bluuebunny/crossref_metadata_2025 huggingface dataset:
PUBLICATION BIAS AND META-ANALYSES
Authors: Burdett Sarah , Stewart Lesley A. , Tierney Jayne F.
Published: February 2003

Objectives: Publication bias is widely appreciated, but considerable time and effort are needed to locate and obtain data from unpublished randomized controlled trials (RCTs), those published in non-English language journals or those reported in the gray literature; for this publication, we will call this collection of trials the “gray+ literature.” However, excluding such trials from systematic reviews could introduce bias and give rise to misleading conclusions.

Methods: We aimed to explore and quantify the impact of inclusion of gray+ literature on the results of all completed individual patient data (IPD) reviews coordinated by our group (13 meta-analyses). For each IPD review, results were calculated for RCTs fully published in English language journals and RCTs fully published in English language journals and the gray+ literature.

Results: The IPD meta-analyses based only on RCTs that were fully published in English language journals tended to give more favorable results than those that included RCTs from the gray+ literature. Although in most cases the addition of gray+ data gave less encouraging results, moving the estimated treatment effect toward a null result, the direction of effect was not always predictable.

Conclusions: We recommend that all systematic reviews should at least attempt to identify trials reported in the gray+thinsp;literature and, where possible, obtain data from them.
PAPER STANDARD GAMBLE
Authors: Ross Phillip L. , Littenberg Benjamin , Fearn Paul , Scardino Peter T. , Karakiewicz Pierre I. , Kattan Michael W.
Published: February 2003

Objectives: To develop and validate a paper-based instrument that is simple to administer and produces a reliable estimate of patient standard gamble (SG) utilities for current health status.

Methods: A 1-page paper questionnaire instrument, paper standard gamble (PSG), was designed to estimate SG utilities. We performed two studies to assess the validity of PSG. First we compared PSG and SG utilities for current health in patients with prostate cancer. They randomly received either PSG followed by SG or vice versa, always with an intervening SF-12. In the second validity study, we assessed the test-retest reliability of PSG by administering it to prostate cancer patients twice, at least 2 weeks apart.

Results: In the first study, utilities were assessed in 64 men (32 per SG/PSG order group). A paired-comparison t test suggested no difference between SG and PSG (mean difference = −0.007; 95% confidence interval (CI), $-$0.022 to 0.008). The concordance correlation coefficient was 0.92 (95% CI, 0.79 to 0.99). In the second study, test and retest PSGs were available for 184 patients. The concordance correlation coefficient was 0.88 (95% CI, 0.73 to 0.94).

Conclusions: These data suggest that PSG may serve as a reliable substitute for SG when current health utility is of interest. PSG may have particular advantages for acquisition of health-related quality-of-life data in longitudinal studies.
ARE EXPERT PANEL JUDGMENTS OF MEDICAL BENEFITS RELIABLE?
Authors: Hotvedt Ragnar , Lossius Hans Morten , Kristiansen Ival Sønbø , Steen Petter Andreas , Søreide Eldar , Førde Olav Helge
Published: February 2003

Objective: We have used multidisciplinary expert panels to assess the health benefits from two different emergency medical service programs in Norway. This gave the opportunity to study the reliability of the expert panel method.

Methods: Two panels assessed case reports for 18 children, and two other panels assessed case reports for 64 adult patients. The assessments of each case report were compared. These assessments were also compared with assessments of the same case reports, done by the same panels 1 and 9 years earlier.

Results: Two different panels agreed on the benefit/no benefit conclusion in at least 75% of the patients, both for children and adult patients (kappa 0.88–0.50). For groups of patients assessed to have some health benefit, the magnitude of the benefit estimates differed by 25% between the panels. When the same panels assessed the same patient groups twice, 1 and 9 years apart, their estimates of total benefit differed up to 30%. However, estimates for single patients, as well as estimates from single panel members, varied considerably more.

Conclusions: Use of multidisciplinary expert panels is a useful method for estimating health benefits on program level or for groups of patients. But assessments from single panelists, and for single patients may be seriously biased.
BEYOND MEDLINE
Authors: Savoie Isabelle , Helmer Diane , Green Carolyn J. , Kazanjian Arminée
Published: February 2003

Objective: To evaluate the sensitivity and precision of various extended search methods in identifying randomized controlled trials (RCTs) for systematic reviews.

Method: Prospective analysis of extended search methods (specialized databases or trial registries, reference lists, hand-searching, personal communication, and Internet) used in two systematic reviews of RCTs. The gold standard was the total number of RCTs identified by major databases (MEDLINE, EMBASE, etc.) and extended search strategies combined. Sensitivity was the proportion of all known RCTs identified by any extended search method. Precision reflected the proportion of all items uncovered by any extended search method that actually were RCTs.

Results: The extended search identified 94 additional RCTs for the systematic reviews beyond those identified with the major databases. Specialized databases and trial registries had the highest sensitivity and precision for the lipid-lowering project (13.6% and 52.7%, respectively; p < .05) followed by scanning of reference lists (7.2% sensitivity and 41.9% precision; p < .05). Hand-searching was more effective than personal communication and Internet searching (1.7% sensitivity and 12.2% precision; p < .05). The acupuncture project had slightly different results, with the specialized databases and trial registries tied with the review of reference lists for highest sensitivity (14.2%). The precision followed the same trend as the lipid-lowering project (17.6% specialized databases; 8.3% reference lists; p < .05). A post-hoc analysis showed that 75 of the 94 RCTs were indexed in the major databases but missed by the major database search.

Conclusions: Extended searching identified additional RCTs for the systematic reviews beyond those found in major databases. Specialized databases and trial registries were most effective. An important number of RCTs were missed by the major database search. Timing and accuracy of indexing may explain this finding. The definitive measure, whether there is an association between the method used to uncover RCTs, the quality of the items uncovered and their impact on systematic review results, is yet to be determined.
THE GREAT ESCAPE?
Authors: Johri Mira , Lehoux Pascale
Published: February 2003

Objective: Health technology assessment (HTA) can be used both to promote access to safe, efficacious, and cost-effective technologies, and to discourage access to undesirable ones. Yet HTA has had less success than might be hoped in pursuing the latter goal. This paper examines the scope of HTA as currently practiced to contribute to regulation of access to undesirable technologies.

Design: The study design is a critical analysis of HTA's methods, based on an exposition of the normative issues involved in restriction of access to health technologies. The paper classifies technologies that might figure as potential candidates for exclusion into five categories and underscores the key social and ethical dilemmas associated with limiting their use.

Results: For four of the five categories of technology outlined, limitation of access necessarily involves denial of benefit. Limitation of access thus inevitably raises difficult normative issues. We show that these are ill-addressed by the range of “evidence” typically considered in technology assessments, which centers predominantly on clinical and technical features such as efficacy, safety, and costs.

Conclusions: If HTA is to enhance our ability to make reasonable decisions concerning the use and diffusion of health technologies, it must better integrate consideration of the social, political, and ethical dimensions of health technologies into the process of technology assessment. We suggest a framework within which to approach this goal.
DECISION MAKING IN ACQUIRING MEDICAL TECHNOLOGIES IN ISRAELI MEDICAL CENTERS
Authors: Greenberg Dan , Pliskin Joseph S. , Peterburg Yitzhak
Published: February 2003

Objectives: This preliminary study had two objectives: a) charting the considerations relevant to decisions about acquisition of new medical technology at the hospital level; and b) creating a basis for the development of a research tool that will examine the function of the Israeli health system in assessment of new medical technologies.

Methods: A comprehensive literature review and in-depth interviews with decision makers at different levels allowed formulation of criteria considered by decision makers when they decide to purchase and use (or disallow the use) of new medical technology. The resulting questionnaire was sent to medical center directors, along with a letter explaining the goals of the study. The questionnaire included 31 possible considerations for decision making concerning the acquisition of new medical technology by medical centers. The interviewees were asked to indicate the relevance of each consideration in the decision-making process.

Results: The most relevant criteria for the adoption of new technologies related to the need for a large capital investment, clinical efficacy of the technology as well as its influence on side effects and complication rates, and a formal approval by the Ministry of Health. Most interviewees stated that pressures exerted by the industry, by patients, or by senior physicians in the hospital are less relevant to decision making. Very small and usually not statistically significant differences in the ranking of hospital directors were found according to the hospitals' ownership, size, or location.

Conclusions: The present study is a basis for a future study that will map and describe the function of hospital decision makers within the area of new technology assessment and the decision-making process in the adoption of new healthcare technologies.
CONNECTING PRE-MARKETING CLINICAL RESEARCH AND MEDICAL PRACTICE
Authors: Wieringa Nicolien F. , Peschar Jules L. , Denig Petra , de Graeff Pieter A. , Vos Rein
Published: February 2003

Objectives: To identify core issues that contribute to the gap between pre-marketing clinical research and practice as seen from the perspective of medical practice, as well as possible changes and potential barriers for closing this gap.

Methods: Interviews with 47 physicians and pharmacists who were liaised to drug regulation through their role in the pre- and post-marketing shaping of new cardiovascular drugs. Data were analyzed using methods of grounded theory and analytical evaluations.

Results: Six core issues were identified that referred to the standards in drug regulation, the organization of the regulatory system, and conflicting interests. Pre-marketing trials should focus more on populations and research questions relevant to medical practice. In particular, variability in drug responses between subgroups of patients and demonstration of effectiveness should become major principles in drug regulation. An interactive post-marketing process in which public interests are represented was considered necessary to further guide research and development according to the needs in daily practice. Strategies for change could be applied within the present system of drug regulation, or affect its basic principles. Regulatory authorities were primarily identified to initiate changes, but many other parties should be involved. Barriers for change were identified regarding differences in interests between parties, organizational matters, and with respect to broader healthcare policies.

Conclusions: Based on the respondents' opinions, there is a need to focus regulatory standards more on the needs in medical practice. Therefore, regulatory authorities should further develop their influence in the pre- and post-marketing drug development process, together with other parties involved, in order to bridge the gap between clinical research and medical practice.
DISSEMINATION AND CHARACTERISTICS OF ACUTE CARE FOR ELDERS (ACE) UNITS IN THE UNITED STATES
Authors: Jayadevappa Ravishankar , Bloom Bernard S. , Raziano Donna Brady , Lavizzo-Mourey Risa
Published: February 2003

Objective: The objective of this paper is to determine prevalence and characteristics of acute care for elders (ACE) units and hospital characteristics associated with the presence of an ACE unit.

Methods: Data on characteristics and prevalence of ACE units were obtained by surveying all established geriatric medical divisions across U.S. medical schools. Data on hospital characteristics such as number of beds, revenue, number of Medicare inpatients, and average length of stay were obtained from the 1999 American Hospital Association Annual Survey Data. Descriptive statistics and t test were used to analyze the characteristics of ACE units. Stepwise logistic regression was used to analyze the hospital characteristics associated with the presence of an ACE unit.

Results: The survey identified 16 geriatric divisions and programs with ACE units. Hospitals that have ACE units differ significantly with respect to number of beds and total revenue, compared with institutions that do not have an ACE unit. Stepwise logistic regression indicated total hospital revenue was the only factor significantly associated with the presence of an ACE unit.

Conclusions: ACE units are attractive interdisciplinary models to address the particular needs of the elderly during their hospital stay. Low presence of ACE units warrants further research as to reasons more hospitals have not included them, given the available evidence for clinical, functional, and economic benefits.
EU AND MEMBER STATE MEDICAL DEVICES REGULATION
Authors: Altenstetter Christa
Published: February 2003

This article examines European Union (EU) and member state regulation of medical devices, particularly: a) the similarities and differences between medical devices and prescription drugs, including the respective industries, market authorization pathways, and boundary issues between the two sectors; b) the political background, current nature, and future prospects for EU medical device regulation; and c) regulatory responsibilities of the member states. Included are definitions of medical devices and in vitro diagnostics, and a brief history of their treatment by European law. The erosion of boundaries between exclusive and shared responsibilities of the EU and member states will be addressed, especially as it affects market approval of medical devices, clinical investigations, labeling and instructions for use, price setting and reimbursement, and evidence-based medicine and healthcare technology assessment. Finally, the article discusses medical device reporting and surveillance systems, which may be the weakest link in the EU integrative process. If patient safety is as important to the EU regulatory scheme as free movement and competitiveness, then both Brussels and member states will require additional resources, as well as measures to overcome obstacles to implementation, evaluation, and accountability.
BIOMEDICAL RESEARCH PRODUCTIVITY
Authors: Rahman Mahbubur , Fukui Tsuguya
Published: February 2003

Objective: The objective of this study was to elicit the factors related to worldwide variation in biomedical research productivity.

Methods: Biomedical research articles published in 1990–2000 were accessed through the MEDLINE database. The number of articles (journal articles) originating from each of the countries of the world was elicited and normalized to publication per million population per year.

Results: In a multiple regression model, where publication per million population was the dependent variable and 10 social and economic indicators were independent variables, gross national product (GNP) per capita and research and development (R&D) expenditure emerged as significant factors. In separate simple linear regression analyses, all but two independent variables were found significant.

Conclusions: To increase biomedical research output, GNP per capita and R&D expenditure are the most important factors to address.
A MODEL TO FACILITATE OUTCOME ASSESSMENT OF OBSTRUCTIVE SLEEP APNEA
Authors: Sonnad Seema S. , Moyer Cheryl A. , Patel Shushma , Helman Joseph I. , Garetz Susan L. , Chervin Ronald D.
Published: February 2003

Objectives: Obstructive sleep apnea is a common disorder with significant morbidity and effects on quality of life. Management can include a range of mechanical, behavioral, and surgical approaches. This paper aims to devise a model of management options to assist in initial cost-effectiveness investigations.

Methods: In the absence of practice pattern data and widely accepted guidelines, we reviewed published literature and devised a model of treatment options to facilitate initial studies of outcomes, costs, and cost-effectiveness.

Results: Obstructive sleep apnea is rarely addressed by conservative behavioral-based strategies because these options, while inexpensive, have only limited effectiveness. Effective treatment most often relies on nasal continuous positive airway pressure, but poor tolerance or compliance sometimes leads to treatment with oral appliances or surgery. Patients treated by one modality may try another if the initial strategy is ineffective. Laboratory evidence that sleep apnea is effectively treated, and long-term follow-up, are necessary regardless of the treatment modality chosen.

Conclusions: Each patient's treatment plan must be individually tailored, but the management model proposed here reflects available evidence-based literature and the authors' impression of current practice patterns. This model should be useful for initial cost-effectiveness investigations.
Noninvasive recording and response characteristics of the
rat dc-electroretinogram
Authors: PEACHEY NEAL S. , STANTON J. BRETT , MARMORSTEIN ALAN D.
Published: February 2003

In response to light, the retinal pigment epithelium (RPE)
generates a series of potentials that can be recorded using
the dc-electroretinogram (dc-ERG). As these potentials can be
related to specific cellular events, they provide information
about RPE function and how that may be altered by disease or
experimental manipulation. The purposes of the present study
were to define a noninvasive means for recording the rat dc-ERG,
to use this to define the stimulus–response properties
of the major components, and to relate these results to measures
of the rat electrooculogram (EOG). Parallel studies were conducted
in two strains of rats (Long-Evans, LE; Sprague-Dawley, SD)
that are commonly used in vision research. Rats were sedated
with ketamine/xylazine and placed on a heating pad. Ag/AgCl
wire electrodes were bridged with capillary tubes filled with
Hanks balanced salt solution. The active electrode was placed
in contact with the corneal surface and referenced to a second
electrode placed within the orbit. The dc-ERG signal was amplified
(dc-100 Hz), digitized, and stored offline. The duration of
full-field flash stimuli was controlled using a mechanical shutter
and flash luminance was controlled with neutral density filters.
EOGs were recorded using subdermal platinum needle electrodes
placed near the eye. In response to a 5-min light exposure,
the dc-ERG of LE and SD rats included a distinct b-wave,
after potential, c-wave, fast oscillation, and a slow
potential of positive polarity the characteristics of which
are consistent with a light peak.
Modeling receptive-field structure of koniocellular,
magnocellular, and parvocellular LGN cells in the owl monkey
(Aotus trivigatus)
Authors: XU XIANGMIN , BONDS A.B. , CASAGRANDE VIVIEN A.
Published: February 2003

Most cells in the retina and lateral geniculate nucleus (LGN)
of primates have a concentric center/surround receptive-field
organization. Details of the relationship between center and
surround often can be used to predict how cells respond to visual
stimuli. Models of the receptive-field organization and
center/surround relationships also are useful when comparing
cell classes. In the present study, we used the
difference-of-Gaussians (DOG) model to quantitatively examine
and compare the receptive-field center/surround organization
of koniocellular (K), magnocellular (M), and parvocellular (P)
LGN cells of owl monkeys. We obtained estimates of receptive-field
center size (rc) and center sensitivity
(Kc), and surround size
(rs), and surround sensitivity
(Ks) from 62 K, M, and P LGN cells
by fitting their spatial-frequency responses with a DOG function
(Rodieck, 1965; Croner & Kaplan, 1995). The DOG function not
only accounted for the responses of P and M cells, but also provided
a good description of K-cell responses. We found that at matched
eccentricities of less than 15 deg, K cells had the largest
rc and rs
among the three cell classes. K cells also had the lowest
Kc and Ks.
Calcium-induced calcium release and calcium buffering in
retinal horizontal cells
Authors: SOLESSIO EDUARDO , LASATER ERIC M.
Published: February 2003

Calcium plays an integral role in intracellular signaling and
process control in neurons. In the outer retina, it is a key
component to the phototransduction cycle and neurotransmitter
release in photoreceptor and bipolar cell terminals. It also
contributes to the responses of horizontal and bipolar cells.
In the dark, horizontal cells are depolarized and calcium enters
via calcium permeant AMPA receptors and voltage-activated
calcium channels. As a result, horizontal cells must be capable
of handling high calcium loads without sustaining damage. The
aim of this study was to examine the components determining
the intracellular calcium levels in H2 horizontal cells in the
retina of white bass. Calcium responses were evoked in isolated
cells by depolarizing voltage steps and monitored by conventional
imaging techniques. The responses consisted of two components:
calcium entry through voltage-gated calcium channels and subsequent
release from intracellular stores by calcium-induced calcium
release (CICR). Under control conditions, changes in calcium
levels reached 541 nM on average from a basal level of 60 nM.
When release from CICR stores was blocked with ryanodine or
dantrolene, calcium levels barely reached 180 nM. The threshold
level needed to trigger CICR was dependent on the duration of
the applied depolarization and increased in response to shorter
pulses.
Spatial organization of displaced ganglion cells in the chick
retina
Authors: DEPLANO STEFANIA , PEDEMONTE NICOLETTA
Published: February 2003

This study presents a morphological and quantitative analysis
of displaced ganglion cells performed in the chick retina at
different stages of development (E11, E17, & P2). The
lipophilic dye DiI inserted into the optic nerve provided a
complete staining of displaced ganglion cell population and
of their dendritic trees. From 11 days of incubation (E11) all
neurons present a uniform morphology and are unmistakably
recognizable by the dimensions of their cell body and by the
presence of the axon. Their dendritic arborizations shape a
complex network through the retina. Cell bodies are randomly
distributed but dendritic trees of neighboring cells constantly
present two levels of dendritic overlap: about 50% of the cells
present a high degree of overlap, more than the 30% up to 95%
of their total area, while the other half overlaps less than
20%. The high degree of overlap identifies a cluster, which
is regularly formed by three and more rarely by four neurons
starting from 17 days of incubation (E17) onward and after birth.
From E17 onward, 94% of clusters is constantly formed by three
cells and 6% of the clusters by four neurons. The distribution
and the spatial arrangement of clusters are very regular, forming
a mosaic that gives rise to a precise retinal coverage. The
nearest-neighbor analysis unequivocally demonstrated that the
mosaic of clusters is the most regular array so far described.
This exact arrangement starts from 11 days of incubation and
is maintained and refined through the following stages of
development and after birth.
A simple model accounts for the response of disparity-tuned
V1 neurons to anticorrelated images
Authors: READ JENNY C.A. , PARKER ANDREW J. , CUMMING BRUCE G.
Published: February 2003

Disparity-tuned cells in primary visual cortex (V1) are thought
to play a significant role in the processing of stereoscopic
depth. The disparity-specific responses of these neurons have
been previously described by an energy model based on local,
feedforward interactions. This model fails to predict the response
to binocularly anticorrelated stimuli, in which images presented
to left and right eyes have opposite contrasts. The original energy
model predicts that anticorrelation should invert the disparity tuning
curve (phase difference π), with no change in the amplitude of the response. Experimentally, the amplitude tends to be reduced with
anticorrelated stimuli and a spread of phase differences is
observed, although phase differences near π are the most
common. These experimental observations could potentially reflect
a modulation of the V1 signals by feedback from higher visual
areas (because anticorrelated stimuli create a weaker or
nonexistent stereoscopic depth sensation). This hypothesis could
explain the effects on amplitude, but the spread of phase
differences is harder to understand. Here, we demonstrate that
changes in both amplitude and phase can be explained by a
straightforward modification of the energy model that involves
only local processing. Input from each eye is passed through
a monocular simple cell, incorporating a threshold, before being
combined at a binocular simple cell that feeds into the energy
computation. Since this local feedforward model can explain
the responses of complex cells to both correlated and
anticorrelated stimuli, there is no need to invoke any influence
of global stereoscopic matching.
Evidence for a potential role of glucagon during eye growth
regulation in chicks
Authors: FELDKAEMPER MARITA P. , SCHAEFFEL FRANK
Published: February 2003

Eye growth and refraction are regulated by visual processing
in the retina. Until now, the messengers released by the retina
to induce these changes are largely unknown. Previously, it
was found that glucagon amacrine cells respond to defocus in
the retinal image and even to its sign. The expression of the
immediate-early gene product ZENK increased in this cell population
in eyes wearing plus lenses and decreased in minus lens-treated
chicks. Moreover, it was shown that the amount of retinal glucagon
mRNA increased during treatment with positive lenses. Therefore,
it seems likely that these cells contribute to the visual
regulation of ocular growth and that glucagon may act as a stop
signal for eye growth. The purpose of the present study was
to accumulate further evidence for a role of glucagon in the
visual control of eye growth. Chicks were treated with plus
and minus lenses after injection of different amounts of the
glucagon antagonist des-His1-Glu9-glucagon-amide
or the agonist Lys17,18,Glu21-glucagon,
respectively. Refractive development and eye growth were recorded by
automated infrared photorefraction and A-scan ultrasound, respectively.
The glucagon antagonist inhibited hyperopia development, albeit only in
a narrow concentration range, and at most by 50%, but not myopia
development. In contrast, the agonist inhibited myopia development
in a dose-dependent fashion. At high concentrations, it also
prevented hyperopia development.
A morphological classification of ganglion cells in the
zebrafish retina
Authors: MANGRUM WELLS I. , DOWLING JOHN E. , COHEN ETHAN D.
Published: February 2003

We examined the distribution and morphological types of ganglion
cells in the retina of the zebrafish, a model vertebrate genetic
organism. Using cresyl violet and methylene blue staining, a
prominent central area was observed in the ventral temporal
retina. The density of ganglion cell layer neurons averaged
from ∼12,000/mm2 in the dorsal-nasal retina
to a peak of ∼37,000/mm2 in the ventral-temporal
retina. Individual zebrafish ganglion cells were labeled by backfilling
with DiI through the optic nerve followed by reconstruction
using confocal microscopy. The dendritic stratification and
branching pattern of each labeled ganglion cell was examined
in relation to the borders of the inner plexiform layer (IPL).
We identified 11 different morphological types of ganglion cell.
The most commonly labeled ganglion cells were two types termed
Type III or IV, which displayed highly stratified dendritic
arborizations in their respective ON-, OFF-sublaminae of the
IPL. Their dendritic branching patterns were highly asymmetric
with many thorn-like varicosities that profusely filled the
area of arborization. In contrast, Type V cells formed a small
simply branching dendritic field in the innermost portion of
the ON-sublamina of the IPL. Two large ganglion cell types (Types
I and II) with wide monostratified dendritic fields were found
in both the ON- and OFF-sublamina of the IPL. Three different
types of multistratified/bistratified ganglion cells were
found (Types, IX, X, and XI.) whose dendrites occupied different
regions of the IPL. The multistratified dendrites of IX cells
occupied the whole width of the IPL, while the dendrites of
Type XI cells formed vertical claw-like endings in only the
ON-sublamina of the IPL. We conclude that zebrafish ganglion
cells display a rich variety of types and branching patterns.
This study establishes a series of baseline measurements of
zebrafish ganglion cells to facilitate examination of genes
playing a role in the specification and stratification of ganglion
cell types.
Temperature effects on spectral properties of red and green
rods in toad retina
Authors: ALA-LAURILA PETRI , SAARINEN PIA , ALBERT RAULI , KOSKELAINEN ARI , DONNER KRISTIAN
Published: February 2003

Temperature effects on spectral properties of the two types
of rod photoreceptors in toad retina, “red” and
“green” rods, were studied in the range
0–38°C. Absorbance spectra of the visual pigments
were recorded by single-cell microspectrophotometry (MSP) and
spectral sensitivities of red rods were measured by
electroretinogram (ERG) recording across the isolated retina.
The red-rod visual pigment is a usual rhodopsin
(λmax = 503.6 nm and 502.3 nm at room temperature
(21°C) in, respectively, Bufo marinus and Bufo
bufo), that of green rods (λmax = 432.6
nm in Bufo marinus) belongs to the “blue”
cone pigment family. In red rods, λmax depended
inversely and monotonically on temperature, shifting by −2.3
nm when temperature was raised from 0°C to 38°C. Green-rod
λmax showed no measurable dependence on
temperature. In red rods, warming caused a relative increase
of sensitivity in the long-wavelength range. This effect can
be used for estimating the energy needed for photoexcitation,
giving Ea = 44.3 ±
0.6 kcal/mol for Bufo marinus rhodopsin and 48.8
± 0.5 kcal/mol for Bufo bufo rhodopsin.
The values are significantly different (P < 0.001),
although the two rhodopsins have very similar absorption spectra
and thermal isomerization rates. Our recording techniques did not
allow measurement of the corresponding effect at long wavelengths
in green rods. Although spectral effects of temperature changes in
the physiological range are small and of little significance for
visual function, they reveal information about the energy states and
different spectral tuning mechanisms of the visual pigments.
D2-dopamine receptor blockade modulates temporal resolution
in goldfish
Authors: MORA-FERRER CARLOS , GANGLUFF VOLKER
Published: February 2003

A possible effect of dopamine on the temporal resolution of
goldfish was investigated in a behavioral, two-alternative,
forced-choice procedure. Flicker fusion frequency (FFF) was
measured before and after bilateral intravitreal injections
of D1- or D2-dopamine receptor (D1-/D2-R) antagonists, or
after depletion of retinal dopamine by bilateral intravitreal
injections of the dopaminergic neurotoxin 6-hydroxydopamine
(6-OHDA). Prior to drug injections, fish achieved FFFs of
33–39 Hz. A D1-R antagonist, SCH 23390, reduced FFF by
about 12% (P > 0.1), whereas a D2 antagonist,
sulpiride, reduced the relative FFF by 25% (P <
0.03). Depletion of retinal dopamine with 6-OHDA induced a gradual
reduction in the FFF to a maximal reduction of 50% (P
< 0.001) at 2 weeks postinjection. There was recovery to
control levels after 3–4 weeks postinjection. The recovery
of FFF, at least in one animal, was due to the return of retinal
dopamine because FFF could be reduced by intravitreal injections
of sulpiride during the recovery phase. These experiments
demonstrate that retinal dopamine, particularly acting on D2-R,
is important for photopic temporal resolution.
Implication of nigral tachykinin NK3 receptors in the maintenance of hypertension in spontaneously hypertensive rats: a pharmacologic and autoradiographic study
Authors: Lessard Andrée , Campos Maria M , Neugebauer Witold , Couture Réjean
Published: February 2003

The role of nigral tachykinin NK1, NK2 and NK3 receptors in central cardiovascular regulation was studied by measuring the effects of selective agonists and antagonists on mean arterial pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra of spontaneously hypertensive rats (SHR). Quantitative in vitro autoradiography was also performed in the midbrain of SHR and Wistar‐Kyoto (WKY) with the NK3 receptor ligand [125I]‐HPP‐Senktide.

Tachycardia was elicited by the NK1 ([Sar9,Met(O2)11]SP) and NK2 ([βAla8]NKA(4‐10)) agonists at 25 and 100 pmol while the NK3 agonist (senktide, 50 and 100 pmol) had no significant effect. The three agonists had no effect on behaviour, and increases in MAP were elicited by the NK1 agonist only.

Whereas antagonists at NK1 (RP 67580, 500 pmol) and NK2 (SR 48968, 500 pmol) receptors had no significant effect on MAP and HR, the NK3 antagonist (R‐820, 500 pmol) reduced MAP for over 3 h in SHR. That anti‐hypertensive effect did not occur after intracerebroventricular or intravenous injection of R‐820. Also, R‐820 had no cardiovascular effect in WKY.

The affinity (KD: 0.7 nM) and densities of specific NK3 receptor binding sites measured in the substantia nigra, ventral tegmental area, hippocampus and amygdala were not significantly different in SHR and WKY.

It is concluded that endogenous tachykinins exert a tonic activity on NK3 receptors in the substantia nigra of SHR to maintain high blood pressure. Hence, nigral tachykinin NK3 receptors may represent a promising therapeutic target in the treatment of arterial hypertension.

British Journal of Pharmacology (2003) 138, 554–563. doi:10.1038/sj.bjp.0705042
Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti‐absorptive effect via the VPAC1 receptor in a human enterocyte‐like cell line (Caco‐2)
Authors: Anderson Catriona M H , Mendoza Maria E , Kennedy David J , Raldua Demetrio , Thwaites David T
Published: February 2003

Optimal dipeptide and peptidomimetic drug transport across the intestinal mucosal surface is dependent upon the co‐operative functional activity of the di/tripeptide transporter hPepT1 and the Na+/H+ exchanger NHE3. The ability of the anti‐absorptive enteric neuropeptide VIP (vasoactive intestinal peptide) to modulate dipeptide uptake was determined using human intestinal (Caco‐2) epithelial cell monolayers.

Uptake of glycylsarcosine (Gly‐Sar) across the apical membrane of Caco‐2 cell monolayers is inhibited by basolateral exposure to either VIP, pituitary adenylate cyclase‐activating polypeptide (PACAP), or the VPAC1 receptor agonist [11,22,28Ala]‐VIP. Inhibition of Gly‐Sar uptake is observed only in the presence of extracellular Na+. Reverse‐transcription polymerase chain reaction (RT–PCR) demonstrates that VPAC1 mRNA is expressed in Caco‐2 cells whereas VPAC2 mRNA is not detected.

The VIP‐induced inhibition of Gly‐Sar uptake is abolished in the presence of the protein kinase A (PKA) inhibitor H‐89 (N‐[2‐(p‐bromocinnamylamino)ethyl]‐5‐isoquinolinesulfonamide.2HCl).

22Na+ uptake across the apical membrane is inhibited by the selective NHE3 inhibitor S1611. Experiments with BCECF [2′,7′‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein]‐loaded Caco‐2 cells demonstrate that VIP reduces the NHE3‐dependent recovery of intracellular pH (pHi) after dipeptide‐induced acidification. Western blot of Caco‐2 cell protein demonstrates expression of the NHE regulatory factor NHERF1 (expression of which is thought to be required for PKA‐mediated inhibition of NHE3).

VIP has no effect on Gly‐Sar uptake in the presence of S1611 suggesting that VIP and S1611 both modulate dipeptide uptake via the same mechanism.

These observations demonstrate that VIP (and PACAP) modulate activity of the H+/dipeptide transporter hPepT1 in a Na+‐dependent manner consistent with the modulation being indirect through inhibition of NHE3.

British Journal of Pharmacology (2003) 138, 564–573. doi:10.1038/sj.bjp.0705049
Selective blockade of endothelial Ca2+‐activated small‐ and intermediate‐conductance K+‐channels suppresses EDHF‐mediated vasodilation
Authors: Eichler Ines , Wibawa Judith , Grgic Ivica , Knorr Andrea , Brakemeier Susanne , Pries Axel R , Hoyer Joachim , Köhler Ralf
Published: February 2003

Activation of Ca2+‐activated K+‐channels (KCa) has been suggested to play a key role in endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation. However, due to the low selectivity of commonly used KCa‐channel blockers it is still elusive which endothelial KCa‐subtypes mediate hyperpolarization and thus initiate EDHF‐mediated vasodilation.

Using the non‐cytochrome P450 blocking clotrimazole‐derivatives, 1‐[(2‐chlorophenyl) diphenylmethyl]‐1H‐pyrazole (TRAM‐34) and 2‐(2‐chlorophenyl)‐2,2‐diphenylacetonitrile (TRAM‐39) as highly selective IK1‐inhibitors, we investigated the role of the intermediate‐conductance KCa (rIK1) in endothelial hyperpolarization and EDHF‐mediated vasodilation.

Expression and function of rIK1 and small‐conductance KCa (rSK3) were demonstrated in situ in single endothelial cells of rat carotid arteries (CA). rIK1‐currents were blocked by TRAM‐34 or TRAM‐39, while rSK3 was blocked by apamin. In current‐clamp experiments, endothelial hyperpolarization in response to acetylcholine was abolished by the combination of apamin and TRAM‐34.

In phenylephrine‐preconstricted CA, acetylcholine‐induced NO and prostacyclin‐independent vasodilation was almost completely blocked by ChTX, CLT, TRAM‐34, or TRAM‐39 in combination with the SK3‐blocker apamin. Apamin, TRAM‐34, and CLT alone or sulphaphenzole, a blocker of the cytochrome P450 isoform 2C9, were ineffective in blocking the EDHF‐response.

In experiments without blocking NO and prostacyclin synthesis, the combined blockade of SK3 and IK1 reduced endothelium‐dependent vasodilation.

In conclusion, the use of selective IK1‐inhibitors together with the SK3‐blocker apamin revealed that activation of both KCa, rIK1 and rSK3 is crucial in mediating endothelial hyperpolarization and generation of the EDHF‐signal while the cytochrome P450 pathway seems to play a minor or no role in rat CA.

British Journal of Pharmacology (2003) 138, 594–601. doi:10.1038/sj.bjp.0705075
The cyclopentenone prostaglandin 15‐deoxy‐Δ12,14‐ PGJ2 attenuates the development of colon injury caused by dinitrobenzene sulphonic acid in the rat
Authors: Cuzzocrea Salvatore , Ianaro Angela , Wayman Nicole S , Mazzon Emanuela , Pisano Barbara , Dugo Laura , Serraino Ivana , Di Paola Rosanna , Chatterjee Prabal K , Di Rosa Massimo , Caputi Achille P , Thiemermann Christoph
Published: February 2003

Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM‐1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15‐deoxy‐Δ12,14‐PGJ2 (15d‐ PGJ2) functions as an early anti‐inflammatory signal.

The aim of the present paper is to investigate the effects of 15d‐PGJ2 in rats subjected to experimental colitis.

Colitis was induced in rats by intra‐colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d‐PGJ2 was administered daily as intraperitoneal injection (20 or 40 μg kg−1). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis.

15d‐PGJ2 significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d‐PGJ2 also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐α) and interleukin‐1β (IL‐1β).

Furthermore, 15d‐PGJ2 reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP‐ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM‐1 caused by DNBS in the colon.

Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d‐ PGJ2 also caused a substantial reduction of the activation of nuclear factor‐kappaB (NF‐κB). Furthermore, 15d‐PGJ2 stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis.

In conclusion, 15d‐PGJ2 reduces the development of experimental colitis.

British Journal of Pharmacology (2003) 138, 678–688. doi:10.1038/sj.bjp.0705077
Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells
Authors: Sciulli Maria G , Seta Francesca , Tacconelli Stefania , Capone Marta L , Ricciotti Emanuela , Pistritto Giuseppa , Patrignani Paola
Published: February 2003

Acetaminophen, an analgesic and antipyretic drug with weak antiinflammatory properties, has been suggested to act as a tissue‐selective inhibitor of prostaglandin H synthases (PGHSs) (e.g. COX‐1 and COX‐2) through its reducing activity, that is influenced by the different cellular levels of peroxides.

We have studied the effects of acetaminophen on inducible and constitutive prostanoid biosynthesis in monocytes and platelets in vitro. To discriminate between the inhibitory effect of the drug on PGHS‐isozymes vs PGE‐synthases (PGESs), parallel measurements of PGE2 and thromboxane (TX) B2 were carried out. Since antioxidant enzymes and cofactors, present in plasma, may affect acetaminophen‐dependent inhibition of prostanoids, comparative experiments in whole blood vs isolated monocytes were performed.

Acetaminophen inhibited LPS‐induced whole blood PGE2 and TXB2 production, in a concentration‐dependent fashion [IC50 μM (95% confidence intervals): 44 (27–70) and 94 (79–112), respectively]. Therapeutic plasma concentrations (100 and 300 μM) of the drug more profoundly reduced PGE2 than TXB2 (71±3 vs 54±4 and 95±0.8 vs 78±2%, respectively, mean±s.e.mean, n=6, P<0.01).

Differently, in isolated monocytes stimulated with LPS, both PGE2 and TXB2 production was maximally reduced by only 60%.

At 100 and 300 μM, the drug caused a similar and incomplete inhibition of platelet PGE2 and TXB2 production during whole blood clotting (45±4 vs 54±4 and 75±2 vs 75±1%, respectively, mean±s.e.mean, n=4).

In conclusion, therapeutic concentrations of acetaminophen caused an incomplete inhibition of platelet COX‐1 and monocyte COX‐2 but in the presence of plasma, the drug almost completely suppressed inducible PGE2 biosynthesis through its inhibitory effects on both COX‐2 and inducible PGES.

British Journal of Pharmacology (2003) 138, 634–641. doi:10.1038/sj.bjp.0705078
Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia‐reperfusion injury and preconditioning
Authors: Ferdinandy Péter , Schulz Richard
Published: February 2003

There appears to be a controversy in the study of myocardial ischaemia‐reperfusion injury and preconditioning whether nitric oxide (NO) plays a protective or detrimental role. A number of findings and the interpretation of the results to date do not support such a controversy. An understanding of the latest developments in NO, superoxide (O2−·) and peroxynitrite (ONOO−) biology, as well as the various ischaemic animal models utilized is necessary to resolve the apparent controversy. NO is an important cardioprotective molecule via its vasodilator, antioxidant, antiplatelet, and antineutrophil actions and it is essential for normal heart function. However, NO is detrimental if it combines with O2−· to form ONOO− which rapidly decomposes to highly reactive oxidant species. There is a critical balance between cellular concentrations of NO, O2−·, and superoxide dismutase which physiologically favour NO production but in pathological conditions such as ischaemia and reperfusion result in ONOO− formation. In contrast, exposure of the heart to brief episode(s) of ischaemia markedly enhances its ability to withstand a subsequent ischaemic injury. The triggering of this endogenous cardioprotective mechanism known as preconditioning requires both NO and O2−· synthesis. However, preconditioning in turn attenuates the overproduction of NO, O2−· and ONOO− during a subsequent episode of ischaemia and reperfusion, thereby protecting the heart. Here we review the roles of NO, O2−·, and ONOO− in both ischaemia‐reperfusion injury and preconditioning.

British Journal of Pharmacology (2003) 138, 532–543. doi:10.1038/sj.bjp.0705080
Differential engagements of glutamate and GABA receptors in cardiovascular actions of endogenous nNOS or iNOS at rostral ventrolateral medulla of rats
Authors: Chan Samuel H H , Wang Ling‐Lin , Chan Julie Y H
Published: February 2003

We evaluated in Sprague–Dawley rats anaesthetized with propofol the engagement of soluble guanylyl cyclase (sGC)/cGMP cascade, glutamatergic and GABAergic neurotransmission in the cardiovascular actions of endogenous nitric oxide (NO) at the rostral ventrolateral medulla (RVLM).

Microinjection bilaterally into the RVLM of a selective iNOS inhibitor, S‐methylisothiourea (SMT, 250 pmoles), or a selective nNOS inhibitor, 7‐nitroindazole (7‐NI, 5 pmoles), induced respectively an enhancement or a reduction in systemic arterial pressure, heart rate and power density of the vasomotor components in the spectrum of arterial blood pressure signals, our experimental index for sympathetic neurogenic vasomotor tone.

The cardiovascular actions of SMT or 7‐NI in the RVLM were significantly antagonized by co‐administration into the RVLM of the sGC inhibitor, 1H‐[1,2,4]Oxadiazole[4,3‐α]quinoxalin‐1‐one (ODQ, 250 or 500 pmoles).

The cardiovascular excitatory effects after blockade of endogenous iNOS activity were significantly attenuated when N‐methyl‐D‐aspartate (NMDA) receptor antagonist, dizocilpine (20 or 50 pmoles), or non‐NMDA receptor antagonist, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (250 or 500 pmoles), was co‐microinjected bilaterally into the RVLM.

On the other hand, the cardiovascular depressive responses to blockade of endogenous nNOS activity were significantly antagonized on co‐administration of GABAA receptor antagonist, bicuculline methiodine (5 or 10 pmoles), but not GABAB receptor antagonist, 2‐hydroxy saclofen (50 or 100 pmoles).

We conclude that the cardiovascular actions of endogenous NO in the RVLM engage the sGC/cGMP pathway. In addition, whereas NO derived from nNOS induced sympathoexcitation via both NMDA and non‐NMDA receptors in the RVLM, NO generated by iNOS elicited sympathoinhibition via GABAA receptors.

British Journal of Pharmacology (2003) 138, 584–593. doi:10.1038/sj.bjp.0705081