bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk perception and communication: recent developments and implications for anaesthesia
Authors: Adams A. M. , Smith A. F.
Published: March 2003

This review begins by outlining the history of probability theory, exposing cultural differences between scientists and lay people in the way risks are viewed. The basic principles of the science of risk perception are described, and the various methods of communicating risk in health care, both verbal and numerical, are then discussed critically. These concepts are then applied to the practice of anaesthesia. Risk perception may affect anaesthetists' choice of career and may be involved in the genesis and evolution of critical incidents; we also discuss possibilities for training in risk perception issues. The place of risk communication in informed consent and its ethical implications are discussed.
The impact of low‐risk intensive care unit admissions on mortality probabilities by SAPS II, APACHE II and APACHE III
Authors: Beck D. H. , Smith G. B. , Taylor B. L.
Published: March 2003

A large proportion of intensive care unit patients are low‐risk admissions. Mortality probabilities generated by predictive systems may not accurately reflect the mortality experienced by subpopulations of critically ill patients. We prospectively assessed the impact of low‐risk admissions (mortality risk < 10%) on the mortality estimates generated by three prognostic models. We studied 1497 consecutive admissions to a general intensive care unit. The performance of the three models for subgroups and the whole population was analysed. The proportions of patients designated as low risk varied with the model and differences in model performance were most pronounced for these patients. The APACHE II mortality ratios (1.32 vs. 1.19) did not differ for low‐ and higher risk patients, but mortality ratios generated by APACHE III (2.38 vs. 1.23) and SAPS II (2.19 vs. 1.16) were nearly two‐fold greater. Calibration for higher risk patients was similar for all three models but the APACHE III system calibrated worse than the other models for low‐risk patients. This may have contributed to the poorer overall calibration of the APACHE III system (Hosmer–Lemeshow C‐test: APACHE III χ2 = 329; APACHE II χ2 = 42; SAPS II χ2 = 62). Imperfect characterisation of the large proportion of low‐risk intensive care unit admissions may contribute to the deterioration of the models' predictive accuracies for the intensive care population as a whole.
Osteocalcin and the hormonal, inflammatory and metabolic response to major orthopaedic surgery
Authors: Nicholson G. , Bryant A. E. , Macdonald I. A. , Hall G. M.
Published: March 2003

Summary  Plasma osteocalcin, a marker of osteoblastic activity, decreases after major abdominal and gynaecological surgery. Increased cortisol secretion and other hormonal and inflammatory components of the peri‐operative stress response may play a role in mediating this response. We␣assessed the effects of three different anaesthetic techniques on peri‐operative osteocalcin concentrations. Thirty‐six female patients undergoing elective total hip replacement were randomly assigned to receive propofol, propofol plus ‘three‐in‐one’ block or etomidate as part of a general anaesthetic technique. We measured plasma osteocalcin and serum cortisol, bone specific alkaline phosphatase, interleukin‐6, plasma epinephrine, norepinephrine, plasma glucose and cystatin C concentrations for up to 3 days after surgery. Etomidate successfully inhibited the cortisol response to surgery but plasma osteocalcin declined in all patients. This was accompanied by increased plasma catecholamines, interleukin‐6 and glucose concentrations, and decreased cystatin C‐values. Inhibition of the cortisol response to surgery failed to prevent a decrease in plasma osteocalcin concentrations after surgery, suggesting that other factors such as cytokines or catecholamines may play a significant role.
Monitored transtracheal jet ventilation using a triple lumen central venous catheter
Authors: Dhara S. S. , Liu E. H. C. , Tan K. H. S.
Published: March 2003

Summary Two patients with nasopharyngeal carcinoma, radiotherapy treatment and ‘difficult’ airways were anaesthetised for oral surgery. A triple lumen central venous catheter was inserted through the cricoid membrane and transtracheal jet ventilation with an AMS 1000 jet ventilator was performed via the distal lumen. The middle and proximal lumens were connected to an airway pressure monitor and a capnograph, enabling breath‐by‐breath monitoring of ventilation.
A retrospective observational study of pre‐operative sickle cell screening
Authors: Pemberton P. L. , Down J. F. , Porter J. B. , Bromley L. M.
Published: March 2003

The aim of this study was to determine the ethnic mix of those patients being pre‐operatively screened for sickle cell disease in a London teaching hospital and to determine the rate of ␣carriage of sickle haemoglobin amongst those tested. We retrospectively studied 1879 patients undergoing surgery over a 2‐month period. Two hundred and thirteen (11%) were screened for sickle cell disease and of these, 12 (5%) tested positive for sickle cell trait (HbAS). There were no patients homozygous for sickle cell disease (HbSS) or with haemoglobin SC disease (HbSC). Screening rates varied widely in different ethnic groups from 0% of the Chinese population to 85.2% of the Afro‐Caribbean population. We conclude that at present there is no coherent pre‐operative screening policy for sickle cell disease in our institution. Sickle cell disease poses unique anaesthetic risks and with a rapidly expanding ‘mixed race’ population high‐risk patients are difficult to identify phenotypically. We propose a universal screening policy be implemented in high‐risk areas.
The effect of dexamethasone upon patient‐controlled analgesia‐related nausea and vomiting
Authors: Lee Y. , Lin Y. S. , Chen Y. H.
Published: March 2003

Summary Ninety female patients were enrolled in this randomised, double‐blind, placebo‐controlled study to compare the anti‐emetic effect of intravenous dexamethasone 8 mg with saline control in preventing patient‐controlled analgesia‐related nausea and vomiting following major orthopaedic surgery. The prophylactic administration of dexamethasone 8 mg significantly reduced the overall incidence of patient‐controlled analgesia‐related nausea and vomiting (p < 0.001) and the need for rescue anti‐emetics (p < 0.01). Furthermore, patients who received dexamethasone showed a higher incidence of complete responses (no vomiting or need for rescue anti‐emetic for a 24‐h postoperative period) than those who received saline (p < 0.05). We conclude that dexamethasone 8 mg may be valuable for preventing patient‐controlled analgesia‐related nausea and vomiting in women undergoing major orthopaedic surgery.
The effects of hypertonic saline solution (7.5%) on coagulation and fibrinolysis: an in vitro assessment using thromboelastography
Authors: Tan T. S. , Tan K. H. S. , Ng H. P. , Loh M. W.
Published: March 2003

Summary We studied the effects of hypertonic (7.5%) and normal saline on coagulation and fibrinolysis in an in vitro model using thromboelastography of human whole blood. Reaction times increased and alpha angles decreased with hypertonic saline replacement at 7.5% blood volume compared with similar dilution with normal saline. At 10% blood volume replacement with hypertonic saline, reaction and coagulation times were significantly increased and alpha angles were decreased. Clot lysis at 30 min was also significantly reduced. We conclude that 7.5% hypertonic saline solution has anticoagulant effects if it replaces 7.5% or more of blood volume.
Off‐pump coronary artery surgery
Authors: Heames R. M. , Gill R. S. , Ohri S. K. , Hett D. A.
Published: March 2003

Summary Cardiopulmonary bypass has several associated deleterious effects that include a systemic inflammatory response, coagulopathy, central nervous system complications and a variable degree of end‐organ damage. The recent upsurge in interest in ‘beating‐heart’ surgery attempts to avoid these deleterious effects. Advances in surgical technique, such as the use of intracoronary shunts and the Octopus retractor, have made beating‐heart surgery a reality. The challenges for the anaesthetist are greater than for coronary artery surgery using cardiopulmonary bypass, and whilst some advantages are proven, such as the lack of the inflammatory response and the decreased need for blood or blood products, others have yet to be proved and there is a need for further research. The advantages and disadvantages need to be evaluated in randomised studies in order to confirm the safety and efficacy of these new techniques in terms of long‐term graft patency and decreased morbidity.
The effects of two methods for customising the original SAPS II model for intensive care patients from South England
Authors: Beck D. H. , Smith G. B. , Pappachan J. V.
Published: March 2003

Model customisation is used to adjust prognostic models by re‐calibrating them to obtain more reliable mortality estimates. We used two methods for customising the Simplified Acute Physiology Score II model for 15 511 intensive care patients by altering the logit and the coefficients of the original equation. Both methods significantly improved model calibration, but customising the coefficients was slightly more effective. The Hosmer‐Lemeshow χ2‐value improved from 306.0 (p< 0.001) before, to 14.5 (p < 0.07) and 23.3 (p < 0.06) after customisation of the coefficients and the logit, respectively. Discrimination was not affected. The standardised mortality ratio for the entire population declined from 1.16 (95% confidence interval: 1.13–1.20, p < 0.001) to 0.99 (95% confidence interval: 0.96–1.02, p < 0.22) after customisation of the coefficients. The uniformity‐of‐fit for patients grouped by operative status and comorbidities also improved, butremained imperfect for patients stratified by location before intensive care unit admission. Amalgamation of large, regional databases could provide the basis for the re‐calibration of standard prognostic models, which could then be used as a national reference system to allow more reliable comparisons of the efficacy and quality of care based on severity adjusted outcome measures.
The use of nitrous oxide in anaesthetic practice: a questionnaire survey
Authors: Henderson K. A. , Raj N. , Hall J. E.
Published: March 2003

Where practicable, exposure to a hazardous substance should be eliminated or adequately controlled. A postal questionnaire survey was sent to 10% of consultants from the Association of Anaesthetists of Great Britain and Ireland, to identify the level of use of nitrous oxide in current anaesthetic practice and identify any change of practice over the last 5 years. Details of anaesthetic practice were requested in three areas: nitrous oxide usage, availability of medical air on anaesthetic machines and the use of total intravenous anaesthesia. Replies were received from 320 consultants (75%). Of these, 49% felt that, over the last 5 years, their use of nitrous oxide had decreased. Twenty per cent of anaesthetists felt that there should be some restriction in availability of nitrous oxide. Where medical air was available, 32% felt that they would use it frequently. A total of 263 (83%) stated that they use total intravenous anaesthesia to some extent. The results showed that, although 49% of consultant anaesthetists had reduced their use of nitrous oxide, this was due to medical considerations rather than concerns over health and pollution issues arising from the use of nitrous oxide.
A standard XML Schema for computerised anaesthetic records
Authors: Gardner M. , Peachey T.
Published: March 2003

We believe that one of the most influential developments for the practice of anaesthesia in this decade will be the introduction of a national (or possibly international) standard XML Schema for computerised anaesthetic records, and that such development should be actively promoted by appropriate professional groups. We discuss the implications of such a schema, and make suggestions regarding its requirements. We also report on one approach to the development of an XML Schema for anaesthetic records (provisionally named SnowSchema in honour of Dr John Snow), and compare the current version with the suggested requirements.
‘Airway Alerts’. How UK anaesthetists organise, document and communicate difficult airway management*
Authors: Barron F. A. , Ball D. R. , Jefferson P. , Norrie J.
Published: March 2003

A questionnaire on organisation, documentation and communication of airway problems during anaesthesia was sent to 271 anaesthetic college tutors in the UK. Their responses were compared with three published recommendations. There was a 72% response rate (195/271). The recommendations of the American Society of Anaesthesiologists Task Force on the Management of the Difficult Airway were met by 71% of respondents; 2% met those suggested by the Canadian Airway Focus Group and 2% met those suggested in a standard UK textbook on difficulties in tracheal intubation. Guidelines for management of the difficult airway were available in 142 departments (73%), but only 41 (21%) had guidelines for communication and dissemination of information. We present an ‘Airway Alert’ scheme which has since been adopted by the Difficult Airway Society.
Calculating rates of syndepositional normal faulting in the western margin of the Mesozoic Subalpine Basin (south‐east France)
Authors: Dromart  , Allem  , Quiquerez
Published: March 2003

A method is developed to quantify the rate of fault movement, with a very fine time‐resolution, so that relevant histories of fault movements can be obtained. The study subject is a Triassic–Jurassic syndepositional normal fault located at the margin of an intracratonic deep basin, the Subalpine basin of south‐eastern France. The fault has recently been identified and specifically investigated by a seismic survey along with drilling (Géologie profonde de la France Program). The investigation is based on correlation of time‐lines on both sides of the structure through a period of about 70 Myr. Correlations have been made using variable approaches depending on the stratigraphic interval: recognition of laterally continuous marker‐beds, biostratigraphic information and application of genetic stratigraphy concepts. In the case of biostratigraphic data, absolute ages are assigned to selected lines of correlation to determine time lengths and calculate velocities of fault movements. A specific backstripping procedure is established. The differential subsidence history between the two sites is restored not as a simple subtraction made after conventional backstripping on each site but as the sum of discrete differential subsidence increments calculated for each chronostratigraphic interval. The originality of the work lies in the completion of the supporting data base, implementation of high‐resolution correlations within the large time‐span of the investigation and development of a method to calculate the differential subsidence. Even though unassessable errors and uncertainties are still associated with the stratigraphic correlations, the backstripping procedure and the chronological control, the overall method offers a certain validity because the calculated and the observed differential subsidences are close. Beyond the obvious control on depositional geometries and localization of some reservoirs at the toe of the fault, the kinetic regime of the normal fault played an indirect but crucial part in the differential burial‐related alteration of the reservoirs recorded on both sides of the fault. The high accuracy of the calculation has revealed that: (1) the growth pattern of the fault does not result from a continuous thermomechanical process but is composed of a series of rifting and sliding events related to gravity‐driven extension; (2) the spectacular differential stratigraphic record on both sides of the fault is associated with fairly low values of the fault growth rate (maximum of 165 m Myr−1). The method for measuring the growth of structures can be applied to any tectonic and sedimentary environment and offers a wide range of applications.
The dammed Hikurangi Trough: a channel‐fed trench blocked by subducting seamounts and their wake avalanches (New Zealand–France GeodyNZ Project)
Authors: Lewis Keith B. , Collot Jean‐Yves , Lallem Serge E.
Published: March 2003

The Hikurangi Trough, off eastern New Zealand, is at the southern end of the Tonga–Kermadec–Hikurangi subduction system, which merges into a zone of intracontinental transform. The trough is mainly a turbidite‐filled structural trench but includes an oblique‐collision, foredeep basin. Its northern end has a sharp boundary with the deep, sediment‐starved, Kermadec Trench.

Swath‐mapping, sampling and seismic surveys show modern sediment input is mainly via Kaikoura Canyon, which intercepts littoral drift at the southern, intracontinental apex of the trough, with minor input from seep gullies. Glacial age input was via many canyons and about an order of magnitude greater. Beyond a narrow, gravelly, intracontinental foredeep, the southern trench‐basin is characterized by a channel meandering around the seaward edge of mainly Plio‐Pleistocene, overbank deposits that reach 5 km in thickness. The aggrading channel has sandy turbidites, but low‐backscatter, and long‐wavelength bedforms indicating thick flows. Levées on both sides are capped by tangentially aligned mudwaves on the outsides of bends, indicating centrifugal overflow from heads of dense, fast‐moving, autosuspension flows. The higher, left‐bank levée also has levée‐parallel mudwaves, indicating Coriolis and/or boundary currents effects on dilute flows or tail plumes.

In the northern trough, basin‐fill is generally less than 2 km thick and includes widespread overbank turbidites, a massive, blocky, avalanche deposit and an extensive, buried, debris flow deposit. A line of low seamounts on the subducting plate acts as a dam preventing modern turbidity currents from reaching the Kermadec Trench. Major margin collapse probably occurred in the wake of a large subducting seamount; this seamount and its wake debris flow probably dammed the trench from 2 Ma to 0.5 Ma. Before this, similar dams may have re‐routed turbidity currents across the plateau.
Sedimentation and deformation in a Pliocene–Pleistocene transtensional supradetachment basin, Laguna Salada, north‐west Mexico
Authors: Dorsey  , Martín‐Barajas
Published: March 2003

This study examines a thick section of Pliocene–Pleistocene sedimentary rocks exposed in the footwall of an active normal fault (Cañon Rojo fault) near its intersection with the dextral‐normal Laguna Salada fault in north‐western Mexico. These rocks are situated in the upper plate of an inactive strand of the Cañada David detachment fault, which is cut on the north‐east by the Laguna Salada fault. The stratigraphy is divided into three unconformity‐bounded sequences: (1) marine mudstone of the Pliocene Imperial Formation; (2) nonmarine Pliocene–Pleistocene redbeds, consisting of sedimentary breccia, conglomerate, conglomeratic sandstone (all un‐named) and fine‐grained sandstone and mudstone of the Palm Spring Formation; and (3) uncemented Pleistocene boulder gravel. Coarse deposits of the redbeds sequence were deposited in fault‐bounded, high‐ and low‐gradient alluvial fans that passed laterally into a low‐energy fluvial plain of the ancestral Colorado River (Palm Spring Formation) which occupied the present‐day Laguna Salada.

Detailed mapping reveals convergence and lap‐out of bedding surfaces in the redbeds sequence onto the west limb of a large anticline cored by Imperial Formation. These geometries, combined with fanning dips and thickening of stratigraphy into the flanking syncline, indicate that the anticline grew during deposition of the redbeds. Fold axes of the growth anticline and smaller related folds trend N to NNE, parallel to the strike of associated normal faults and perpendicular to the extension direction. Based on its orientation, large size and relationship to neighbouring structures, the anticline is interpreted to be a fault‐bend fold that grew in response to slip of the upper plate over a bend in the Cañada David detachment fault during deposition in a transtensional supradetachment basin. Localized subsidence in the flanking syncline resulted in deposition of >1000 m of alluvial sediments near its intersection with the Laguna Salada fault. Sedimentary detritus is derived exclusively from the north‐east (footwall) side of the dextral‐normal Laguna Salada fault, indicating that topographic relief was high in the Sierra Cucapa and was subdued or negligible in the footwall of the coeval Cañada David detachment. Following deposition of the redbeds and grey gravel units, the northern part of the detachment fault was abandoned and the modern Cañon Rojo fault was initiated, producing rapid footwall uplift and erosion of previously buried stratigraphy. Slip rate on the Cañon Rojo fault is estimated to be ≈2–4 mm yr−1 since middle Pleistocene time, similar to the late Pleistocene to Holocene rate determined in previous studies.
Detrital zircon geochronology: enhancing the quality of sedimentary source information through improved methodology and combined U–Pb and fission‐track techniques
Authors: Carter A. , Bristow C. S.
Published: March 2003

ABSTRACT Zircon is the most widely used mineral in detrital dating studies because it is common to multiple rock types, is chemically and physically resistant, and can endure successive cycles of burial, metamorphism and erosion. Zircon also has the advantage that single grains may be dated by either the fission‐track (FT) or U–Pb method, which, because of their contrasting thermal sensitivities (total resetting occurs at temperatures > 320 °C for FT and > 700–900 °C for U–Pb), can provide unique information about both the age structure and the thermal evolution of a sediment source. However, single method‐based bias and difficulties associated with interpreting measured ages can influence both the quality and the level of useful provenance information. For example, the zircon FT system is sensitive to metamorphic overprinting and hence measured ages alone cannot be interpreted as unambiguously dating formation age of the source rock. In contrast, U–Pb zircon data have high resistance (700–900 °C) to thermal overprinting and therefore recorded formation ages may not relate to an immediate source but may instead reflect a polycyclical history. The focus of this paper is to examine, from a practical standpoint, the provenance potential of detrital zircon fission track data and to investigate the method’s complementary role as an aide to the interpretation of high‐temperature detrital U–Pb zircon data by combining U–Pb and FT methods in a single study.
Synsedimentary tensional features in Upper Triassic shallow‐water platform carbonates of the Carnian Prealps (northern Italy) and their importance as palaeostress indicators
Authors: Cozzi
Published: March 2003

The extensive shallow‐water carbonate platform deposits of the Dolomia Principale Formation (Southern Alps, northern Italy) accumulated during the Late Triassic, a time of plate‐scale reorganization and rifting. Synsedimentary tensional features such as fractures, neptunian dykes, normal faults, shatter breccias and laterally discordant intraformational breccias have been studied within a well‐preserved platform‐to‐basin transition in the Monte Pramaggiore area (Carnian Prealps). These tensional features follow three preferential orientations: N–S, E–W and NE–SW. To fully explain these different arrays it is proposed that the study area experienced during the Late Triassic the waning rifting phase connected to the westward propagation of the NeoTethys (N–S extension) and the onset of the rifting phase that led in the Middle Jurassic to the opening of the Central Atlantic (E–W extension), with a contemporaneous reactivation of Early–Middle Triassic NE–SW‐orientated faults. This palaeostress analysis reveals the good potential of tensional features as reliable palaeostress indicators.
Drainage patterns and tectonic forcing: a model study for the Swiss Alps
Authors: Kühni A. , Pfiffner O. A.
Published: March 2003

ABSTRACTA linear surface process model is used to examine the effect of different patterns of rock uplift on the evolution of the drainage network of the Swiss Alps. An asymmetric pattern of tectonic forcing simulates a phase of rapid retrothrusting in the south of the Swiss Alps (‘Lepontine’‐type uplift). A domal pattern of tectonic forcing in the north of the model orogen simulates the phase of the formation of the ‘Aar massif’, an external basement uplift in the frontal part of the orogenic wedge (‘Aar’‐type uplift).

Model runs using the ‘Lepontine’‐type uplift pattern result in a model mountain chain with a water divide in the zone of maximum uplift and orogen‐normal rivers. Model runs examining the effect of ‘Lepontine’‐type uplift followed by ‘Aar’‐type uplift show that the initially formed orogen‐normal river system and the water divide are both very stable and hardly affected by the additional uplift. This indifference to changes in tectonic forcing is mainly due to the requirement of a high model erosion capacity for the river systems in order to reproduce the exhumation data (high‐grade rocks in the south of the Swiss Alps point to removal of a wedge‐shaped nappe stack with a maximum thickness of about 25 km). The model behaviour is in agreement with the ancestral drainage pattern of the Alps in Oligocene and Miocene times and with the modern pattern observed in the Coast Range of British Columbia; in both cases river incision occurred across a zone of rapid uplift in the lower course of the rivers. The model behaviour does not, however, explain the modern drainage pattern in the Alps with its orogen‐parallel rivers.

When the model system is forced to develop two locally independent main water divides (simultaneous ‘Lepontine’‐ and ‘Aar’‐type uplift), a zone of reduced erosional potential forms between the two divides. As a consequence, the divides approach each other and eventually merge. The new water divide remains fixed in space independent of the two persisting uplift maxima. The model results suggest that spatial and temporal changes in tectonic forcing alone cannot produce the change from the orogen‐normal drainage pattern of the Swiss Alps in Oligocene–Miocene times to the orogen‐parallel drainage observed in the Swiss Alps today.
Mid‐Palaeocene palaeogeography of the eastern North Sea basin: integrating geological evidence and 3D geodynamic modelling
Authors: Gemmer Lykke , Huuse Mads , Clausen Ole R , Nielsen Søren B
Published: March 2003

The Mid‐Palaeocene palaeogeography of Denmark and the surrounding areas have been reconstructed on the basis of published geological data integrated with 3D geodynamic modelling. The use of numerical modelling enables quantitative testing of scenarios based on geological input alone and thus helps constrain likely palaeo‐water depths in areas where the geological data are inconclusive or incomplete.

The interpretation of large‐scale erosional valleys and small‐scale circular depressions at the Mid‐Palaeocene Top Chalk surface in the Norwegian–Danish basin as either submarine or subaerial features is enigmatic and has strong implications for palaeogeographical reconstructions of the eastern North Sea basin.

A 3D thermo‐mechanical model is employed in order to constrain the likely palaeo‐water depths of the eastern North Sea basin during the Palaeocene. The model treats the lithosphere as an elasto‐visco‐plastic continuum and models the lithospheric response to the regional stress field and thermal structure. The model includes the effects of sea‐level change, sedimentation and erosion, from the Mid Cretaceous to the present. Modelling results reproduce to first order geological data such as present sediment isopachs and palaeo‐water depths.

It is concluded that the Mid Palaeocene water depths in the Norwegian–Danish basin were about 250 m. The erosional valleys and circular depressions at the top of the Upper Cretaceous‐Danian Chalk Group are thus interpreted to have formed in relatively deep water rather than due to subaerial exposure. Likely interpretations of the structures are therefore submarine valleys and pockmarks.
Role of initial depth at basin margins in sequence architecture: field examples and computer models
Authors: Uličný David , Nichols Gary , Waltham Dave
Published: March 2003

A delay in the onset of sedimentation during fault‐related subsidence at a basin margin can occur in both extensional settings, where footwall tilting may cause a diversion of drainage patterns, and in strike‐slip basins, where a source area may be translated along the basin margin. The ‘initial depth’ created by this delay acts as pre‐depositional accommodation and is a partly independent variable. It controls the geometry of the first stratal units deposited at the basin margin and thus modifies the response of the depositional system to subsequent, syndepositional changes in accommodation. In systems with a sharp break in the depositional profile, such as the topset edge in coarse‐grained deltas, the initial depth controls the foreset height and therefore the progradational distance of the topset edge. The topset length, in turn, influences topset accommodation during cyclical base level variations and therefore is reflected in the resulting stacking patterns at both long‐ and short‐term time scales. In the simplified cases modelled in this study, it is the relationship between the initial depth and the net increase in depth over the interval of a relative sea‐level cycle (ΔH) that governs long‐ and short‐term stacking patterns. In situations where the initial depth is significantly larger than ΔH, the topset accommodation of the first delta is insufficient to contain the volume of sediment of younger sequences formed during subsequent relative sea‐level cycles. Therefore, the depositional system tends to prograde over a number of relative sea‐level cycles before the topset area increases so that the long‐term stacking pattern changes to aggradation. Stacking patterns of high‐frequency sequences are influenced by a combination of topset accommodation available and position of the short‐term relative sea‐level cycles on the rising or falling limb of a long‐term sea‐level curve. This determines whether deposits of short‐term cycles are accommodated in delta topsets or foresets, or in both. Variations in stacking pattern caused by different initial depths may be misinterpreted as due to relative sea level or sediment supply changes and it is necessary to consider initial bathymetry in modelling and interpretation of stacking patterns, especially in fault‐bounded basins.
The long‐term thermal consequences of rifting: implications for basin reactivation
Authors: Sandiford M. , Frederiksen S. , Braun J.
Published: March 2003

The attenuation of the continental crust during rifting and the subsequent filling of the rift‐related accommodation alter the long‐term thermal and mechanical state of the lithosphere. This is primarily because the Moho is shallowed due to density contrasts between the sediment fill and the crust, but also reflects the attenuation of the pre‐existing crustal heat production and its burial beneath the basin, as well the thermal properties of the basin fill. Moho shallowing and attenuation of pre‐existing heat production contribute to long‐term cooling of the Moho and thus lithospheric strengthening, as has been pointed out in many previous studies. In contrast, basin filling normally contributes to significant Moho heating allowing the possibility of long‐term lithospheric weakening, the magnitude of which is dependent on the thermal properties of the basin‐fill and the distribution of heat sources in the crust. This paper focuses on the thermal property structure of the crust and basin‐fill in effecting long‐term changes in lithospheric thermal regime, with particular emphasis on the distribution of heat producing elements in the crust. The parameter space appropriate to typical continental crust is explored using a formalism for the heat production distributions that makes no priori assumptions about the specific form of the distribution. The plausible parameter space allows a wide range in potential long‐term thermal responses. However, with the proviso that the accommodation created by the isostatic response to rifting is essentially filled, the long‐term thermal response to rift basin formation will generally increase average crustal thermal gradients beneath basins but cool the Moho due to its reduction in depth. The increase in the average crustal thermal gradient induces lateral heat flow that necessarily heats the Moho along basin margins, especially in narrow rift basins. Using coupled thermo‐mechanical models with temperature sensitive creep‐parameters, we show that such heating may be sufficient to localise subsequent deformation in the vicinity of major basin bounding structures, potentially explaining the offset observed in some stacked rift basin successions.
Pharmacokinetics of recombinant human interleukin‐2 in advanced renal cell carcinoma patients following subcutaneous application
Authors: Kirchner G. I. , Franzke A. , Buer J. , Beil W. , Probst‐Kepper M. , Wittke F. , Övermann K. , Lassmann S. , Hoffmann R. , Kirchner H. , Ganser A. , Atzpodien J.
Published: March 2003

Aims
 The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin‐2 (rhIL‐2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.

Methods
 RhIL‐2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×106 IU m−2 once daily and group B 10×106 IU m−2 twice daily (every 12 h). Additionally, in all patients the influence of soluble interleukin‐2 receptor (sIL‐2R) on the pharmacokinetics of rhIL‐2 was investigated.

Results
 The mean area under the serum concentration‐time curve to 24 h (AUC(0,24 h)) was 627 IU ml−1 h in treatment group A and 1130 IU ml−1 h (P=0.029) in treatment group B. In both study groups Cmax and AUC(0,12 h) were not significantly different. Seventy‐two hours after the beginning of s.c. rhIL‐2 therapy the sIL‐2R increased significantly (P=0.016), and sIL‐2R levels over 1200 pmol l−1 seemed to reduce the AUC.

Conclusions
 In patients with metastatic renal cell cancer administration of 20×106 IU m−2 of rhIL‐2 s.c. in two daily doses (10×106 IU m−2 every 12 h) provides better bioavailability and is preferable to the single dose administration.
Exogenous L‐arginine does not affect angiotensin II‐induced renal vasoconstriction in man
Authors: Wolzt Michael , Ugurluoglu Ara , Schmetterer Leopold , Dorner Guido , Zanaschka Gabriele , Mensik Christa , Eichler Hans‐Georg
Published: March 2003

Aims
 It has been suggested that provision of the substrate of nitric oxide (NO) synthesis, l‐arginine, might influence the effects of renal vasoconstrictors. We have therefore studied the effects of pretreatment or concomitant administration of l‐arginine on angiotensin II (ANG II)‐increased renovascular resistance.

Methods
 The study was conducted in a double‐blind, randomized, cross‐over design. Eight healthy subjects were assigned to placebo or a continuous intravenous coinfusion of ANG II (5.0 ng kg−1 min−1, infusion period 75 min) with l‐arginine (17 mg kg−1 min−1, infusion period 30 min). Nine further subjects received a continuous infusion of ANG II with or without pretreatment of l‐arginine. Changes in renal plasma flow (RPF) were estimated by the steady state clearance of PAH.

Results
 l‐arginine alone increased RPF to 110±10% over baseline (P<0.003). The ANG II‐induced decrease in RPF was not affected by pretreatment or coinfusion of l‐arginine.

Conclusions
 Our results demonstrate that a counterregulatory response of the renal vasculature to high levels of ANG II does not depend on exogenous l‐arginine. In healthy subjects, this lack of functional antagonism at the renal vasculature is therefore not a result of NO substrate availability.
Concomitant administration of cholestyramine influences the absorption of troglitazone
Authors: Young M. A. , Lettis S. , Eastmond R.
Published: March 2003

Aim
 Troglitazone is an orally active anti‐diabetic agent. Cholestyramine is an orally administered lipid‐lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclinical studies suggesting the potential for an interaction between troglitazone and cholestyramine require confirmation in a clinical setting.

Methods
 In vitro and in vivo experiments in the dog were carried out prior to a clinical study. Twelve healthy volunteers (mean age 32 years, range 20–44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazone) in an open, two‐way crossover study.

Results
 In vitro, about 99% of troglitazone was adsorbed by cholestyramine at an incubate concentration of 3 μg ml−1 whilst at 500 μg ml−1 adsorption fell to about 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 μg ml−1 h (95% CI for difference 28–57, P=0.01) in 11 beagle dogs receiving troglitazone 200 mg and cholestyramine 1 g compared with control values. Mean maximum plasma concentration (Cmax ) was 49% of control values (7.08 vs 3.42 μg ml−1 (95% CI for difference 14–85, P=0.05)). In the clinical study median AUC for troglitazone and its two major metabolites were statistically significantly lower when troglitazone was administered with cholestyramine (17.9 vs 5.2 μg ml−1 h (95% CI for difference −20.5, −8.7), 133.7 vs 27 1 μg ml−1 h (−166.4, −67.8) and 18.4 vs 2.5 μg ml−1 h (−21.6, −10.6) for troglitazone, sulphate and quinone metabolite respectively (all P<0.01) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in Cmax for the sulphate metabolite (4.56 vs 1.28 μg ml−1 (95% CI for difference −4.42, −1.99, P<0.01)), but not for troglitazone (1.85 vs 1.23 μg ml−1 (−1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 μg ml−1 (−0.77, 0.09)).

Conclusions
 The results were indicative of an alteration in the extent of troglitazone's absorption. Concomitant administration of troglitazone and cholestyramine could severely impair troglitazone's clinical utility as an antihyperglycaemic agent.
Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide
Authors: Noon Joseph P. , Walker Brian R. , Hand Malcolm F. , Webb David J.
Published: March 2003

Aims
 Impaired function of the vascular endothelium has been well documented in hypertension and hypercholesterolaemia. However, the ‘gold standard’ method for assessing endothelial function, using intra‐arterial drug infusion, is invasive and has only been applied in the forearm and coronary circulations in vivo. The aim of the present study was to establish the non‐invasive technique of transdermal drug iontophoresis to assess endothelial function in human dermal vessels in vivo.

Methods
 In healthy male volunteers, we delivered acetylcholine (ACh) and sodium nitroprusside (SNP) to dermal vessels of the forearm using iontophoresis, and measured vasodilatation using laser Doppler fluximetry. Drugs were diluted in a methylcellulose gel vehicle which did not induce vasodilatation. To assess the contribution of nitric oxide and vasoactive prostanoids to cholinergic dilatation, the procedure was repeated during brachial artery infusion of the nitric oxide synthase inhibitor, l‐NG‐monomethyl‐arginine (l‐NMMA) and after intravenous administration of the cyclooxygenase inhibitor, aspirin. As a control for the vasoconstrictor effect of l‐NMMA, which was measured by venous occlusion plethysmography, iontophoresis was repeated during brachial artery infusion of noradrenaline.

Results
 Flux increased in response to iontophoresis of ACh (from 45±9 to 499±80 units; P<0.0001) and SNP (from 32±11 to 607±82 units; P<0.0001). Brachial artery infusions of l‐NMMA or noradrenaline caused reductions in forearm blood flow (by 43±2% and 44±2%, respectively) but did not inhibit vasodilatation in response to iontophoresis of ACh or SNP. In contrast, aspirin inhibited the response to iontophoresis of ACh (from 473±81 to 222±43 units; P<0.0001) but did not affect the response to SNP (from 348±59 to 355±58).

Conclusions
 We conclude that in healthy subjects, in contrast to the forearm circulation, dermal vasodilatation in response to iontophoresis of ACh is mediated predominately by a dilator prostanoid rather than by nitric oxide generation. Furthermore, the non‐invasive technique of iontophoresis could complement existing invasive tests of endothelial function in future clinical studies.
Terfenadine and risk of acute liver disease
Authors: Wald Myers Marian , Jick Hershel
Published: March 2003

Aims
 To estimate the risk of idiopathic acute liver disease among users of terfenadine.

Methods
 We conducted a population‐based cohort study based on the General Practice Research Database (GPRD) in the U.K. All persons who received at least one prescription for terfenadine during the period 1991 through 1995 were eligible for the study. Among these patients we identified all those with a diagnosis of a liver disorder requiring hospitalization or referral to a consultant within 60 days of a prior prescription for terfenadine. We obtained clinical records, including hospital discharge summaries, consultant reports and relevant laboratory results in order to identify a potentially drug‐inducible liver illness.

Results
 From a cohort of 210 683 recipients of terfenadine, we found only three cases of acute liver disease where a causal connection to terfenadine could not be ruled out, yielding a risk estimate of 1.4/100 000 users (95% CI 0.5, 4.2) and 0.5/100 000 prescriptions (95% CI 0.2, 1.4). All cases were receiving a concomitant hepatotoxic drug and all had a full recovery.

Conclusion
 The use of terfenadine is rarely associated with idiopathic acute liver disease.
A comparison of the cardiovascular effects of levobupivacaine and rac‐bupivacaine following intravenous administration to healthy volunteers
Authors: Bardsley Hazel , Gristwood Robert , Baker Helen , Watson Norma , Nimmo Walter
Published: March 2003

Aims
 The aim of this study was to compare the cardiovascular effects of levobupivacaine with those of rac‐bupivacaine following i.v. administration to 14 healthy male volunteers.

Methods
 Drugs were infused (at 10 mg min−1 ) using a randomized, double‐blind, complete crossover procedure with a washout period of at least 1 week. The administration of drug was discontinued on the appearance of defined CNS symptoms or when a total of 150 mg had been given. Parameters measured were arterial blood pressure, heart rate, ECG, ejection fraction, acceleration index, stroke index and cardiac index.

Results
 The mean doses administered were 56.1 mg and 47.9 mg for levobupivacaine and rac‐bupivacaine respectively and the maximum mean plasma concentrations were 2.62 and 2.25 μg ml−1 respectively. Despite the dose and plasma concentrations being comparable, levobupivacaine produced a statistically significant smaller reduction in mean stroke index (−5.14 vs−11.86 ml m−2, P=0.001), acceleration index (−0.09 vs−0.20 s−2, P=0.011) and the ejection fraction (−2.50 vs−4.29%, P=0.024). Both levobupivacaine (non significant) and rac‐bupivacaine (significant) produced small increases in the PR interval and the corrected QT interval and although the effects of rac‐bupivacaine appeared to be greater the difference between the two drugs was not significant.

Conclusions
 In conclusion, this study has shown that following i. v. administration levobupivacaine produces significantly less effects on cardiovascular function than does rac‐bupivacaine. In particular the negative inotropic effect for levobupivacaine was less than that for rac‐bupivacaine as indicated by changes in stroke index, acceleration index and ejection fraction.
Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease
Authors: Fontana Robert J. , DeVries Tina M. , Woolf Thomas F. , Knapp Margaret J. , Brown AS , Kaminsky Laurence S. , Tang Bing‐Kuo , Foster Norman L. , Brown Richard R. , Watkins Paul B.
Published: March 2003

Aims
 To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease.

Methods
 The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg−1 [13C‐3‐methyl] caffeine orally and had breath and urine samples collected.

Results
 Tacrine oral clearance (CL F−1 kg−1 ), which varied 15‐fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the raxanthine/caffeine ratio’ (1,7X+1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the ‘caffeine metabolic ratio’ (AFMU+1X+1U)/1, 7U)(r=0.76, P=0.0001).

Conclusions These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not suffcient to be clinically useful in individualizing tacrine therapy.
Expanding clinical applications of population pharmacodynamic modelling
Authors: Minto Charles , Schnider Thomas
Published: March 2003

Population pharmacokinetics or pharmacodynamics is the study of the variability in drug concentration or pharmacological effect between individuals when standard dosage regimens are administered. We provide an overview of pharmacokinetic models, pharmacodynamic models, population models and residual error models. We outline how population modelling approaches seek to explain interpatient variability with covariate analysis, and, in some approaches, to characterize the unexplained interindividual variability. The interpretation of the results of population modelling approaches is facilitated by shifting the emphasis from the perspective of the modeller to the perspective of the clinician. Both the explained and unexplained interpatient variability should be presented in terms of their impact on the dose–response relationship. Clinically relevant questions relating to the explained and unexplained variability in the population can be posed to the model, and confidence intervals can be obtained for the fraction of the population that is estimated to fall within a specific therapeutic range given a certain dosing regimen. Such forecasting can be used to develop optimal initial dosing guidelines. The development of population models (with random effects) permits the application of Bayes’s formula to obtain improved estimates of an individual’s pharmacokinetic and pharmacodynamic parameters in the light of observed responses. An important challenge to clinical pharmacology is to identify the drugs that might benefit from such adaptive‐control‐with‐feedback dosing strategies. Drugs used for life threatening diseases with a proven pharmacokinetic‐pharmacodynamic relationship, a small therapeutic range, large interindividual variability, small interoccasion variability and severe adverse effects are likely to be good candidates. Rapidly evolving changes in health care economics and consumer expectations make it unlikely that traditional drug development approaches will succeed in the future. A shift away from the narrow focus on rejecting the null hypothesis towards a broader focus on seeking to understand the factors that influence the dose–response relationship—together with the development of the next generation of software based on population models—should permit a more efficient and rational drug development programme.