bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal Bipolar Cell Input Mechanisms in Giant Danio. III. on-off Bipolar Cells and Their Color-Opponent Mechanisms
Authors: Wong Kwoon Y. , Dowling John E.
Published: March 2005

Whole cell patch recording was performed from morphologically identified cone-driven on-off bipolar cells (Cabs) in giant danio retinal slices to study their glutamate receptors and light-evoked responses. Specific agonists were puffed in the presence of cobalt, picrotoxin, and strychnine to identify glutamate receptors on these cells. Most Cabs responded to both the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor agonist kainate and the excitatory amino acid transporter (EAAT) substrate d-aspartate, and both responses were localized to the dendrites. Kainate generated depolarizations whereas d-aspartate had Erev close to ECl and generated hyperpolarizations, indicating that the AMPA/kainate receptors are sign-preserving, whereas the EAATs are sign-inverting. In response to white light, some Cabs gave on bipolar cell-like responses whereas others gave off bipolar cell-like ones, but many cells' responses had both on and off bipolar cell components. In response to appropriately colored center-selective stimuli, many Cabs responded to short and long wavelengths with opposite polarities and were thus double color-opponent. The depolarizing components of the responses to white or colored stimuli were suppressed by the EAAT blocker dl- threo-β-benzyloxyaspartate (TBOA), whereas the hyperpolarizing components were reduced by the AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). These results are consistent with the hypothesis that both EAATs and AMPA/kainate receptors are involved in the generation of light-evoked responses in Cabs and that they confer these cells with on and off bipolar cell properties, respectively. Cabs can generate double color-opponent center responses by receiving inputs from certain cones through EAATs and from other cones through AMPA/kainate receptors.
Cortical Maps of Separable Tuning Properties Predict Population Responses to Complex Visual Stimuli
Authors: Baker Tanya I. , Issa Naoum P.
Published: March 2005

In the earliest cortical stages of visual processing, a scene is represented in different functional domains selective for specific features. Maps of orientation and spatial frequency preference have been described in the primary visual cortex using simple sinusoidal grating stimuli. However, recent imaging experiments suggest that the maps of these two spatial parameters are not sufficient to describe patterns of activity in different orientation domains generated in response to complex, moving stimuli. A model of cortical organization is presented in which cortical temporal frequency tuning is superimposed on the maps of orientation and spatial frequency tuning. The maps of these three tuning properties are sufficient to describe the activity in orientation domains that have been measured in response to drifting complex images. The model also makes specific predictions about how moving images are represented in different spatial frequency domains. These results suggest that the tangential organization of primary visual cortex can be described by a set of maps of separable neuronal receptive field features including maps of orientation, spatial frequency, and temporal frequency tuning properties.
Adaptation at Synaptic Connections to Layer 2/3 Pyramidal Cells in Rat Visual Cortex
Authors: Beck Oliver , Chistiakova Marina , Obermayer Klaus , Volgushev Maxim
Published: March 2005

Neocortical synapses express differential dynamic properties. When activated at high frequencies, the amplitudes of the subsequent postsynaptic responses may increase or decrease, depending on the stimulation frequency and on the properties of that particular synapse. Changes in the synaptic dynamics can dramatically affect the communication between nerve cells. Motivated by this question, we studied dynamic properties at synapses to layer 2/3 pyramidal cells with intracellular recordings in slices of rat visual cortex. Synaptic responses were evoked by trains of test stimuli, which consisted of 10 pulses at different frequencies (5–40 Hz). Test stimulation was applied either without any adaptation (control) or 2 s after an adaptation stimulus, which consisted of 4 s stimulation of these same synapses at 10, 25, or 40 Hz. The synaptic parameters were then assessed from fitting the data with a model of synaptic dynamics. Our estimates of the synaptic parameters in control, without adaptation are broadly consistent with previous studies. Adaptation led to pronounced changes of synaptic transmission. After adaptation, the amplitude of the response to the first pulse in the test train decreased for several seconds and then recovered back to the control level with a time constant of 2–18 s. Analysis of the data with extended models, which include interaction between different pools of synaptic vesicles, suggests that the decrease of the response amplitude was due to a synergistic action of two factors, decrease of the release probability and depletion of the available transmitter. After a weak (10 Hz) adaptation, the decrease of the response amplitude was accompanied by and correlated with the decrease of the release probability. After a strong adaptation (25 or 40 Hz), the depletion of synaptic resources was the main cause for the reduced response amplitude. Adaptation also led to pronounced changes of the time constants of facilitation and recovery, however, these changes were not uniform in all synapses, and on the population level, the only consistent and significant effect was an acceleration of the recovery after a strong adaptation. Taken together, our results suggest, that apart from decreasing the amplitude of postsynaptic responses, adaptation may produce synapse-specific effects, which could result in a kind of re-distribution of activity within neural networks.
An Alternative Explanation for the Failure of the UNCED Forest Negotiations
Authors: Davenport Deborah S.
Published: March 2005

Scholars have offered numerous explanations for success stories such as the ozone regime but have paid little attention to failed cases, such as the failure to attain agreement on a global forest convention in 1992. Discussions of this case frequently attribute the failure to a prioritization of sovereignty above all other interests on the part of Malaysia and other developing countries. I offer an alternative explanation, based on interview data and documents and reports from the era. Although the US was the first state to propose a global forest convention in 1990 and remained the lead state in negotiations, the benefits of a global forest treaty at the domestic level did not outweigh the potential costs to the US of manipulating the preferences of the anti-convention coalition towards favoring agreement. Use of counter-factual scenarios demonstrates that it was this rather than sovereignty issues that precluded a forest treaty.
A Herd Mentality in the Design of International Environmental Agreements?
Authors: Victor David G. , Coben Lesley A.
Published: March 2005

When addressing an externality such as air pollution, regulators can control policy inputs (e.g., pollution taxes and technology standards) or outputs (e.g., emission caps). Economists are familiar with this debate, known broadly as “prices vs. quantities,” but analysts of international environmental agreements have rarely focused sustained attention to such questions. Using an inventory of all international air pollution agreements, we document the historical patterns in instrument choice. Those agreements that require little effort beyond the status quo are usually codified in terms of effort, but agreements that require substantial actions by the parties nearly always deploy a cap on emission quantities as the central regulatory instrument. We suggest that this concentration of experience with emission caps and paucity of serious efforts to coordinate policy inputs may explain why the architects of international environmental agreements appear to believe that emission caps work best. We illustrate what's at stake with the example of international efforts to control the emissions that cause global climate change. We also show that the conventional history of the agreement that is most symbolic of the superiority of emission caps—the Montreal Protocol on Substances that Deplete the Ozone Layer—has wrongly overlooked a little-known provision that operates akin to a “price” instrument.
Utilization and accessibility of social services for Chinese Canadians
Authors: Ma Ambrose , Chi Iris
Published: March 2005

English

The findings show that the awareness of service agencies and opinions on the services provided are predictors of Chinese Canadians’ service utilization, and that one-third of Chinese Canadians have not used any social services, for various reasons. When planning services for an ethnic minority group like Chinese Canadians, planners should consider socio-cultural and structural factors alike.

French

Les résultats de cette étude démontrent que l’utilisation des services sociaux est liée à la connaissance et aux opinions des canadiens d'origine chinoise de ces mêmes services. Un tiers des canadiens d’origine chinoise n’ont pas eu recours aux services sociaux, pour plusieurs raisons. Des facteurs structurels et culturels devraient être pris en considération lors de la planification des services sociaux.

Spanish

Los resultados muestran que el conocimiento y la opinión sobre las agencias de servicios sociales predicen su utilización por los canadienses de origen chino. También que un tercio de estos ciudadanos, debido a varias razones, no han usado ningún servicio social. En la planificación de servicios para grupos étnicos minoritarios tales como el de los canadienses de origen chino, se han de considerar tanto los factores socioculturales como los estructurales.
Ukrainian women in the new economy
Authors: Yegidis Bonnie L. , Robinson Margaret M. , Toyt-Korshinska Marianna , Havyryluk Nadiya O. , Westbrook Tonya W.
Published: March 2005

English

Ukraine has been independent since 1991. This study explored through a qualitative methodology how Ukrainian women perceived their lives had changed in the 1990s. It was found that women believed their families were barely able to subsist. They also believed that their lives were better under Soviet rule.

French

L’Ukraine a gagné son indépendance depuis 1991. Cette étude exploratoire menée avec une méthodologie qualitative, a exploré comment les femmes ukrainiennes perµoivent leurs changements de vie au cours de la décennie. On constate que les femmes croient que leurs familles subsistent à peine de 1990. Elles croient également que leurs vies étaient meilleures durant les années du régime soviétique.

Spanish

Ucrania es independiente desde 1991. Este estudio exploró, a través de la metodología cualitativa, como perciben las mujeres ucranianas que sus vidas han cambiado en la última década. Se encontró que las mujeres creen que sus familias son ahora capaces apenas de subsistir. También creen que su vida era mejor bajo las reglas soviéticas.
Signs of Americanization in Italian Domestic Life: Italy’s Postwar Conversion to Consumerism
Authors: Scrivano Paolo
Published: March 2005

Americanization is usually considered the major factor in Italy’s social and economic transformation after the second world war, so much so that the influence of the USA has long been taken for granted. However, this assumption is based upon a misleading account of the relationship between the two countries. A multifaceted process characterized by contradictory meanings, Americanization took various forms and developed in different ways. Indeed, it is difficult to estimate the extent to which American models were adopted: closer analysis reveals that such influences were subject to repeated misinterpretation, negotiation and even resistance. Initially reluctant to follow American examples, Italian society soon demonstrated an unusual capacity for remaking and hybridizing imported transatlantic models. Nowhere was this more evident than in the domestic sphere which served as a central target of the broader cultural campaign to start afresh after 1945.
Philosophy, Theory and Method in Social Work
Authors: Houston Stanley
Published: March 2005

• Summary: For quite some time the evidence-based practice discourse in social work has been influential. While this may be viewed as a positive development, problems arise when some of the proponents of the discourse deride other approaches in social work as unscientific. In particular, it is of concern that those who embrace a psychodynamic perspective have been corralled into a ‘mentalist’ enclosure which, it is argued, lacks scientific rigour. By way of rebuttal, this paper argues that approaches promoting an understanding of ‘deep structure’ have a legitimate place within the evidence-based discourse in social work. Bhaskar’s critical realism is adopted to make the case.

• Findings: The retroductive method, as articulated by Bhaskar, can be extrapolated to social workers’ assessments of complex situations. This method provides a way of generating and testing hypotheses and evidence by drawing on realist, explanatory theories to gain understanding of the deep, causal mechanisms at play in social life.

• Applications: This paper makes a contribution to the continuing discussion about the nature of evidence, and how it is acquired, in social work. Critically, it argues that the pursuit of evidence is central not only to the intimate, micro-domain of face-to-face interaction but also to the macro-domain of oppressive social structure.
Educational Leadership as a Causal Factor
Authors: Levačić Rosalind
Published: March 2005

There has been an increasing emphasis in educational policies, practices and professional development on the capacity of educational leadership to exert a causal impact on student cognitive and non-cognitive outcomes. If the strict criteria of counterfactual causality are adhered to no causal inference could be made about the effects of leadership, given that experimental research designs are inappropriate. Statistical studies of leadership ‘effects’ need to operationalize the concept of leadership and use data from natural settings. They are unable reliably to disentangle associational from counterfactual causal relationships. Given this dilemma, the article argues for using less purist criteria for causal inference but making this methodological approach explicit. Relationships observed in both quantitative and qualitative data can be interpreted only through insights derived from theoretical and conceptual knowledge of the area of inquiry. Causal social explanation (as distinct from counterfactual causality) provides a justification for ‘mixed methods’ to build a more secure empirical basis for knowledge about the effects of leadership.
Methodological Issues Related to Causal Studies of Leadership
Authors: Teddlie Charles
Published: March 2005

This article explores different understandings of causality and their implications for the study of educational leadership. The article first details differences among three broad methodological traditions in educational research (the quantitative, qualitative, and mixed methods approaches), especially with regard to causal explanations. This is followed by a presentation of different methodological approaches for assessing the impact of educational leadership on school outcomes, drawing specifically from school effectiveness research. Five propositions regarding causality issues in studies of educational leadership are presented and then assessed. The article concludes with a brief description of specific educational leadership research studies that were guided by the pragmatic, mixed methods approach advocated throughout this text.
Presbyteral Ministry in the Roman Catholic Church
Authors: McPartlan Paul
Published: March 2005

This paper considers the teaching of Vatican II on the presbyterate in relation to the episcopate, against the background of the history of these ministries. The Council used Ignatius of Antioch and the Apostolic Tradition in its renewed teaching that presbyters form a college in union with the bishop, who is high priest of his local church. Since the fourth century, however, presbyters have been dispersed to act as individual parish priests. Tensions between this model and the earlier one are explored, as is the liturgical and theological renewal that led to Vatican II’s teaching. It is finally proposed that the Council offers valuable resources, not yet fully realized, for pastoral planning in a time of priestly shortage.
Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with Pbx and a novel function of the Meis1 C-terminus
Authors: Wang Gang G. , Pasillas Martina P. , Kamps Mark P.
Published: March 2005

Meis1 is a homeodomain transcription factor coexpressed with Hoxa9 in most human acute myeloid leukemias (AMLs). In mouse models of leukemia produced by Hoxa9, Meis1 accelerates leukemogenesis. Because Hoxa9 immortalizes myeloid progenitors in the absence of Meis1 expression, the contribution of Meis1 toward leukemia remains unclear. Here, we describe a cultured progenitor model in which Meis1 programs leukemogenicity. Progenitors immortalized by Hoxa9 in culture are myeloid-lineage restricted and only infrequently caused leukemia after more than 250 days. Coexpressed Meis1 programmed rapid AML-initiating character, maintained multipotent progenitor potential, and induced expression of genes associated with short-term hematopoietic stem cells (HSCs), such as FLT3 and CD34, whose expression also characterizes the leukemia-initiating stem cells of human AML. Meis1 leukemogenesis functions required binding to Pbx, binding to DNA, and a conserved function of its C-terminal tail. We hypothesize that Meis1 is required for the homing and survival of leukemic progenitors within their hematopoietic niches, functions mediated by HSC-specific genes such as CD34 and Fms-like tyrosine kinase 3 (FLT3), respectively. This is the first example of a transcription factor oncoprotein (Meis1) that establishes expression of a tyrosine kinase oncoprotein (FLT3), and explains their coexpression in human leukemia. This cultured progenitor model will be useful to define the genetic basis of leukemogenesis involving Hoxa9 and Meis1.
NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia
Authors: Lin Ying-Wei , Slape Christopher , Zhang Zhenhua , Aplan Peter D.
Published: March 2005

The myelodysplastic syndromes (MDSs) are a group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis and dysplasia. A wide spectrum of genetic aberrations has been associated with MDS, including chromosomal translocations involving the NUP98 gene. Using a NUP98-HOXD13 fusion gene, we have developed a mouse model that faithfully recapitulates all of the key features of MDS, including peripheral blood cytopenias, bone marrow dysplasia, and apoptosis, and transformation to acute leukemia. The MDS that develops in NUP98-HOXD13 transgenic mice is uniformly fatal. Within 14 months, all of the mice died of either leukemic transformation or severe anemia and leucopenia as a result of progressive MDS. The NUP98-HOXD13 fusion gene inhibits megakaryocytic differentiation and increases apoptosis in the bone marrow, suggesting a mechanism leading to ineffective hematopoiesis in the presence of a hypercellular bone marrow. These mice provide an accurate preclinical model that can be used for the evaluation of MDS therapy and biology.
A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis
Authors: Voskoboinik Ilia , Thia Marie-Claude , Trapani Joseph A.
Published: March 2005

Up to 60% of cases of the autosomal recessive immunodeficiency hemophagocytic lymphohistiocytosis (HLH) are associated with mutations in the perforin (PRF1) gene. In this study, we expressed wild-type and mutated perforin in rat basophil leukemia cells to study the effect on lytic function of the substitutions A91V and N252S (commonly considered to be neutral polymorphisms) and 22 perforin missense substitutions first identified in HLH patients. Surprisingly, we found that A91V perforin was expressed at reduced levels compared with wild-type perforin, resulting in partial loss of lytic capacity. In contrast, expression and function of N252S-substituted perforin were normal. Most HLH-associated mutations resulted in protein degradation (probably due to misfolding) and complete loss of perforin activity, the exception being R232H, which retained approximately 30% wild-type activity. Several other mutated proteins (H222Q, C73R, F157V, and D313V) had no detectable lytic activity but were expressed at normal levels, suggesting that their functional defect might map downstream at the level of the target cell membrane. One further perforin substitution identified in an HLH patient (V183G) was normally expressed and displayed normal lysis. This report represents the first systematic functional analysis of HLH-associated missense mutations and the 2 most common perforin polymorphisms. (Blood. 2005;105:4700-4706)
Interrupted or continuous slowly absorbable sutures – Design of a multi-centre randomised trial to evaluate abdominal closure techniques INSECT-Trial [ISRCTN24023541]
Authors: Knaebel Hanns-Peter , Koch Moritz , Sauerland Stefan , Diener Markus K , Büchler Markus W , Seiler Christoph M ,   the INSECT Study Group of the Study Centre of the German Surgical Society (SDGC)
Published: March 2005

Background

The closure of the abdomen after median laparotomy is still a matter of debate among surgeons. Further well designed and performed randomised controlled trials determining the optimal method of abdominal fascial closure are needed.

Design

This is a three armed, multi-centre, intra-operatively randomised, controlled, patient blinded trial. Over 20 surgical departments will enrol 600 patients who are planned for an elective primary abdominal operation. The objective of this study is to compare the frequency of abdominal incisional hernias between two continuous suture techniques with different, slowly absorbable monofilament materials and an interrupted suture using an absorbable braided suture material at one year postoperatively.

Conclusion

This trial will answer the question whether the continuous abdominal wall closure with a slowly absorbable material with longitudinal elasticity is superior to the continuous suture with a material lacking elasticity and to interrupted sutures with braided thread.
Activation of p53, inhibition of telomerase activity and induction of estrogen receptor beta are associated with the anti-growth effects of combination of ovarian hormones and retinoids in immortalized human mammary epithelial cells
Authors: Zhang Jiahui , Tu Yifan , Smith-Schneider Sallie
Published: March 2005

Background

A full-term pregnancy has been associated with reduced risk for developing breast cancer. In rodent models, the protective effect of pregnancy can be mimicked with a defined regimen of estrogen and progesterone combination (E/P). However, the effects of pregnancy levels of E/P in humans and their underlying mechanisms are not fully understood. In this report, we investigated the growth inhibitory effects of pregnancy levels of E/P and both natural and synthetic retinoids in an immortalized human mammary epithelial cell line, 76N TERT cell line.

Results

We observed that cell growth was modestly inhibited by E/P, 9-cis-retinoic acid (9-cis RA) or all-trans-retinoic acid (ATRA), and strongly inhibited by N-(4-hydroxyphenyl) retinamide (HPR). The growth inhibitory effects of retinoids were further increased in the presence of E/P, suggesting their effects are additive. In addition, our results showed that both E/P and retinoid treatments resulted in increasedRAREandp53gene activity. We further demonstrated that p53 and p21 protein expression were induced following the E/P and retinoid treatments. Furthermore, we demonstrated that while the telomerase activity was moderately inhibited by E/P, 9-cis RA and ATRA, it was almost completely abolished by HPR treatment. These inhibitions on telomerase activity by retinoids were potentiated by co-treatment with E/P, and correlated well with their observed growth inhibitory effects. Finally, this study provides the first evidence that estrogen receptor beta is up-regulated in response to E/P and retinoid treatments.

Conclusion

Taken together, our studies show that part of the anti-growth effects of E/P and retinoids is p53 dependent, and involve activation ofp53and subsequent induction of p21 expression. Inhibition of telomerase activity and up-regulation of estrogen receptor beta are also associated with the E/P- and retinoid-mediated growth inhibition. Our studies also demonstrate that the potency of retinoids on cell growth inhibition may be increased through combination of estrogen and progesterone treatment.
Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID): Frequently asked questions
Authors: Emery Marie-Pierre , Perrier Laure-Lou , Acquadro Catherine
Published: March 2005

The exponential development of Patient-Reported Outcomes (PRO) measures in clinical research has led to the creation of the Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID) to facilitate the selection process of PRO measures in clinical research. The project was initiated by Mapi Research Trust in Lyon, France. Initially called QOLID (Quality of Life Instruments Database), the project's purpose was to provide all those involved in health care evaluation with a comprehensive and unique source of information on PRO and HRQOL measures available through the Internet.

PROQOLID currently describes more than 470 PRO instruments in a structured format. It is available in two levels, non-subscribers and subscribers, at http://www.proqolid.org. The first level is free of charge and contains 14 categories of basic useful information on the instruments (e.g. author, objective, original language, list of existing translations, etc.). The second level provides significantly more information about the instruments. It includes review copies of over 350 original instruments, 120 user manuals and 350 translations. Most are available in PDF format. This level is only accessible to annual subscribers. PROQOLID is updated in close collaboration with the instruments' authors on a regular basis. Fifty or more new instruments are added to the database annually.

Today, all of the major pharmaceutical companies, prestigious institutions (such as the FDA, the NIH's National Cancer Institute, the U.S. Veterans Administration), dozens of universities, public institutions and researchers subscribe to PROQOLID on a yearly basis. More than 800 users per day routinely visit the database.
Assessing the capacity of the health services research community in Australia and New Zealand
Authors: Pirkis Jane , Goldfeld Sharon , Peacock Stuart , Dodson Sarity , Haas Marion , Cumming Jackie , Hall Jane , Boulton Amohia
Published: March 2005

Background

In order to profile the health services research community in Australia and New Zealand and describe its capacity, a web-based survey was administered to members of the Health Services Research Association of Australia and New Zealand (HSRAANZ) and delegates of the HSRAANZ's Third Health Services Research and Policy Conference.

Results

Responses were received from 191 individuals (68%). The responses of the 165 (86%) who conducted or managed health services research indicated that the health services research community in Australia and New Zealand is characterised by highly qualified professionals who have come to health services research via a range of academic and professional routes (including clinical backgrounds), the majority of whom are women aged between 35 and 54 who have mid- to senior- level appointments. They are primarily employed in universities and, to a lesser extent, government departments and health services. Although most are employed in full time positions, many are only able to devote part of their time to health services research, often juggling this with other professional roles. They rely heavily on external funding, as only half have core funding from their employing institution and around one third have employment contracts of one year or less. Many view issues around building the capacity of the health services research community and addressing funding deficits as crucial if health services research is to be translated into policy and practice. Despite the difficulties they face, most are positive about the support and advice available from peers in their work settings, and many are actively contributing to knowledge through academic and other written outputs.

Conclusion

If health services research is to achieve its potential in Australia and New Zealand, policy-makers and funders must take the concerns of the health services research community seriously, foster its development, and contribute to maximising its capacity through a sustainable approach to funding. There is a clear need for a strategic approach, where the health services research community collaborates with competitive granting bodies and government departments to define and fund a research agenda that balances priority-driven and investigator-driven research and which provides support for training and career development.
Jessner-Kanof lymphocytic infiltration of the skin associated with glatiramer acetate
Authors: Nolden S , Casper C , Kuhn A , Petereit H F
Published: March 2005

Glatiramer acetate (GLAT) is a well tolerated and safe immunomodulatory drug for the treatment of relapsing=remitting multiple sclerosis. The most commonly recognized side effects are localized injection site reactions consisting of pain, pruritus, mild erythema and induration, which sometimes persist for several days. We describe the first case of a biopsy-proven lymphocytic infiltration (T-cell pseudolymphoma) with the clinical appearance of a figured erythema on the ventrolateral thighs in the first four weeks under GLAT treatment, resolving without any evidence of recurrence despite ongoing therapy. A T-cell pseudolymphoma is a very rare side effect of GLAT treatment. For clinical purposes it is important to state that re-exposition after GLAT-induced pseudolymphoma is possible without permanent sequelae.
Depression and fatigue in relapsing-remitting MS: the role of symptomatic variability
Authors: Randolph John J , Arnett Peter A
Published: March 2005

Depression and fatigue are common psychosocial sequelae of MS. An infrequently examined issue in the MS literature is the effect of MS-related symptom variability on incidence of depression and fatigue. The current study was designed to examine the relationship of variability in physical, cognitive, and social/environmental functioning with depression and fatigue in MS. Forty-eight relapsing-remitting MS patients from a larger sample completed self-report measures of depression and fatigue. They were also administered a structured interview that assessed current, best, and worst levels of functioning since being diagnosed with MS. Higher levels of symptom variability since disease onset were associated with depression and fatigue, even after accounting for MS-related physical disability. Regression analyses indicated that variability in social and environmental functioning was particularly associated with depression, and variability in physical abilities was associated with fatigue. These findings suggest that a more variable course of MS symptoms is associated with increased depression and fatigue. Focused assessment of variability in symptoms may be useful in detecting and subsequently treating depression and fatigue in MS patients.
Optimization of the safety and efficacy of interferon beta 1b and azathioprine combination therapy in multiple sclerosis
Authors: Pulicken M , Bash C N , Costello K , Said A , Cuffari C , Wilterdink J L , Rogg J M , Mills P , Calabresi P A
Published: March 2005

We conducted an open-label pilot clinical trial to evaluate the safety and efficacy of adding oral azathioprine to the treatment regimen of 15 multiple sclerosis patients breaking through monotherapy with interferon β-1b. There were no serious adverse events. Gastrointestinal side effects and leukopenia were the most common adverse events and limited dose escalation. There was a 65% reduction in the number of gadolinium-enhanced magnetic resonance imaging (MRI) lesions on combination therapy compared to the baseline values (P=0.003). A total WBC count less than 4800/mm3 was the best predictor of MRI response.
Tumefactive demyelinating lesions: conventional and advanced magnetic resonance imaging
Authors: Enzinger Christian , Strasser-Fuchs Siegrid , Ropele Stefan , Kapeller Peter , Kleinert Reinhold , Fazekas Franz
Published: March 2005

In rare instances, demyelinating disorders present with radiological features that mimic a brain tumour. This often leads to biopsy, which-apart from carrying significant morbidity-frequently turns out as nondiagnostic or dispensable. We therefore set out to assess the contribution of repeated conventional magnetic resonance imaging (MRI), 1H-MR spectroscopy and magnetization transfer imaging in establishing a correct diagnosis of tumefactive demyelinating lesions (TDLs). We studied two females and one male, who presented with TDLs that led to brain biopsy in two cases, for up to three years. TDLs were characterized by the following features: (a) delayed or absent response to high-dose steroids together with progressive lesion growth over several weeks; (b) late or sparse enhancement, ill-defined borders, signal inhomogeneity and considerable concomitant oedema; and (c) normalization of initial increases in lipid and lactate peaks within three to four weeks, followed by persistent, marked reductions of the neuronal marker NAA and MTR values around or below 30%. These imaging characteristics reflected the histological correlate of marked demyelination in the absence of significant inflammation. MRI techniques thus appear to have the potential to establish a correct diagnosis of this subtype of TDLs. Awareness of these possibilities might obviate the need for biopsy at least in some cases in future.
Recombinant Cell Ultrasensitive Bioassay for Measurement of Estrogens in Postmenopausal Women
Authors: Wang Shuping , Paris Francoise , Sultan Charles S. , Song Robert X.-D. , Demers Laurence M. , Sundaram Bhaskar , Settlage James , Ohorodnik Susan , Santen Richard J.
Published: March 2005

A recent analysis of data from nine studies provided convincing evidence that plasma estradiol measurements predict the risk of breast cancer in normal postmenopausal women. However, the median values detected by the various assays used in this study varied by 5-fold. These and other published data in normal postmenopausal women suggest that assays measuring low plasma estradiol concentrations suffer from problems of sensitivity, specificity, and precision. Availability of a practical, low-cost, specific, precise, and ultrasensitive estrogen assay might allow enhanced prediction of the risk of breast cancer and provide an objective means of selecting postmenopausal women for breast cancer prevention. A recombinant cell ultrasensitive bioassay (RCUB) for estrogen was recently validated for use in prepubertal children. We postulated that the RCUB might also prove useful for measurement of postmenopausal levels and designed the present study to examine this possibility.

Thirty normal postmenopausal volunteers provided blood samples for measurement of estrogen by RCUB and, for comparison, by RIA. The estrogenic activity measured by RCUB [mean ± sd, 11.9 ± 10.9 pmol/liter (SI units, 3.23 ± 2.96 pg/ml] was significantly lower than estradiol levels measured by RIA [43.7 ± 44.0 pmol/liter (11.9 ± 12.0 pg/ml)] in our volunteer subjects (P < 0.00001). Nonetheless, plasma estradiol levels measured by bioassay were significantly correlated with the estrogenic activity measured by RIA (r = 0.84) and by gas chromatography/tandem mass spectrometry (r = 0.85). To obtain biological evidence of the validity of the RCUB, we related plasma estrogen levels to body weight and body mass index and found highly significant correlations (r = 0.54 and r = 0.53, respectively). Surprisingly, 28 of 30 postmenopausal women were found to have estrogen levels in the prepubertal range with the RCUB. The levels detected by RCUB were similar to those previously reported using an ultrasensitive but less practical yeast bioassay. These results provide validation for the RCUB in postmenopausal women and suggest that it might prove useful for selection of women for drug therapy to prevent breast cancer.
Value of Gonadotropin-Releasing Hormone Testing in the Differential Diagnosis of Androgen Deficiency in Elderly Men
Authors: Christ-Crain M. , Meier C. , Huber P. R. , Zimmerli L. , Mueller B.
Published: March 2005

Elderly men with low testosterone (T) levels are increasingly diagnosed to have partial androgen deficiency of the aging male (PADAM). Frequently, magnetic resonance imaging is performed to exclude pituitary adenoma. The value of GnRH testing to differentiate PADAM from secondary hypogonadism is unknown.

Serum levels of T as well as LH and FSH at baseline and after GnRH were evaluated in the following groups: 1) 24 elderly men with low serum T (<11.7 nmol/liter), 2) 25 elderly men with normal serum T levels (>11.7 nmol/liter), 3) 10 men with primary hypogonadism, 4) 24 men with secondary hypogonadism, and 5) 13 healthy young volunteers.

In elderly men, T levels were lower (P < 0.001) and gonadotropin levels higher (P = 0.03) compared with younger controls. LH and FSH response to GnRH was higher in elderly men with low T levels (PADAM) compared with elderly men with normal T levels (P = 0.02 and P < 0.001) in the presence of similar basal gonadotropin levels. To differentiate secondary hypogonadism from PADAM with a sensitivity of 100%, a T less than 10 nmol/liter had a specificity of 50%. This specificity was improved to 75% by using a cutoff of less than or equal to 15 mU/liter increase of LH upon GnRH stimulation.

Overall, decreased T levels and increased LH levels in elderly men suggest a primary Leydig cell dysfunction. In the subgroup of elderly men with low T levels, an increased LH response to GnRH with normal basal LH levels suggests additional, possibly hypothalamic changes. To exclude secondary hypogonadism in PADAM, diagnostic accuracy can be improved by using GnRH testing.
Significantly Higher Adrenocorticotropin-Stimulated Cortisol and 17-Hydroxyprogesterone Levels in 337 Consecutive, Premenopausal, Caucasian, Hirsute Patients Compared with Healthy Controls
Authors: Glintborg D. , Hermann A. P. , Brusgaard K. , Hangaard J. , Hagen C. , Andersen M.
Published: March 2005

Objective: To investigate whether elevated ACTH-stimulated 17-hydroxyprogesterone (17OHP) levels are caused by CYP21 genetic defects or by a general adrenal hyperresponsiveness in hirsute patients.

Methods: A total of 337 hirsute patients were evaluated by Ferriman-Gallwey score, serum testosterone, ACTH-stimulated 17OHP, and cortisol during the follicular phase. A cutoff value of 16 nmol/liter for maximum ACTH-stimulated 17OHP (M17OHP) responses was defined as the upper limit of the 95% confidence interval (CI) for the 97.5 percentile in 42 female controls. All patients were offered total screening of the CYP21 gene, and 252 healthy, premenopausal women with regular menses underwent genetic screening.

Results: Patients were divided into idiopathic hirsutism (IH) (n = 180) and polycystic ovary syndrome (PCOS) (n = 157) groups. M17OHP levels were significantly higher in IH [geometric mean value (nmol/liter ± 2 sd) 12.2 (4.6–32.3)] and PCOS [11.9 (5.3–27.2)] compared with controls [8.5 (5.1–14.2)] (P < 0.001). A similar percentage of IH and PCOS patients had elevated M17OHP (20.5 vs. 20.8%, not significant), and these also had significantly higher 30-min cortisol levels compared with controls (P < 0.05). The prevalence of CYP21 mutations in patients was 8.6% compared with 6.3% in controls (P = 0.38). Ten of 19 carriers had M17OHP levels below the cutoff limit.

Conclusion: The significantly higher ACTH-stimulated levels of cortisol and 17OHP in hirsute patients indicated adrenal hyperresponsiveness in IH and PCOS. CYP21-carrier status could not explain the observed high prevalence of abnormal ACTH-stimulated 17OHP levels in the hirsute population.
In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism
Authors: Bertherat Jérôme , Contesse Vincent , Louiset Estelle , Barrande Gaëlle , Duparc Céline , Groussin Lionel , Émy Philippe , Bertagna Xavier , Kuhn Jean-Marc , Vaudry Hubert , Lefebvre Hervé
Published: March 2005

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing’s syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1–H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing’s syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.
Reversible Kallmann Syndrome, Delayed Puberty, and Isolated Anosmia Occurring in a Single Family with a Mutation in the Fibroblast Growth Factor Receptor 1 Gene
Authors: Pitteloud Nelly , Acierno James S. , Meysing Astrid U. , Dwyer Andrew A. , Hayes Frances J. , Crowley William F.
Published: March 2005

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder. Recently, loss-of-function mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been shown to cause autosomal dominant KS. To date, the detailed reproductive phenotype of KS associated with mutations in the FGFR1 has yet to be described. We report a kindred comprising a male proband with KS and spontaneous reversibility, whose mother had delayed puberty and whose maternal grandfather isolated anosmia. The proband presented at age 18 yr with KS and was subsequently treated with testosterone (T) therapy. Upon discontinuation of T therapy, he recovered from his hypogonadotropic hypogonadism, as evidenced by a normal LH secretion pattern, sustained normal serum T levels, and active spermatogenesis. The three members of this single family harbor the same FGFR1 mutation (Arg622X) in the tyrosine kinase domain. This report demonstrates 1) the first genetic cause of the rare variant of reversible KS, 2) the reversal of hypogonadotropic hypogonadism in a proband carrying an FGFR1 mutation suggests a role of FGFR1 beyond embryonic GnRH neuron migration, and 3) a loss of function mutation in the FGFR1 gene causing delayed puberty.
Refining Hormonal Diagnosis of Type II 3β-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping
Authors: Mermejo Livia M. , Elias Lucila L. K. , Marui S. , Moreira Ayrton C. , Mendonca Berenice B. , de Castro Margaret
Published: March 2005

Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3βHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3βHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3βHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-hydroxypregnenolone (Δ5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3βHSD2 deficiency. Basal and ACTH-stimulated Δ5-17P levels (nanomoles per liter) ranged from 4–41 (−0.2 to 14 sd) and 36–97 (3.5–15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69–153 (25–57 sd) and 201–351 (36–65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Δ5-17P to F ratios ranged from 11–159 (0.5–25 sd) and 42–122 (2.4–11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29–282 sd) and 487-1523 (52–167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3βHSD2 deficiency in children with premature pubarche: ACTH-stimulated Δ5-17P and Δ5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Δ5-17P and Δ5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Δ5-17P levels and Δ5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3βHSD2 deficiency.