Fertility and ovarian function in high-dose estrogen-treated tall women.

BACKGROUND/OBJECTIVE: High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence. METHODS: This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22-47 yr served as controls. RESULTS: Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44, 95% CI 1.76-6.73). Moreover, fecundity was notably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased. CONCLUSION: High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility.

Mapping OpenSDE domain models to SNOMED CT. Applied to the domain of cardiovascular disease.

UNLABELLED: To explore the strengths and pitfalls of mapping structured EPR (electronic patient record) terms (OpenSDE) to SNOMED codes. METHODS: The OpenSDE model was developed for cardiovascular diseases in the context of the I4C project. We employed 35 patient records as references to adjust the model. We then performed automated and manual matches following the design of matching terms in the thesaurus of the resulting OpenSDE domain model to SNOMED concepts. Subsequently, we assessed what number of OpenSDE terms within the domain model can be matched to SNOMED concepts. RESULTS: The OpenSDE domain tree contains 3230 nodes, involving 689 unique terms (terms can be associated with more than one node in different parts of a domain model tree). After final manual work for the 689 tree terms, 616 resulted in a good match, 31 in a partial match, and 42 in no match. Of the good matches, 23 produced multiple matches. The matches were used to represent the mapping of each node in the domain tree by concatenation of the matching terms. CONCLUSIONS: Mapping predefined terms in OpenSDE domain models to SNOMED Clinical Terms (CT) concepts eliminates laborious mapping for each individual patient record. The assignment of SNOMED codes to OpenSDE tree nodes facilitates exchange, aggregation, and research involving patient data. The mapping will serve the construction of queries at higher semantic levels than explicitly modeled in an OpenSDE domain model. However, the usefulness of the mapping result depends on the completeness of the mapping to SNOMED CT, for which there is no gold standard.

Are structured data structured identically? Investigating the uniformity of pediatric patient data recorded using OpenSDE.

OBJECTIVE: OpenSDE is an application that supports structured recording of narrative patient data to enable use of the data in both clinical practice and clinical research. Reliability and accuracy of collected data are essential for subsequent data use. In this study we analyze the uniformity of data entered with OpenSDE. Our objective is to obtain insight into the consensus and differences of recorded data. METHODS: Three pediatricians transcribed 20 paper patient records using OpenSDE. The transcribed records were compared and all recorded findings were classified into one of six categories of difference. RESULTS: Of all findings 22% were recorded identically; 17% of the findings were recorded differently (predominantly as free text); 61% was omitted, inferred, or in conflict with the paper record. CONCLUSION: The results of this study show that recording patient data using structured data entry does not necessarily lead to uniformly structured data.

Considerations for the representation of meta-data for the support of structured data entry.

OBJECTIVES: Research and decision support require patient data to be structured. Flexible data representation, to cope with expansion and new recording demands, can be achieved through abstraction of the data model. Such a model, however, does not include explicit information for the support of structured data entry (SDE), i.e. the definition of what is relevant to say in a specific context. The objective of this paper is to provide considerations for an intuitive conceptual representation of such meta-data for domain experts. METHODS: The content of meta-data for SDE is compared with that of controlled medical terminologies in the context of its purpose. RESULTS: Upon analysis of medical descriptions, a network and a tree both emerge as an intuitive structure to represent meta-data for the support of SDE. The pros and cons of a tree versus a network are dominated by the challenges of representing multiple contexts for description. Meta-data for SDE only partially overlap with the content of controlled medical terminologies. CONCLUSIONS: Integration of meta-data for SDE and controlled terminologies would benefit standardization and retrieval, but the requirements for flexible data entry are at odds with the rigidity and limited granularity of a standard. The preferred strategy seems to be a mapping between the concepts from a terminology standard and meta-data for SDE.

Extensions to the HISA standard--the SynEx computing environment.

OBJECTIVES: This paper reports on the integration work required to support the delivery of healthcare. Specifically, four elements are included being: the DHE (a standards based distributed healthcare environment), Synapses which is a patient record server, XML as a technology to deliver records, and finally two client applications that facilitate structured data entry (SDE) and the remote booking of specialist services. METHODS: A general motivation for the work is presented and augmented on hand of a clinical scenario. Additionally, the adoption of a middleware approach is reviewed. The role of computerised patient records is described followed by an account of a federated record server. The approach favoured by standards bodies in utilising XML is covered and the tailoring to suit the needs of the integration is explained. The main practical challenges in achieving integration are presented, one of these being the mapping between the DHE data model and the Synapses server record architecture. RESULTS: The described environment has been demonstrated to provide the functionality that is required and in addition it has been shown that the engineering challenges can be met in a controlled and orderly manner. CONCLUSIONS: The role of the DHE middleware component acting as an 'anchor' has been shown to be a valid one onto which other specialised components can be added to provide a richer service environment. Additionally, it has been demonstrated that XML is a good candidate technology that facilitates connectivity to client applications over an extranet. The demands inherent in both the clinical scenario and the computerised patient record can be met by the computing environment described in the paper.

Principles of structured data entry applied to reference sources.

Our Structured Data Entry application makes use of a domain specific data model. The principles governing the modeling of this data model, are similar to the requirements of the criteria underlying taxonomic systems. Using the DSM-IV as reference source to create a data model for psychiatry, revealed a number of flaws in the criteria of this system, which potentially influence the reliability and validity of this taxonomic system. We conclude that the modeling process provides us with a powerful tool which can be used during the revision process of such systems.

Experiences with extracting structured patient data for use in clinical research.

Routinely collected patient data are often recorded as unstructured and ambiguous free text by physicians. These data are, however, also of interest to clinical researchers, for whom they must be clearly defined and preferably coded. We have developed an application to support physicians in recording patient data in a structured, yet expressive manner. The flexible domain-independent data representation and storage approach underlying the application made data extraction for research purposes very complex. The changes that we made to the representation and storage approach to facilitate extraction, without reducing expressiveness for data entry, are presented in this paper, together with the underlying principles of the data extraction tool that we created to enable data extraction for clinical research.

Ionic mechanism of delayed afterdepolarizations in ventricular cells isolated from human end-stage failing hearts.

BACKGROUND: Animal studies have shown that the Ca(2+)-activated Cl(-) current (I(Cl(Ca))) and the Na(+)/Ca(2+) exchange current (I(Na/Ca)) contribute to the transient inward current (I(ti)). I(ti) is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of I(ti) and DADs in human cardiac cells. METHODS AND RESULTS: Human ventricular cells were enzymatically isolated from explanted hearts of patients with end-stage heart failure and studied with patch-clamp methodology. I(ti)s were elicited in the presence of 1 micromol/L norepinephrine by trains of repetitive depolarizations from -80 to +50 mV. DADs were induced in the presence of 1 micromol/L norepinephrine at a stimulus frequency of 1 Hz. I(ti) currents were inwardly directed over the voltage range between -110 and + 50 mV. Neither the Cl(-) channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid nor changes in [Cl(-)](i) affected I(ti) or DAD amplitude. This excludes an important role for I(Cl(Ca)). Blockade of Na(+)/Ca(2+) exchange by substitution of all extracellular Na(+) by Li(+), conversely, completely inhibited I(ti). In rabbit, I(Cl(Ca)) density in ventricular cells isolated from control hearts did not differ significantly from that in ventricular cells isolated from failing hearts. CONCLUSIONS: In contrast to many animal species, I(ti) and DADs in human ventricular cells from failing hearts consist only of I(Na/Ca). In rabbits, heart failure per se does not alter I(Cl(Ca)) density, suggesting that I(Cl(Ca)) may also be absent during DADs in nonfailing human ventricular cells.

Structured physical examination data: a modeling challenge.

The success of systems facilitating collection of structured data by clinicians is largely dependent on the flexibility of the interface. The Open Record for CAre (ORCA) makes use of a generic model to support knowledge-based structured data entry for a variety of medical domains. An endeavor undertaken recently aimed to cover the broader area of Physical Examination by expanding the contents of the knowledge base. The model was found to be adequately expressive for supporting this task. Maintaining the balance between flexibility of the interface and constraints dictated by reliable retrieval, however, proved to be a considerable challenge. In this paper we illustrate through specific examples the effect of this trade off on the modeling process, together with the rationale for the chosen solutions and suggestions for future research focus.

A multi-disciplinary approach to a user interface for structured data entry.

Physician data entry (PDE) is still an obstacle to the adoption of a CPR that replaces the paper chart. Most interfaces have been designed primarily on the basis of the functional requirements. Few studies document methods to elicit interface preferences from the clinician-user. We used insights from the fields of both medicine and Human Computer Interfaces to explore interface alternatives for structured data entry (SDE). We present and discuss three designs as alternatives for the SDE module in ORCA (Open Record for CAre). The methodology is applied to SDE in particular, but many aspects also apply to CPRs in general.

Computer-based diagnostic support systems in histopathology: what should they do?

In many fields in histopathology diagnosis making is notoriously difficult. We explored the diagnostic process in the area of CL and related disorders. The field of cutaneous lymphomas (CL) and borderline lesions is complex and representative for the type of diagnostic problems encountered. A review of diagnostic support systems in diagnostic pathology revealed that the usefulness of these systems has been disappointing. We contribute this to the fact that these systems target only part of the diagnostic process. A tentative model of diagnosis making in pathology is presented. This model assumes a two-step process, from observation to feature recognition and from features to diagnosis. In a retrospective study of existing skin biopsy pathology reports we assessed detail and scope of the histological descriptions. In a second, prospective study, a pathologist panel described a set of 16 skin biopsies using a standard set of descriptors. The retrospective study showed a large variability in the nature and details of described features, whereas the prospective study showed lack of consensus regarding both feature descriptions and diagnostic category. Both studies provide an indication that lack of consensus in feature recognition may be an important contributor to lack of consensus at the diagnostic level. Diagnostic expert systems target the step from feature to diagnosis. Evidently different input into such systems produces different output. We conclude that support of the feature recognition step can contribute to better diagnostic consensus because of more uniform interpretation of observations.

Role of Ca(2+)-activated Cl(-) current in ventricular action potentials of sheep during adrenoceptor stimulation.

Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca(2+)-activated Cl(-) current (I(Cl(Ca))) and depolarising L-type Ca(2+) current (I(Ca,L)) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole-cell current-clamp recordings revealed that noradrenaline accelerated and prolonged phase-1 repolarisation. We define the minimal potential at the end of phase-1 repolarisation as "notch level". Noradrenaline (1 microM) caused the notch level to fall from 14 +/- 2.6 to 7.8 +/- 2.8 mV (n = 24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole-cell voltage-clamp recordings showed that 1 microM noradrenaline increased both I(Ca,L) and I(Cl(Ca)), but it had no significant effect on the principal K(+) currents. Blockage of I(Cl(Ca)) by 0.5 mM 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase-1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased I(Ca,L) upon adrenoceptor stimulation is prevented by an increased I(Cl(Ca)) in sheep ventricular myocytes. Experimental Physiology (2001) 86.2, 151-159.

Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias.

OBJECTIVE: The delayed phase of ventricular arrhythmias during acute ischemia (phase-1b arrhythmia) is associated with depletion of catecholamines and cell-to-cell uncoupling between depressed depolarized intramural ischemic region and surviving cells in subepicardium and subendocardium. In the present study we determined the effects of uncoupling and catecholamines on development of proarrhythmic afterdepolarizations. METHODS: Depressed depolarized ischemic region was simulated by a passive electronic circuit with a potential of -73, -53, -33 or -13 mV. Using patch-clamp methodology, single sheep Purkinje and ventricular cells were coupled to the simulated ischemic region via a variable conductance. By varying coupling conductance, we were able to selectively study the effects of various degrees of uncoupling. RESULTS: At strong coupling, cells were inexcitable and depolarized to potentials near those of the simulated ischemic region. Excitability, action potential duration and resting potential increased with progressive uncoupling. In a critical range of uncoupling, ventricular and "high-plateau" Purkinje cells developed early afterdepolarizations when the potential of the simulated ischemic region was -13 mV. Norepinephrine (1 microM) frequently induced early and delayed afterdepolarizations in both ventricular and Purkinje cells, but these afterdepolarizations were only present during uncoupling when the potential of the simulated ischemic region was -33 mV or more positive. CONCLUSIONS: In a critical range of uncoupling, afterdepolarizations were present when the potential of the simulated ischemic region was -33 or -13 mV, suggesting that triggered activity plays a role in phase-1b arrhythmias when surviving layers uncouple from a highly depolarized intramural ischemic region.

Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts.

AIMS: Congestive heart failure is characterized by high levels of norepinephrine which is considered to be arrhythmogenic. It is unclear whether increased norepinephrine is only a marker of the severity of heart failure or whether it directly triggers ventricular arrhythmias. METHODS AND RESULTS: Ventricular myocytes were isolated from eight explanted hearts of patients with end-stage heart failure (ischaemic or dilated cardiomyopathy). With the whole-cell configuration of the patch-clamp technique the effect of 1 micromol x l(-1)norepinephrine on action potentials and membrane currents was studied. The cells had a membrane capacitance of 256 +/- 25 pF (n = 26) and action potential duration (APD90) during control conditions was 620 +/- 45 ms at 1 Hz (n = 14). Norepinephrine induced action potential prolongation in all cells and early afterdepolarizations in 50% of them. Norepinephrine significantly increased the calcium current but had no effect on the delayed rectifier current, the inward rectifier current or the transient outward current. Norepinephrine also significantly increased the steady-state calcium window-current measured between -40 and 0 mV. CONCLUSIONS: In contrast to many animal species, norepinephrine induces action potential prolongation in ventricular myocytes from human failing hearts, as well as early afterdepolarization, by an increase in both the calcium peak current and window current. Thus norepinephrine seems to be an important arrhythmogenic factor in congestive heart failure.

Cl- current blockade reduces triggered activity based on delayed afterdepolarisations.

OBJECTIVES: Increasing evidence suggests that a Ca2+-activated Cl- current (ICl(Ca)) contributes to the transient inward current (Iti), the current responsible for proarrhythmic delayed after-depolarisations (DADs). Because the equilibrium potential for Cl- ions (ECl) in myocytes is around - 50 mV, activation of the ICl(Ca) results in an inward depolarising current at resting membrane potential and ICl(Ca) may thus be responsible for a part of the depolarisation during a DAD. In this study, we investigated the ionic nature of Iti and the effects of Cl- current blockade on DADs. METHODS AND RESULTS: The ionic mechanisms of Iti and underlying DADs were studied in sheep ventricular myocytes using the patch-clamp methodology. The DADs were induced in the myocytes by exposure to 1 µM noradrenaline and the Iti were elicited by repetitive depolarisations from -93 mV to +37 mV in the presence of the drug. The current-voltage relation of Iti reversed in sign around -20 mV. The outward Iti was completely blocked by the anion current blocker 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), whereas the inward Iti was only slightly affected. The DIDS-sensitive component of Iti was outwardly rectifying with a reversal potential close to ECl. The DIDS-insensitive component of Iti was abolished by blockade of the Na+-Ca2+ exchanger by substitution of extracellular Na+ by equimolar Li+. Interestingly, DIDS reduced the DAD amplitude and triggered activity based on DADs. CONCLUSION: In sheep ventricular myocytes, Iti consists of two ionic mechanisms: a Cl- current and a Na+-Ca2+ exchange current. Blockade of the Cl- current may be potentially antiarrhythmic by lowering DAD amplitude and triggered activity based on DADs.

The advantages of standardized evaluation of male infertility.

Healthcare can be improved by standardization and by evaluation of diagnostic methods and treatments. In the field of andrology, in which large patient numbers are required for the evaluation of diagnostic procedures and treatments, structured data collection and multicentre studies are especially warranted. Concomitant with routine clinical practice, a large amount of clinical data are collected that may be used to evaluate andrological care. Structuring and electronic storage of data holds promise in terms of clarity and accessibility of the data and its use for validation studies. The aim of the present work was to study the merits of routine collection of a common dataset in a computer-based patient record (CPR) for standardization, quality of data and clinical research. It was studied whether the data were of sufficient quality and accessibility for much needed studies on aetiology, interventions and diagnostics in andrology. Data collection in a structured CPR promoted complete and comprehensive data. We describe the advantages, pitfalls and solutions with this approach. Data on the uniform examination of 1549 infertile men became readily accessible. Population characteristics, basal associations and original studies were enabled and provided insight into the efficiency of clinical practice. In 66% of men, a cause for their infertility was identified, which provides a better rationale for treatment than semen parameters alone. For more than 30% of the patients, a rational andrological treatment was available, which could be deployed before assisted reproductive technologies were resorted to. However, most treatments have not been properly validated. The thorough diagnostic evaluation identifies subgroups that require an evidence base for treatment and further study on aetiology and diagnosis. Structured collection of uniform patient data through a CPR was feasible and facilitated the evaluation of diagnostic and therapeutic modalities. The reported advantages, pitfalls and solutions with this approach may help other centres to decide on how to implement a CPR. Conscientious collection of a standard data set in infertility centres facilitates pooling of data and evidence-based multicentre research.

Calcium-activated Cl(-) current contributes to delayed afterdepolarizations in single Purkinje and ventricular myocytes.

BACKGROUND: The ionic mechanism underlying the transient inward current (I(ti)), the current responsible for delayed afterdepolarizations (DADs), appears to be different in ventricular myocytes and Purkinje fibers. In ventricular myocytes, I(ti) was ascribed to a Na(+)-Ca(2+) exchange current, whereas in Purkinje fibers, it was additionally ascribed to a Cl(-) current and a nonselective cation current. If Cl(-) current contributes to I(ti) and thus to DADs, Cl(-) current blockade may be potentially antiarrhythmogenic. In this study, we investigated the ionic nature of I(ti) in single sheep Purkinje and ventricular myocytes and the effects of Cl(-) current blockade on DADs. METHODS AND RESULTS: In whole-cell patch-clamp experiments, I(ti) was induced by repetitive depolarizations from -93 to +37 mV in the presence of 1 micromol/L norepinephrine. In both Purkinje and ventricular myocytes, I(ti) was inward at negative potentials and outward at positive potentials. The anion blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) blocked outward I(ti) completely but inward I(ti) only slightly. The DIDS-sensitive component of I(ti) was outwardly rectifying, with a reversal close to the reversal potential of Cl(-) currents. Blockade of Na(+)-Ca(2+) exchange by substitution of extracellular Na(+) by equimolar Li(+) abolished the DIDS-insensitive component of I(ti). DIDS reduced both DAD amplitude and triggered activity based on DADs. Conclusions-In both Purkinje and ventricular myocytes, I(ti) consists of 2 ionic mechanisms: a Cl(-) current and a Na(+)-Ca(2+) exchange current. Blockade of the Cl(-) current may be potentially antiarrhythmogenic by lowering DAD amplitude and triggered activity based on DADs.

Injury current modulates afterdepolarizations in single human ventricular cells.

OBJECTIVE: Injury current (I(injury)) and afterdepolarizations are thought to play an important role in arrhythmias that occur during acute ischemia. However, little is known about the effects of I(injury) on afterdepolarizations. The present study was designed to study the effect of I(injury) on afterdepolarizations and action potentials in single human ventricular cells. METHODS: The patch-clamp technique was used to record action potentials and to apply I(injury) to human ventricular cells. In these cells, early and delayed afterdepolarizations (EADs and DADs) were induced by 1 microM norepinephrine. I(injury) was simulated by coupling cells via a variable coupling resistance to a passive resistance circuit with a potential of 0, -20, or -40 mV, mimicking a depolarized ischemic region. RESULTS: At all potentials, I(injury) induced depolarization of the resting membrane potential and action potential shortening. Flowing from 0 mV, I(injury) induced EADs by itself and aggravated the EADs and DADs that were induced by norepinephrine. Flowing from -40 mV, I(injury) abolished the noradrenaline-induced EADs and DADs. CONCLUSIONS: Our results demonstrate that I(injury) may either prevent or promote the occurrence of afterdepolarizations in human ventricle. The latter holds if conduction is slowed to such an extent that it permits flow of current from depolarized ischemic cells at plateau level to cells in phase 3 or phase 4.

Two types of action potential configuration in single cardiac Purkinje cells of sheep.

Membrane potentials and currents of isolated sheep Purkinje and ventricular cells were compared using patch-clamp and microelectrode techniques. In approximately 50% of Purkinje cells, we observed action potentials that showed a prominent phase 1 repolarization and relatively negative plateau (LP cells). Action potential configuration of the remaining Purkinje cells was characterized by little phase 1 repolarization and relatively positive plateau (HP cells). Microelectrode impalement of Purkinje strands also revealed these two types of action potential configuration. In LP cells, the density of L-type Ca(2+) current (I(Ca,L)) was lower, whereas the density of transient outward K(+) current was higher, than in HP cells. Action potentials of HP cells strongly resembled those of ventricular cells. Densities of inward rectifier current and I(Ca,L) were significantly higher in ventricular cells compared with densities in both LP and HP Purkinje cells. Differences in current densities explain the striking differences in action potential configuration and the stimulus frequency dependency thereof that we observed in LP, HP, and ventricular cells. We conclude that LP Purkinje cells, HP Purkinje cells, and ventricular cells of sheep each have a unique action potential configuration.