addition of exogenous PRL to LS14 cells resulted in a dose-dependent inhibition of IL-6 release. In summary, we have established a novel human adipocyte cell line with many characteristics of primary adipocytes. The LS14 cells open up new avenues for research on human adipocyte biology and add to the repertoire of nonpituitary, PRL-producing cell lines.
Differential Requirement of Signal Transducer and Activator of Transcription-4 (Stat4) and Stat6 in a Thyrotropin Receptor-289-Adenovirus-Induced Model of Graves’ Hyperthyroidism
Authors: Land Kimberly J. , Gudapati Prathyusha , Kaplan Mark H. , Seetharamaiah Gattadahalli S.
Published: September 2005

T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4−/− mice, which lack Th1 cells, are susceptible, whereas Stat6−/− mice, which lack Th2 cells, are resistant to the induction of Graves’ hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4−/−, and Stat6−/− mice with an adenovirus expressing amino acid residues 1–289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4−/−, and 39% of Stat6−/− mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4−/− mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6−/− mice. BALB/c and Stat4−/− mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6−/− mice. In contrast, Stat6−/− mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-γ than BALB/c and Stat4−/− mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves’ hyperthyroidism.
Insulin-Like Growth Factor-I Signaling in Smooth Muscle Cells Is Regulated by Ligand Binding to the 177CYDMKTTC184 Sequence of the β3-Subunit of αVβ3
Authors: Maile Laura A. , Busby Walker H. , Sitko Kevin , Capps Byron E. , Sergent Tiffany , Badley-Clarke Jane , Clemmons David R.
Published: September 2005

The response of smooth muscle cells to IGF-I requires ligand occupancy of the αVβ3 integrin. We have shown that vitronectin (Vn) is required for IGF-I-stimulated migration or proliferation, whereas the anti-αVβ3 monoclonal antibody, LM609, which inhibits ligand binding, blocks responsiveness of these cells to IGF-I. The amino acids 177–184 (177CYDMKTTC184) within the extracellular domain of β3 have been proposed to confer the ligand specificity of αVβ3; therefore, we hypothesized that ligand binding to the 177–184 cysteine loop of β3 may be an important regulator of the cross talk between αVβ3 and IGF-I in SMCs. Here we demonstrate that blocking ligand binding to a specific amino acid sequence within the β3 subunit of αVβ3 (i.e. amino acids 177–184) blocked Vn binding to the β3 subunit of αVβ3 and correspondingly β3 phosphorylation was decreased. In the presence of this antibody, IGF-I-stimulated Shc phosphorylation and ERK 1/2 activation were impaired, and this was associated with an inhibition in the ability of IGF-I to stimulate an increase in migration or proliferation. Furthermore, in cells expressing a mutated form of β3 in which three critical residues within the 177–184 sequence were altered β3 phosphorylation was decreased. This was associated with a loss of IGF-I-stimulated Shc phosphorylation and impaired smooth muscle cell proliferation in response to IGF-I. In conclusion, we have demonstrated that the 177–184 sequence of β3 is necessary for Vn binding to αVβ3 and that ligand occupancy of this site is necessary for an optimal response of smooth muscle cells to IGF-I.
The Evolution of Mineralocorticoid Receptors
Authors: Hu Xiao , Funder John W.
Published: September 2005

When the human mineralocorticoid receptor (hMR) was cloned and sequenced by the Evans laboratory, its close homology with the human glucocorticoid receptor (hGR) was noted; subsequently, on the basis of its higher sequence similarity to the GR than to the progesterone receptor (PR) or androgen receptor (AR), MR and GR have commonly been considered to share an immediate common ancestral “corticoid receptor.” When, however, homology is determined for the full-length receptor, or helices 3/4/5/12, MR is least like any of the other three receptors; for the ligand binding domain, AR is clearly the least homologous. When relative binding and activation capacity of a broad panel of LXXLL cofactor peptides are compared by mammalian two-hybrid assay, GR and PR show a highly similar profile, interacting with many of the 39 peptides, with MR and AR binding very few, supporting a close functional homology between PR and GR. In addition, recent studies by He et al. on FXXLF binding by GR and PR mutants suggest that these two receptors may be closer to AR than to MR. The sequence and transcriptional activity of the S810L mutant reported by Geller et al. can be interpreted as supporting MR as being closer than GR/PR/AR to estrogen receptor/retinoid X receptor, and thus potentially the first rather than the last branch from a common MR/GR/PR/AR ancestor. On the basis of these studies together, we propose reconsideration of the evolutionary tree for the MR/GR/PR/AR subfamily, with MR closest to the primordial ancestral receptor, GR/PR sharing a common immediate ancestor, and a higher degree of evolutionary drift in the AR ligand binding domain to accommodate C19 rather than C21 steroids as physiological ligands.
Connect the dots: how many random points can a regular curve pass through?
Authors: Arias-Castro Ery , Donoho David L. , Huo Xiaoming , Tovey Craig A.
Published: September 2005

Given a class Γ of curves in [0, 1]2, we ask: in a cloud of n uniform random points, how many points can lie on some curve γ ∈ Γ? Classes studied here include curves of length less than or equal to L, Lipschitz graphs, monotone graphs, twice-differentiable curves, and graphs of smooth functions with m-bounded derivatives. We find, for example, that there are twice-differentiable curves containing as many as OP(n1/3) uniform random points, but not essentially more than this. More generally, we consider point clouds in higher-dimensional cubes [0, 1]d and regular hypersurfaces of specified codimension, finding, for example, that twice-differentiable k-dimensional hypersurfaces in Rd may contain as many as OP(nk/(2d-k)) uniform random points. We also consider other notions of ‘incidence’, such as curves passing through given location/direction pairs, and find, for example, that twice-differentiable curves in R2 may pass through at most OP(n1/4) uniform random location/direction pairs. Idealized applications in image processing and perceptual psychophysics are described and several open mathematical questions are identified for the attention of the probability community.
Descending chains, the lilypond model, and mutual-nearest-neighbour matching
Authors: Daley Daryl J. , Last Günter
Published: September 2005

We consider a hard-sphere model in ℝd generated by a stationary point process N and the lilypond growth protocol: at time 0, every point of N starts growing with unit speed in all directions to form a system of balls in which any particular ball ceases its growth at the instant that it collides with another ball. Some quite general conditions are given, under which it is shown that the model is well defined and exhibits no percolation. The absence of percolation is attributable to the fact that, under our assumptions, there can be no descending chains in N. The proof of this fact forms a significant part of the paper. It is also shown that, in the absence of descending chains, mutual-nearest-neighbour matching can be used to construct a bijective point map as defined by Thorisson.
Perfect simulation of Hawkes processes
Authors: Møller Jesper , Rasmussen Jakob G.
Published: September 2005

Our objective is to construct a perfect simulation algorithm for unmarked and marked Hawkes processes. The usual straightforward simulation algorithm suffers from edge effects, whereas our perfect simulation algorithm does not. By viewing Hawkes processes as Poisson cluster processes and using their branching and conditional independence structures, useful approximations of the distribution function for the length of a cluster are derived. This is used to construct upper and lower processes for the perfect simulation algorithm. A tail-lightness condition turns out to be of importance for the applicability of the perfect simulation algorithm. Examples of applications and empirical results are presented.
Minimal clade size and external branch length under the neutral coalescent
Authors: Blum Michael G. B. , François Olivier
Published: September 2005

Given a sample of genes taken from a large population, we consider the neutral coalescent genealogy and study the theoretical and empirical distributions of the size of the smallest clade containing a fixed gene. We show that the theoretical distribution is strongly related to a Yule distribution of parameter 2, and that the empirical count statistics are asymptotically Gaussian as the number of genes grows to infinity. Then we consider external branches of the coalescent tree, and describe their lengths. Using the infinitely many sites model of mutation, we also describe the conditional distribution of the external branch lengths, given the number of pairwise differences between a reference DNA sequence and the sequence of one closest relative in the sample.
Diffusion approximations for the maximum of a perturbed random walk
Authors: Araman Victor F. , Glynn Peter W.
Published: September 2005

Consider a random walk S=(Sn: n≥0) that is ‘perturbed’ by a stationary sequence (ξn: n≥0) to produce the process S=(Sn+ξn: n≥0). In this paper, we are concerned with developing limit theorems and approximations for the distribution of Mn=max{Sk+ξk: 0≤k≤n} when the random walk has a drift close to 0. Such maxima are of interest in several modeling contexts, including operations management and insurance risk theory. The associated limits combine features of both conventional diffusion approximations for random walks and extreme-value limit theory.
Convergence results on multitype, multivariate branching random walks
Authors: Biggins J. D. , Rahimzadeh Sani A.
Published: September 2005

We consider a multi-type branching random walk ond-dimensional Euclidian space. The~uniform convergence, asngoes to infinity, of a scaled version of the Laplace transform of the point process given by thenth generation particles of each type is obtained. Similar results in the one-type case, where the transform gives a martingale, were obtained in Biggins (1992) and Barral (2001). This uniform convergence of transforms is then used to obtain limit results for numbers in the underlying point processes. Supporting results, which are of interest in their own right, are obtained on (i) ‘Perron-Frobenius theory’ for matrices that are smooth functions of a variableλ∈Land are nonnegative whenλ∈L−⊂L, whereLis an open set in ℂd, and (ii) saddlepoint approximations of multivariate distributions. The saddlepoint approximations developed are strong enough to give a refined large deviation theorem of Chaganty and Sethuraman (1993) as a by-product.
Spatio-temporal variograms and covariance models
Authors: Ma Chunsheng
Published: September 2005

Variograms and covariance functions are the fundamental tools for modeling dependent data observed over time, space, or space-time. This paper aims at constructing nonseparable spatio-temporal variograms and covariance models. Special attention is paid to an intrinsically stationary spatio-temporal random field whose covariance function is of Schoenberg-Lévy type. The correlation structure is studied for its increment process and for its partial derivative with respect to the time lag, as well as for the superposition over time of a stationary spatio-temporal random field. As another approach, we investigate the permissibility of the linear combination of certain separable spatio-temporal covariance functions to be a valid covariance, and obtain a subclass of stationary spatio-temporal models isotropic in space.
Power estimates for ruin probabilities
Authors: Nyrhinen Harri
Published: September 2005

Let X1, X2,… be real-valued random variables. For u>0, define the time of ruin T = T(u) by T = inf{n: X1+⋯+Xn>u} or T=∞ if X1+⋯+Xn≤u for every n = 1,2,…. We are interested in the ruin probabilities of general processes {Xn} for large u. In the presence of heavy tails, one often finds power estimates. Our objective is to specify the associated powers and provide the crude estimate P(T≤xu)≈u−R(x) for large u, for a given x∈ℝ. The rate R(x) will be described by means of tails of partial sums and maxima of {Xn}. We also extend our results to the case of the infinite time horizon.
Maxima of stochastic processes driven by fractional Brownian motion
Authors: Buchmann Boris , Klüppelberg Claudia
Published: September 2005

We study stationary processes given as solutions to stochastic differential equations driven by fractional Brownian motion. This rich class includes the fractional Ornstein-Uhlenbeck process and those processes that can be obtained from it by state space transformations. An explicit formula in terms of Euler's Γ-function describes the asymptotic behaviour of the covariance function of the fractional Ornstein-Uhlenbeck process near zero, which, by an application of Berman's condition, guarantees that this process is in the maximum domain of attraction of the Gumbel distribution. Necessary and sufficient conditions on the state space transforms are stated to classify the maximum domain of attraction of solutions to stochastic differential equations driven by fractional Brownian motion.
Central limit theorems for the number of records in discrete models
Authors: Gouet Raul , López F. Javier , Sanz Gerardo
Published: September 2005

Consider a sequence (Xn) of independent and identically distributed random variables taking nonnegative integer values, and call Xn a record if Xn> max{X1,…,Xn−1}. By means of martingale arguments it is shown that the counting process of records among the first n observations, suitably centered and scaled, is asymptotically normally distributed.