VasCog 2023: 20 years of research on vascular behavioural and cognitive disorders.

This Commentary describes the 20th Anniversary of VasCog 2023, held in Gothenburg, Sweden.

[3D printed medical devices and anatomical models: What kind of distribution and which uses in French hospitals?] / Dispositifs médicaux et modèles anatomiques produits par impression 3D : quelle diffusion et quelles utilisations dans les établissements de santé français ?

3D printing plays an increasingly important role in the medical sector and particularly in surgery. Nowadays, numerous manufacturers benefit from this technology to produce their medical devices and some hospitals have also purchased 3D printers. In this context, the aim of the present study was to study the distribution and the use of 3D printing in French hospitals in order to its main features in surgery. By conducting a national survey, we targeted hospitals equipped with 3D printers and those using external providers to benefit from this technology. Forty-seven hospitals were identified as using 3D printing including eight equipped with in-house 3D printers. This work gives us a first picture of 3D printing for hospital use in France and it raises questions about hospital pharmacists' involvement in 3D printed medical device production.

[Mindfulness training for psychiatrists in residency: a pilot study]. / Mindfulnesstraining voor aiossen psychiatrie: een pilotstudie.

BACKGROUND: Medical students and psychiatrists in residency run a high risk for burnout. Furthermore, while at medical school, students seem to experience a reduction in empathy; this seems to be linked to a high level of stress. Interventions based on mindfulness training appear to reduce stress and increase empathy in medical students. Trainees in psychiatric residency might also benefit from mindfulness training.
AIM: To assess the effects that a mindfulness course has on perceived stress and empathy in psychiatrists in residency.
METHOD: In this pilot study 13 trainees in psychiatric residency participated in an eight-week course in mindfulness. Before and after the training, 11 of the participants completed questionnaires relating to their empathy, perceived stress and mindfulness.
RESULTS: Participants reported experiencing considerably more empathy after their course than before it. Perceived stress also diminished, but not significantly.
CONCLUSION: The results support our suggestion that mindfulness training can be a valuable part of the curriculum for trainees in psychiatric residency.

[Hospital-based health technology assessment in France: how to proceed to evaluate innovative medical devices?]. / Évaluation des technologies de santé en milieu hospitalier : quelle organisation pour évaluer et acquérir des dispositifs médicaux innovants ?

Innovative medical devices offer solutions to medical problems and greatly improve patients' outcomes. Like National Health Technology Assessment (HTA) agencies, hospitals face numerous requests for innovative and costly medical devices. To help local decision-makers, different approaches of hospital-based HTA (HB-HTA) have been adopted worldwide. The objective of the present paper is to explore HB-HTA models for adopting innovative medical devices in France and elsewhere. Four different models have been conceptualized: "ambassador" model, "mini-HTA" model, "HTA unit" model and "internal committee". Apparently, "HTA unit" and "internal committee" (or a mixture of both models) are the prevailing HB-HTA models in France. Nevertheless, some weaknesses of these models have been pointed out in previous works. Only few examples involving hospital pharmacists have been found abroad, except in France and in Italy. Finally, the harmonization of the assessment of innovative medical devices in France needs a better understanding of HB-HTA practices.

The development and implementation of pharmaceutical care across borders.

The community pharmacist is an essential professional for a high standard healthcare delivery system. However, many indicators, at the EU level or national level, suggest that the tasks entrusted to him, since the beginning of the 20th century, must ensure a safe and efficient treatment to patient. In several member states, the legislation has recently been changed and community pharmacists in Europe have redefined their role in the healthcare delivery system in order to focus more on patients' care. In France, the new reform concerning hospitals and the report on community pharmacy, written by social inspectors for the government, in some aspects, contains propositions similar to those adopted in Canada.

Assessment of parenting and developmental problems in toddlers: development and feasibility of a structured interview.

BACKGROUND: Assessment of (early signs of) parenting and developmental problems in young children by preventive child health care (CHC) workers is recommended, but no validated instruments exist. The aim of this project was to develop and test an instrument for early detection and assessment of problems in toddlers, using the perspectives and experience of both the parent and the professional. METHODS: Using an iterative process, we adapted and expanded a structured interview on need for parenting support into the Structured Problem Analysis of Raising Kids (SPARK). The SPARK consists of 16 subject areas, ranging from somatic health to family issues. The SPARK was tested in daily practice for feasibility and discriminative capacity. The sample consisted of all toddlers aged 18 months living in Zeeland, a province of the Netherlands, during the study period (n= 1140). RESULTS: The response rate was 97.8%. Although the median level of support needed according to the SPARK was low, 4.5% of the toddlers and their parents required intensive help or immediate action. The risk assessment showed 2.9% high, 16.5% increased and 80.6% low risk for parenting and developmental problems. The risk assessment of the CHC professional was associated with known risk factors for child maltreatment. CONCLUSIONS: This study shows that a structured interview, named the SPARK, is feasible in daily practice and clarifies risks and care needs for parenting and developmental problems in toddlers.

[Protocol for complementary and alternative medicine within the Dutch mental health services]. / Protocol voor complementaire en alternatieve geneeswijzen; naar een verantwoorde toepassing binnen de ggz.

Complementary and alternative medicine (CAM) is the subject of heated debate. There are many prejudices for and against CAM. At the centre for Integrative Psychiatry (CIP) of Lentis CAM is offered alongside conventional treatments, but under strict conditions. Because of the controversy surrounding CAM and the potential health risks involved, the CIP in Lentis has formulated a protocol for CAM which is presented in this article.

Protocolo para medicina complementaria y alternativa; hacia una aplicación responsable dentro del sistema de salud mental / Protocol voor complementaire en alternatieve geneeswijzen; naar een verantwoorde toepassing binnen de ggz

Complementary and alternative medicine (cam) is the subject of heated debate. There are many prejudices for and against cam. At the centre for Integrative Psychiatry (cip) of Lentis cam is offered alongside conventional treatments, but under strict conditions. Because of the controversy surrounding cam and the potential health risks involved, the cip in Lentis has formulated a protocol for cam which is presented in this article.

Uncertainties in extreme surge level estimates from observational records.

Ensemble simulations with a total length of 7540 years are generated with a climate model, and coupled to a simple surge model to transform the wind field over the North Sea to the skew surge level at Delfzijl, The Netherlands. The 65 constructed surge records, each with a record length of 116 years, are analysed with the generalized extreme value (GEV) and the generalized Pareto distribution (GPD) to study both the model and sample uncertainty in surge level estimates with a return period of 104 years, as derived from 116-year records. The optimal choice of the threshold, needed for an unbiased GPD estimate from peak over threshold (POT) values, cannot be determined objectively from a 100-year dataset. This fact, in combination with the sensitivity of the GPD estimate to the threshold, and its tendency towards too low estimates, leaves the application of the GEV distribution to storm-season maxima as the best approach. If the GPD analysis is applied, then the exceedance rate, lambda, chosen should not be larger than 4. The climate model hints at the existence of a second population of very intense storms. As the existence of such a second population can never be excluded from a 100-year record, the estimated 104-year wind-speed from such records has always to be interpreted as a lower limit.

[Short-term steroid therapy, sometimes with long-term sequelae]. / Korte steroïdkuur, soms een lange nasleep.

Two patients developed osteonecrosis, respectively one and two years after the short-term intravenous use of dexamethasone. A 35-year-old man received 150 mg over a period of 3 weeks associated with a craniotomy for a subarachnoidal haemorrhage. He developed bilateral osteonecrosis of the femoral and humeral heads, which necessitated bilateral hip replacement surgery. He still experiences pain in both shoulders. A 45-year-old woman received 42.5 mg over a period of 1 week as a treatment for reflex dystrophy with oedema. She developed bilateral osteonecrosis in the femoral condyles, the talus and the calcaneus and after treatment she continued to experience pain in her right knee and ankle whilst walking. The only other risk factor for osteonecrosis identified in these patients was hyperlipidaemia in the man. Corticosteroid-induced osteonecrosis is typically multifocal and usually occurs 0.5 to 3 years after the therapy was initiated. There is a relationship with the dose and length of therapy. Even the short-term use of corticosteroids for 3 weeks or less, may lead to this dehabilitating complication.

Method to measure in vivo blood fibrinolytic activity with a (125)I-fibrin coated aorta loop validated with agents which affect blood fibrinolytic activity.

A functional animal model to measure in vivo the blood fibrinolytic activity and pharmacological-induced changes thereof are described. A (125)I-fibrin coated plastic loop is inserted in the rat aorta; the rate of label disappearance (sigmoid curve) is directly registered outside the animal with a gamma scintillation probe. The time needed to let disappear 50% of the removable-labeled fibrin is used as measure for the blood fibrinolytic activity. The direct advantage of this model is the absence of a blood or plasma clot: a thin labeled fibrin layer attached to the inner wall of the loop is in direct contact with the blood and is therefore sensitive to increased or decreased blood fibrinolytic activity. The total experiment needs about 60 min. Experiments with nontreated rats showed that, after an initial lag phase of about 10 min, the labeled fibrin started to disappear from the loop. A sigmoid pattern was obtained showing that about 20-30% of the coated-labeled fibrin is resistant to removal. Registration of the total curve of a nontreated (control or placebo) rat required about 30-40 min. The clinically used thrombolytics (intravenously administered) urokinase and t-PA showed a dose-dependent fibrinolytic activity resulting in increased removal of the bound (125)I-fibrin. Streptokinase was not active, which is in agreement with literature. Tranexamic acid, dexamethasone and endotoxin (inhibitors of fibrinolysis) showed dose-dependent inhibition of removal of the coated fibrin. Retinoic acid was tested as compound, which may enhance the blood fibrinolytic activity; retinoic acid was not found to be significantly active in this model. The disappearance of labeled fibrin is not sensitive to inhibitors of coagulation or platelet aggregation. This technically simple and fast model can thus be used to measure in vivo quantitatively the effects of pharmacological active compounds, which increase or decrease the blood fibrinolytic activity.

Production of 3-nitrocatechol by oxygenase-containing bacteria: optimization of the nitrobenzene biotransformation by Nocardia S3.

Twenty-one microorganisms were screened for their ability to convert nitroaromatics into 3-nitrocatechol as a result of the action of an oxygenase. Cultures containing toluene dioxygenases and phenol monooxygenases accumulated 3-nitrocatechol during incubation with nitrobenzene and nitrophenol, respectively. Nocardia S3 was selected and studied in more detail. Toluene-pregrown cultures were able to degrade nitrobenzene with a concomitant formation of 3-nitrocatechol. The rates of nitrobenzene utilization decreased throughout the biotransformation period and finally the accumulation ceased. The gradual deterioration of the biotransformation rates was not a consequence of depletion of the NADH pool, but was due to the accumulation of 3-nitrocatechol. The inhibition of nitrobenzene biotransformation by 3-nitrocatechol greatly impacts 3-nitrocatechol production processes.

Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation.

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. At this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10 y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of 1 y. Serious clinical signs or exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished.

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (

Cytochrome P450 enzyme systems in fungi.

The involvement of cytochrome P450 enzymes in many complex fungal bioconversion processes has been characterized in recent years. Accordingly, there is now considerable scientific interest in fungal cytochrome P450 enzyme systems. In contrast to S. cerevisiae, where surprisingly few P450 genes have been identified, biochemical data suggest that many fungi possess numerous P450 genes. This review summarizes the current information pertaining to these fungal cytochrome P450 systems, with emphasis on the molecular genetics. The use of molecular techniques to improve cytochrome P450 activities in fungi is also discussed.

Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.

BACKGROUND: The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7.5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day) with sulphasalazine alone. METHODS: 155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation. FINDINGS: At week 28, the mean pooled index was 1.4 (95% CI 1.2-1.6) in the combined treatment group and 0.8 (0.6-1.0) in the sulphasalazine group (p < 0.0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0-28) in the combined-therapy group and 4 (0-44) in the sulphasalazine group (p < 0.0001). The increases at week 56 (2 [0-43] vs 6 [0-54], p = 0.004), and at week 80 (4 [0-80] vs 12 [0-72], p = 0.01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later. INTERPRETATION: This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.

Cytokine production in whole blood cell cultures of patients with rheumatoid arthritis.

OBJECTIVE: The measurement of cytokine production of activated lymphocytes and monocytes in the whole blood cell (WBC) culture system may provide a sensitive tool for evaluating the actual ongoing immune response of patients with rheumatoid arthritis (RA). METHODS: Lipopolysaccharide (LPS) up to 250 pg/ml was used for the stimulation of monocytes for measuring the production of tumour necrosis factor alpha (TNF alpha), interleukin 6 (IL6) and IL12, while the anti-CD3 (1 microgram/ml) and anti-CD28 (5 micrograms/ml) combination was used for T cell stimulation with the measuring of IL4 and interferon gamma (INF gamma) production. Twenty seven patients with RA and 23 healthy controls were studied. RESULTS: The results showed a decreased IL6 (LPS stimulus 4-6 pg/ml) and IL-12 (LPS stimulus 16-62 pg/ml) production in the RA patients. The maximal production of both cytokines was comparable with the normal controls. T cell stimulation showed a significant decreased INF gamma production in the RA patients. CONCLUSIONS: These findings obtained in the WBC culture system are highly suggestive for a decreased TH-1 derived cytokine production by a diminished IL12 production in RA patients. Another possibility is that both IL12 and INF gamma production in WBCs are inhibited by eventual circulating serum factors.

Increased resistance to 14 alpha-demethylase inhibitors (DMIs) in Aspergillus niger by coexpression of the Penicillium italicum eburicol 14 alpha-demethylase (cyp51) and the A. niger cytochrome P450 reductase (cprA) genes.

In this paper we describe the effects of over-expression of the Penicillium italicum gene encoding eburicol 14 alpha-demethylase (cyp51), in Aspergillus niger strains with one or multiple copies of the gene encoding cytochrome P450 reductase (cprA), on the eburicol 14 alpha-demethylase activity. Eburicol 14 alpha-demethylase activity was determined by measuring the resistance of transformants against some eburicol 14 alpha-demethylase inhibitors (DMIs). DMIs are widely used as fungicides in crop protection and human and veterinarian health care. DMI resistance in a transformant overexpressing both CPR and CYP51 was increased 5-30-fold compared to DMI resistance in the wild type strain, depending on the test compound used. Resistance in this strain was approximately 2-5-fold increased compared to DMI resistance in a transformant that was overexpressing the cyp51 gene but had only the wild type copy of the cprA gene and approximately 3-12-fold increased compared to a strain overexpressing the cprA gene (and having only the wild type copy of the cyp51 gene). These results show the importance of CPR overexpression for increasing cytochrome P450 activities in filamentous fungi.

Common variable immunodeficiency in a patient with systemic lupus erythematosus.

This report describes a young girl who developed systemic lupus erythematosus at the age of 11. In the years thereafter a conversion took place from hypergammaglobulinemia to hypogammaglobulinemia with the absence of circulating and bone marrow B-cells. Some aspects of the aetiopathogenesis of common variable immunodeficiency are discussed.

Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis.

BACKGROUND: A favourable benefit/risk ratio for treatment of rheumatoid arthritis (RA) with second-line drugs has been established only in short-term studies. The present investigation addresses the question of whether RA patients with a good response to long-term treatment with second-line drugs benefit from continuation of such treatment. METHODS: A 52-week randomised double-blind placebo-controlled multicentre study was conducted to assess the effect of stopping second-line therapy in 285 RA patients with a good long-term therapeutic response. The patients either continued the second-line drug (n = 142) or received a placebo (n = 143). The endpoint was a flare, defined as recurrence of synovitis. FINDINGS: At entry into the study median duration of second-line drug therapy was 5 years (range 2-33). At 52 weeks the cumulative incidence of a flare was 38% for the placebo group and 22% for the continued therapy group (p = 0.002). The risk of a flare was 2.0 times higher for patients receiving placebo than for those continuing the second-line drug (95% CI 1.27 to 3.17). The same trend was found for each second-line drug separately, with the exception of d-penicillamine. Side-effects that necessitated dose reduction or discontinuation occurred in 2 patients in each group. INTERPRETATION: Second-line drugs continue to be effective in RA patients who have responded well to initial treatment.