[Mediprudence based on previous cases of occupational disability]. / 'Mediprudentie' aan de hand van casuïstiek over arbeidsongeschiktheid.

The assessment of claims on performance restrictions as an expression of illness is a complex business. As well as the illness, personality factors and their interaction with a person's environment play an important part in the process. The assessment requires normative considerations. In 2005, the Health Council of the Netherlands advised the various medical specialists to adjust their guidelines in order to improve the coherence between the assessment, treatment and the supervision of patients. For this purpose, the so-called 3B guidelines had to be developed. Ahead of this and not without a certain amount of political pressure, the Council already drafted ten protocols related to insurance medicine. These protocols concern disorders that often lead to long-term occupational disability. Due to the limitations involved with diagnosis interpretation, the protocols however can only act as a rough guide. The Council therefore advised additional comments on relevant cases to be published. Mediprudence concerns general aspects and dilemmas of the assessment of claims. Such mediprudence has a public character and should primarily be developed by the professional group in collaboration with other (non-medical) disciplines and patient organizations. The initiative of the Health Council of the Netherlands may facilitate the integration of treatment of patients and assessment of claims. The centralized structure does not, however, guarantee the development of professional support. As the representative ofvarious interested parties, the Council avoids formulating starting points for the assessment of claims. It is possible that these will be addressed during the development of the mediprudence but this will put a very great strain on the capacities of the professional group.

[Assessment, treatment and counselling of patients claiming sick leave and disability: recommendation from the Health Council]. / Beoordelen, behandelen, begeleiden bij ziekteverzuim en arbeidsongeschiktheid; een advies van de gezondheidsraad.

As requested by the Minister for Social Services and Employment, the Health Council of The Netherlands reviewed existing medical guidelines on the assessment, treatment and counselling of patients claiming sick leave and disability. These guidelines were developed separately by physicians concerned with their own specific fields. The Health Council recommends the development of more encompassing guidelines, based on scientific evidence whenever possible, starting with 10 diagnoses that frequently lead to long-term industrial disability. The assessment of long-term disability is complex and varies for each individual. The contribution of scientific 'evidence' remains modest. It is not possible to predict permanent disability with lists of diseases and corresponding medical prognoses. It may be possible to support the assessment by 'mediprudence', cases of example. The recommendation of the Health Council offers perspective toward qualitatively improved assessment of the effects of diseases on patient functioning.

[Social medical guidance to achieve resumption of work: an outdated concept]. / Sociaal-medische begeleiding naar werkhervatting: een gedateerd concept.

In the Netherlands there is a strict separation between the attending physician, i.e. the general practitioner, and the occupational physician. However, they are supposed to cooperate so that sick-listed patients will return to work earlier. It has now been demonstrated that this cooperation is far from sufficient and that all the expended effort has not led to an increase in patient satisfaction. It has to be admitted that the cooperation has failed. There is a strong need for adherence to guidelines, for quality audits and for scientific investigation in this sector.

[Illness caused by work: a convincing clinical picture or chiefly a diminished feeling of well-being?]. / Ziek door het werk: een overtuigend medisch beeld of vooral verminderd welbevinden?

Cooperation between occupational-health physicians and treating physicians can lead to a mutually convincing result. The input from the occupational-health physician consists of a careful and critical examination into the social and personal background of the employee on sick leave. The benefit of the doubt in the case of any remaining questions in the assessment of the degree of unfitness for work would then lean towards possibilities and not limitations. The degree of disability is then assessed by a convincing clinical picture and not by the diminished feeling of well-being of the patient.

[Significance of medical data in work disability evaluation]. / De betekenis van medische gegevens bij de beoordeling van arbeidsongeschiktheid.

Research has shown that insurance doctors in assessing a claim mainly use information provided by the client, whose medical data are not checked with the attending physician, unless a refusal of or a reduction in the disability allowance is to be expected. Additionally, further medical investigations are hardly ever requested. After a year of absence company doctors hardly ever provide any information to the attending physicians, who in turn take just as little initiative with respect to employment disability. The significance of proper medical data for the claim assessment is limited; the majority of chronically ill individuals work and allowances are not given merely because of abnormalities or disorders. Medical data only become significant with reference to a problem analysis. This is often lacking; there is too little skepticism and too much compliance, which fits in with the conflict reducing function of being disabled for employment purposes. Providing more doctors so that more time and attention is available is not enough. Radical measures are needed to reduce the influx of claimants and to simplify the assessment process. Yet above all, greater responsibility should be given to the client and a different vision on employment and illness is also needed.

[From limitations to possibilities; the advice from the Donner Committee about disability benefits legislation]. / Van beperkingen naar mogelijkheden; het advies van de commissie-Donner over arbeidsongeschiktheidwetgeving.

In the Netherlands, the number of people declared unfit to work continues to rise: every working day sees more than 100 new benefit claimants. The average age of these claimants is decreasing and the number of women declared unfit for work is showing a disproportionate increase. Against this background, the Dutch government appointed a committee in June 2000 whose task was to examine the functioning of the legislation. The Donner Committee concluded that the claims made under the disability benefits legislation could not be clarified by a worsening of either the public health or the working conditions. The legislation is based on obsolete ideas in which illness effectively excludes employment. This idea fosters a range of social problems in the employment process, which present themselves as medical problems and therefore remain elusive and unsolved. The result is that people are unnecessarily eliminated from society at a time when paid employment is an increasingly important means of social interaction. The Committee proposes a drastic simplification of the legislation so that a disability benefit can only be claimed in the case of complete unfitness for work. Such a claim can only be made in the case of a serious illness which results in permanent and considerable limitations in everyday functioning. For all other cases involving health problems, the employer and employee need to work together to organise appropriate work. The emphasis is on what the employee can do as opposed to what he/she cannot do. If the employer fails to take the necessary measures then he/she will be obliged to continue paying the salary and if the employee fails to cooperate then he/she can be dismissed. If needs be the employee must be prepared to except a salary reduction of 30%. After two years of absence, dismissal is in every case possible. It is anticipated that as a result of the Committee's proposals, more people will remain in employment but that the number of unemployed as well as the number of legal disputes concerning dismissal will increase.

[Disability claim review by non-physicians to meet the legal requirement of Dutch work disability certification laws]. / Claimbeoordeling door niet-artsen voor de arbeidsongeschiktheidswetten.

The number of assessments of incapacity for work has increased to such an extent in the Netherlands (450,000 per year, of which 150,000 are first assessments) that experiments are now being undertaken to employ non-physicians for these assessments. There is no shortage of insurance physicians however: the number available is underestimated as many of these have resigned their regular jobs to perform the same activities on a freelance or second basis. A problem is certainly that these physicians are hindered by an exceedingly bureaucratic system in which e.g. patients are summoned by the administrative section to be reassessed who have already resumed working. Non-physicians may assist in the assessments, but in most cases there is a relation between psychic, somatic and social factors, which requires the generalist physician's eye. The main problem is that government regulations lead to a steady growth in the number of (re)assessments required. A possible but onorthodox solution is proposed which involves medical certification of incapacity for work. This may discourage long-term absenteeism and at the same time it may draw the physician's attention to the existence of an industrial health care problem.

[The Law on (Re)integration of Disabled Persons]. / De Wet (Re)ïntegratie Arbeidsgehandicapten.

In spite of the growing economy, with diminishing unemployment and increasing scarcity of manpower, many people with chronic health problems remain unemployed. To promote their participation in the labour progress, the Law on (Re)integration of Incapacitated Persons (REA) was enacted on 1 July 1998. This law provides a number of facilities for those classified as 'unable to work'; These are persons impaired by chronic health problems in participating in the labour process. The existing allowances have been liberalized and simplified considerably. Employers in certain cases can expect substantial subsidies. In addition, there are more facilities like vocational re-education and psychological and other training courses. The concept of 'incapability' is rather vague. Fortunately, the Law makes it immediately clear who may be regarded as incapable. In other cases, physicians employed by Factories Act organizations, employment policy offices and social insurance will have to take part in the evaluation. The new law has a few paradoxical starting points, those incapable for work are given hardly any voice and there is a clear risk of stigmatization. On the other hand, failure of the (re)integration of handicapped persons into the labour process may lead to further encroaching upon the welfare state.

Parallel production of oligonucleotide arrays using membranes and reagent jet printing.

Here, we present a low-cost method to produce compact arrays using microporous materials and reagent jetting. Oligonucleotides are immobilized on membrane sheets as a series of lines. The membrane sheet is then rolled and bound, and the spiral structure is cut like a "jelly roll" to produce identical arrays. The spiral arrays behave much like larger formats using membranes, and hybridization detection can be accomplished using standard signal-generation mechanisms. The method is particularly useful for producing identical arrays from pre-synthesized oligonucleotides.

[From absenteeism to work incapacity; changed role of physicians involved]. / Van arbeidsverzuim tot arbeidsongeschiktheid; veranderende rol van betrokken artsen.

Hardly any part of the legal regulations on absenteeism and incapacity for work has remained unchanged since 1993 in the Netherlands. The system is becoming increasingly complicated. The essence of the changes is that employers' responsibility has greatly increased. The new regulations mean a transition from industrial health care to Factories Act services and from the industrial insurance board to implementing organs. The legislator emphasizes the evaluation of what people with health disorders are still able to do. Prevention of absenteeism/ incapacity for work and reintegration are given great attention. Treating physicians should not let the complicated regulations keep them from fulfilling their tasks concerning sick employees, since it is increasingly in the patient's interest that chronicity be prevented whenever possible.

Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.

The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.

Pharmacologic characterization of CHIR 2279, an N-substituted glycine peptoid with high-affinity binding for alpha 1-adrenoceptors.

We characterize the in vitro and in vivo pharmacology of CHIR 2279, an N-substituted glycine peptoid previously identified from a combinatorial library as a novel ligand to alpha 1-adrenoceptors. Competitive receptor-binding assays with [3H]prazosin showed that CHIR 2279 was similar to prazosin in binding to alpha 1A (rat submaxillary), alpha 1a, alpha 1b, and alpha 1 d (cDNA expressed in LTK- cells) with high and approximately equipotent affinity. Ki values for CHIR 2279 ranged from 0.7 to 3 nM, and were 10-fold weaker than with prazosin. Functional assays for postsynaptic alpha 1-adrenoceptors showed CHIR 2279 was approximately equipotent in antagonizing agonist-induced contractile responses with rat was deferens (alpha 1A), canine prostate (alpha 1A), rat spleen (alpha 1B) and rat aorta (alpha 1D). The pA2 for CHIR 2279 averaged 7.07 in these assays, indicating a 10- to 100-fold lower in vitro potency than prazosin. In dogs, CHIR 2279 antagonized the epinephrine-induced increase in intraurethal pressure (pseudo pA2, 6.86) and in rats antagonized the phenylephrine-induced increase in mean arterial blood pressure. In rats and guinea pigs, CHIR 2279 induced a dose-dependent decrease in mean arterial blood pressure without eliciting the tachycardia commonly observed with other alpha 1-blockers. Pharmacokinetic/pharmacodynamic modeling showed the i.v. system clearance rate of CHIR 2279 was 60 and 104 ml/min/kg in rats and guinea pigs, respectively, and the in vivo potency for mean arterial blood pressure reduction was twice as great in guinea pigs (EC50, 520 ng/ml) than rats (EC50, 1170 ng/ml).

Alpha 1-adrenoceptor-induced contractility in rat aorta is mediated by the alpha 1D subtype.

Adrenoceptor agonists were used to characterize the alpha 1-adrenoceptor subtype responsible for mediating tension (phasic and tonic combined) in the denuded rat aorta and compared with radioligand binding at alpha 1-adrenoceptor subtypes. The rank order of potency at the rat aorta was the same as that obtained for binding affinity at the rat clonal alpha 1d-adrenoceptor: norepinephrine > epinephrine > cirazoline > phenylephrine > oxymetazoline > A-61603 > methoxamine. Correlation coefficients comparing rat aortic contraction (pD2) to binding (pKi) were 0.09-0.21 for alpha 1A/a receptors, 0.66 for clonal alpha 1b and 0.94 for clonal alpha 1d-adrenoceptors. Correlation coefficients comparing the clonal alpha 1d-adrenoceptor binding affinity to in vitro contractile responses were 0.03 and 0.10 for the rat vas deferens and canine prostate alpha 1A-adrenoceptor responses, respectively, 0.09 for the rat spleen alpha 1B and as noted, 0.94 for the rat aorta. The agreement observed between agonist potency at the rat aorta and affinity for the alpha 1d binding site provide new evidence that the alpha 1D-adrenoceptor subtype is responsible for mediating contractions in the rat aorta.

Actions of terazosin and its enantiomers at subtypes of alpha 1- and alpha 2-adrenoceptors in vitro.

Terazosin and its enantiomers, antagonists of alpha 1-adrenoceptors, were studied in radioligand binding and functional assays to determine relative potencies at subtypes of alpha 1- and alpha 2-adrenoceptors in vitro. The racemic compound and its enantiomers showed high and apparently equal affinity for subtypes of alpha 1-adrenoceptors with Kl values in the low nanomolar range, and showed potent antagonism of alpha 1-adrenoceptors in isolated tissues, with the enantiomers approximately equipotent to the racemate at each alpha 1-adrenoceptor subtype. At alpha 2b sites, R(+) terazosin bound less potently than either the S(-) enantiomer or racemate. R(+) terazosin was also less potent than the S(-) enantiomer or the racemate at rat atrial alpha 2B receptors. These agents were not significantly different in their potencies at alpha 2a or alpha 2A sites. Since the high affinity for alpha 2B sites of quinazoline-type alpha-adrenoceptor antagonists has been used to differentiate alpha 2-adrenoceptor subtypes, the low affinity of R(+) terazosin for these sites was unexpected. Because terazosin or its enantiomers are approximately equipotent at alpha 1-adrenoceptor subtypes, the lower potency of R(+) terazosin at alpha 2B receptors indicates a somewhat greater selectivity for alpha 1-compared to alpha 2B adrenoceptor subtypes. The possible pharmacological significance of this observation is discussed.

A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype.

N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro naphthalen-1-yl] methanesulfonamide hydrobromide (A-61603) is a novel and potent alpha-adrenoceptor agonist. In radioligand binding assays, the compound is at least 35-fold more potent at alpha 1A/a receptors than at alpha 1b or alpha 1d sites. In fibroblast cells transfected with alpha 1a receptors, A-61603 more potently stimulates phosphoinositide hydrolysis than norepinephrine, and is antagonized by prazosin. A-61603 is less potent in cells transfected with alpha 1b or alpha 1d receptors. A-61603 is a potent agonist at alpha 1A receptors in rat vas deferens (200- to 300-fold more potent than norepinephrine or phenylephrine, respectively) and in isolated canine prostate strips (130- to 165-fold more potent than norepinephrine or phenylephrine, respectively). In contrast, A-61603 is only 40-fold more potent than phenylephrine at alpha 1B sites in rat spleen and 35-fold less potent at rat aortic, alpha 1D sites. In an in vivo dog model, A-61603 raises intraurethral prostatic tone to a greater extent than mean arterial blood pressure. A-61603 induces a pressor response in conscious rats at doses 50- to 100-fold lower than phenylephrine, and the response is not attenuated by pretreatment with CEC, whereas YM-617 causes a 100-fold shift in the response. These results indicate that A-61603 is a potent adrenergic agonist, selective for alpha 1A/a receptors, and may prove a useful probe for studies of adrenergic function and alpha 1 adrenoceptor regulation of physiological functions.