Correction to: Late Presentation of HIV Infection in the Netherlands: Reasons for Late Diagnoses and Impact on Vocational Functioning.

The original version of this article was published open access. Unfortunately, due to a technical issue, the copyright holder name in the online version (HTML and XML) is incorrectly published as "Springer Science + Business Media, LLC, part of Springer Nature 2018". Instead, it should be "The Author(s) 2018".

The European study on centralisation of childhood cancer treatment.

BACKGROUND: It is generally agreed to centralise treatment of childhood cancers (CCs). We analysed (1) the degree of centralisation of CCs in European countries and 2) the relations between centralisation and survival. PATIENTS AND METHODS: The analysis comprised 4415 CCs, diagnosed between 2000 and 2007 and followed up to the end of 2013, from Belgium, Bulgaria, Finland, Ireland, the Netherlands and Slovenia. All these countries had national population-based cancer registries and were able to provide information on diagnosis, treatment, treatment hospitals, and survival. Each case was then classified according to whether the patient was treated in a high- or a low-volume hospital among those providing CC treatment. A Cox proportional hazard model was used to calculate the relation between volume category and five-year survival, adjusting by age, sex and diagnostic group. RESULTS: The number of hospitals providing treatment for CCs ranged from six (Slovenia) to slightly more than 40 (the Netherlands and Belgium). We identified a single higher volume hospital in Ireland and in Slovenia, treating 80% and 97% of cases, respectively, and three to five major hospitals in the other countries, treating between 65% and 93% of cases. Outcome was significantly better when primary treatment was given in high-volume hospitals compared to low-volume hospitals for central nervous system tumours (relative risk [RR] = 0.71), haematologic tumours (RR = 0.74) and for all CC combined (RR = 0.83). CONCLUSION: Treatment centralisation is associated with survival benefits and should be further strengthened in these countries. New plans for centralisation should include ongoing evaluation.

Late Presentation of HIV Infection in the Netherlands: Reasons for Late Diagnoses and Impact on Vocational Functioning.

Late diagnosis of HIV remains a major challenge in the HIV epidemic. In Europe, about 50% of all people living with HIV are diagnosed late after infection has occurred. Insight into the reasons for late diagnoses is necessary to increase the number of early diagnoses and optimize treatment options. This qualitative study explored the experiences of 34 late-presenters through in-depth semi-structured interviews. A variety of reasons for late diagnoses emerged from our data and led to a division into four groups, characterized by two dimensions. Regarding vocational functioning, the consequences of late diagnoses were health-related problems prior to and since diagnosis, and problems concealing the HIV status. Healthcare providers should offer HIV tests to groups at risk, and be alert for clinical HIV indicator conditions. It is recommended to increase awareness of HIV transmission routes, symptoms and tests, and the benefits of early testing and early entry to HIV care.

A RCT Comparing Daily Mindfulness Meditations, Biofeedback Exercises, and Daily Physical Exercise on Attention Control, Executive Functioning, Mindful Awareness, Self-Compassion, and Worrying in Stressed Young Adults.

Our Western society is characterized by multitasking, competition, and constant time pressure. Negative effects of stress for the individual (anxiety, depression, somatic complaints) and for organizations and society (costs due to work absence) are very high. Thus, time-efficient self-help interventions to address these issues are necessary. This study assessed the effects of daily mindfulness meditations (MM) versus daily heart rate variability biofeedback (HRV-BF) and daily physical exercise (PE) on attention control, executive functioning, mindful awareness, self-compassion, and worrying. Young adults (n = 75, age range 18 to 40) with elevated stress levels were randomized to MM, HRV-BF, or PE, and measurements were taken at pre-test, post-test, and follow-up. Interventions in all three groups were self-guided and lasted for 5 weeks. Generalized estimating equation analyses showed that overall, all three interventions were effective and did not differ from each other. However, practice time differed between groups, with participants in the PE group practicing much more than participants in the other two groups. Therefore, additional analyses were carried out in two subsamples. The optimal dose sample included only those participants who practiced for at least 70 % of the total prescribed time. In the equal dose sample, home practice intensity was equal for all three groups. Again, the effects of the three interventions did not differ. In conclusion, MM, HRV-BF, and PE are all effective self-help methods to improve attention control, executive functioning, mindful awareness, self-compassion, and worrying, and mindfulness meditation was not found to be more effective than HRV-biofeedback or physical exercise for these cognitive processes.

The biological clock modulates the human cortisol response in a multiplicative fashion.

Human cortisol levels follow a clear circadian rhythm. We investigated the contribution of alternation of sleep and wakefulness and the circadian clock, using forced desynchrony. Cortisol levels were best described by a multiplication of a circadian and a wake-time component. The human cortisol response is modulated by circadian phase. Exposure to stress at an unnatural phase, as in shift work, is predicted to result in abnormal cortisol levels. Health of shift workers may therefore improve when stress is reduced at times when the clock produces high stress sensitivity.

Cancer prevalence estimates in Europe at the beginning of 2000.

BACKGROUND: Complete cancer prevalence data in Europe have never been updated after the first estimates provided by the EUROPREVAL project and referred to the year 1993. This paper provides prevalence estimates for 16 major cancers in Europe at the beginning of the year 2003. PATIENTS AND METHODS: We estimated complete prevalence by the completeness index method. We used information on cancer patients diagnosed in 1978-2002 with vital status information available up to 31 December 2003, from 76 European cancer registries. RESULTS: About 11.6 millions of Europeans with a history of one of the major considered cancers were alive on 1 January 2003. For breast and prostate cancers, about 1 out of 73 women and 1 out of 160 men were living with a previous diagnosis of breast and prostate cancers, respectively. The demographic variations alone will increase the number of prevalent cases to nearly 13 millions in 2010. CONCLUSIONS: Several factors (early detection, population aging and better treatment) contribute to increase cancer prevalence and push for the need of a continuous monitoring of prevalence indicators to properly plan needs, resource allocation to cancer and for improving health care programs for cancer survivors. Cancer prevalence should be included within the EU official health statistics.

Invasive extramammary Paget's disease and the risk for secondary tumours in Europe.

The aim of this study was to determine the incidence and survival of Extramammary Paget's disease (EMPD) and to describe the possible increased risk of tumours after EMPD. All invasive cases diagnosed between 1990 and 2002 were selected from the RARECARE database. Incidence was expressed in European standardized rates. Relative survival was calculated for the period 1995-1999, with a follow-up until 31st December 2003. Standardized incidence ratios of second primary tumours were calculated to reveal possible increased risk after EMPD. European age standardized Incidence of EMPD within Europe is 0.6 per 1000,000 person years. Five-year relative survival for invasive EMPD was 91.2% (95%CI; 83.5-95.4), 8.6 percent of the EMPD patients developed other malignancies. The highest increased risk of developing a second primary tumour was found in the first year of follow-up (SIR:2.0 95%CI; 1.3-2.9), living in the South European region (SIR:2.3 95%CI; 1.5-3.5) or being female (SIR:1.5 95%CI; 1.1-1.9). Female genital organs displayed greatest increased risk of developing a second primary tumour after EMPD (SIR:15,1 95%CI; 0.38-84.23). Due to the increased risk of a second primary tumour after EMPD a thorough search for other tumours during their follow-up is recommended.

Driving performance during word generation--testing the function of human brain lateralization using fTCD in an ecologically relevant context.

It has been hypothesized that cerebral lateralization of function enhances cognitive performance. Evidence was found in birds and fish. However, recent research in humans did not support this hypothesis. We aimed to replicate and extend these findings for single- and dual-task performance in an ecologically relevant task. We combined a word generation task which is assumed to be primarily processed in the left hemisphere with a driving task which is assumed to be primarily processed in the right hemisphere. For each task the individual strength and direction of hemispheric lateralization was assessed by using functional transcranial Doppler sonography (fTCD). For each subject (36 right-handed, 35 nonright-handed) performance was measured in the two single-tasks and in the dual-task condition. On average, subjects showed a left hemisphere bias for the word generation task, a right hemisphere bias for the driving task and dual-task interference. Within subjects, lateralization of language and driving were statistically independent. In accordance with earlier studies, the results show no indication of a positive effect of strength of lateralization on performance in single-tasks or dual-task efficiency. We also found no advantage of a typical compared to an atypical or a contralateral compared to an ipsilateral lateralization pattern. In right-handers, but not in nonright-handers, we even found a negative relationship between strength of lateralization and dual-task efficiency for atypically lateralized subjects. This further supports the suggestion that lateralization does not enhance cognitive performance in humans.

Dinuclear alkyldiamine platinum antitumor compounds: a structure-activity relationship study.

Six related dinuclear trans-platinum complexes, with the formula [[trans-PtCl(2)(NH(3))(L)](2)(mu-H(2)N(CH(2))(n)NH(2))](2+) (L = pyridine, 2-picoline, 4-picoline; n = 4, 6) and chloride or nitrate anions, are compared with known cytotoxic dinuclear compounds (L = NH(3); n = 4, 6) that overcome cisplatin resistance. The cytotoxicity of the compounds was determined in L1210 murine leukemia and L1210/2, a cisplatin-resistant derivative. Unlike the L = NH(3) compounds, the substituted n = 4 compounds are more susceptible toward the resistance mechanisms in L1201/2. The n = 6 compounds, however, have comparable IC(50) values in both cell lines. In general, the substituted compounds are less cytotoxic than their NH(3) counterparts. After incubation with equimolar concentrations, the amount of platinum bound to cellular DNA was determined. The compounds show comparable binding, except for the sterically hindered 2-picoline compounds that bind significantly less. The amounts of platinum bound to DNA do not correlate with the cytotoxicity data. As DNA is considered to be the cellular target of platinum antitumor drugs, structural details of the DNA adducts probably account for the differences in cytotoxic activity.

[Condylar hyperplasia. Early detection is desired]. / Condylaire hyperplasie. Vroegtijdige herkenning gewenst.

When single-sided excessive condylar growth is detected in time, removal of the affected condyle is sufficient. In cases of late detection, extensive surgery of upper and lower jaw and the chin may be necessary.

The solution structure of serine protease PB92 from Bacillus alcalophilus presents a rigid fold with a flexible substrate-binding site.

BACKGROUND: Research on high-alkaline proteases, such as serine protease PB92, has been largely inspired by their industrial application as protein-degrading components of washing powders. Serine protease PB92 is a member of the subtilase family of enzymes, which has been extensively studied. These studies have included exhaustive protein engineering investigations and X-ray crystallography, in order to provide insight into the mechanism and specificity of enzyme catalysis. Distortions have been observed in the substrate-binding region of subtilisin crystal structures, due to crystal contacts. In addition, the structural variability in the substrate-binding region of subtilisins is often attributed to flexibility. It was hoped that the solution structure of this enzyme would provide further details about the conformation of this key region and give new insights into the functional properties of these enzymes. RESULTS: The three-dimensional solution structure of the 269-residue (27 kDa) serine protease PB92 has been determined using distance and dihedral angle constraints derived from triple-resonance NMR data. The solution structure is represented by a family of 18 conformers which overlay onto the average structure with backbone and all-heavy-atom root mean square deviations (for the main body of the molecule) of 0.88 and 1.21 A, respectively. The family of structures contains a number of regions of relatively high conformational heterogeneity, including various segments that are involved in the formation of the substrate-binding site. The presence of flexibility within these segments has been established from NMR relaxation parameters and measurements of amide proton exchange rates. CONCLUSIONS: The solution structure of the serine protease PB92 presents a well defined global fold which is rigid with the exception of a restricted number of sites. Among the limited number of residues involved in significant internal mobility are those of two pockets, termed S1 and S4, within the substrate-binding site. The presence of flexibility within the binding site supports the proposed induced fit mechanism of substrate binding.

Insect-sting challenge in 324 subjects with a previous anaphylactic reaction: current criteria for insect-venom hypersensitivity do not predict the occurrence and the severity of anaphylaxis.

Three hundred twenty-four patients with a history of yellow jacket- (n = 272) or honeybee- (n = 52) sting anaphylaxis were prospectively subjected to an in-hospital sting challenge. Plasma levels of specific IgE and IgG4, skin venom tests, severity of previous reaction, sex, age, atopic constitution, histamine skin test results, location and number of previous stings, time interval between previous anaphylactic reaction and sting challenge, and time interval between sting challenge and onset of anaphylaxis were studied in relation to the clinical severity of a reaction after sting challenge. A recurrent anaphylactic reaction after sting challenge was observed in 25% of yellow jacket- and in 52% of honeybee-sensitive persons. The severity of this reaction correlated significantly with age and the time interval between sting challenge and onset of anaphylaxis only: older persons with faster reactions had more severe symptoms after sting challenge. None of the current criteria for insect-sting hypersensitivity (IgE, IgG4, skin test) significantly related on an individual basis or in combinations to the reaction after sting challenge. We conclude that the current criteria to assess insect-venom hypersensitivity do not relate to the occurrence and severity of anaphylactic symptoms after an insect-sting challenge.

Development of a new, more sensitive immunoassay for human tryptase: use in systemic anaphylaxis.

Tryptase, a neutral protease, is selectively concentrated in the secretory granules of human mast cells, and its release into the circulation serves as a clinical marker of mast cell activation. The current study describes a new, more sensitive ELISA utilizing a newly developed, mouse monoclonal IgG1 antibody for capture called B12 and capable of detecting tryptase in normal plasma and serum. The greater sensitivity of the new immunoassay results in part from a greater portion of tryptase being detected. Mean levels of tryptase in serum from normal subjects from Richmond, Virginia (4.9 ng/ml; n = 56), Munich, Germany (3.8 ng/ml; n = 19), and Amersfoort, The Netherlands (1.9 ng/ml; n = 8) were as indicated. In 62 subjects with ongoing allergic rhinitis, tryptase levels were no different in serum than for 19 normal controls, indicating that local mast cell activation is not necessarily reflected in the circulation. In 61 subjects sensitive to honey bee or yellow jacket venom by history, the 17 destined to have a severe, hypotensive response to a sting challenge had higher levels of tryptase at baseline than mild reactors, nonreactors, and controls, suggesting that baseline levels of tryptase may predict the severity of the clinical response to allergen in sensitive subjects.

Controlled insect-sting challenge in 55 patients: correlation between activation of plasminogen and the development of anaphylactic shock.

The pathogenesis of anaphylactic shock is not completely understood. Mast cell degranulation products may stimulate endothelial cells, leading to activation of fibrinolytic and coagulation systems. We investigated the activation of these systems in insect-sting anaphylaxis. Fifty-five patients with a previous insect-sting anaphylactic reaction and 8 volunteers were challenged with an in-hospital sting. Plasma levels of von Willebrand factor (vWF), coagulation, and fibrinolytic parameters were assessed. After the sting challenge, 20 patients developed anaphylactic symptoms, 7 of whom developed hypotension. In only these 7 patients, but not in the volunteers or in the other patients with no or mild anaphylactic symptoms, vWF levels increased from 107% +/- 33% (mean +/- SD) before, to 235% +/- 134% 60 minutes after the onset of clinical symptoms. This increase of vWF was accompanied by an increase of circulating tissue-type plasminogen-activator (tPA) levels from 5 +/- 3 micrograms/L to 50 +/- 59 micrograms/L and of plasminogen-alpha 2-antiplasmin complex (PAP-c) levels from 6 +/- 3 nmol/L to 297 +/- 225 nmol/L. Both tPA and PAP-c levels peaked 5 minutes after the onset of clinical symptoms. Such increases of tPA and PAP-c were not observed in the volunteers or in the patients who did not develop shock. The increase of tPA and PAP-c levels in the hypotensive patients correlated positively with the degree of mast cell degranulation and inversely with the mean arterial pressure. We conclude that activation of plasminogen may be involved in the pathogenesis of anaphylactic shock induced by insect venom.

Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock.

A postulated role of the contact system in anaphylactic reactions to insect stings was investigated. During prospective, in-hospital sting challenge, we collected serial blood samples from five normal volunteers and 16 patients with a history of insect-sting anaphylaxis. Activation of the contact system was assessed by measuring plasma levels of factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes as well as those of cleaved high molecular weight kininogen (HK). In addition, antigenic levels of (pre)kallikrein, factor XII, and HK were measured. No significant changes in contact system parameters were observed in any of the five volunteers or the four patients who did not develop an anaphylactic reaction after sting challenge. In contrast, significant changes in contact system parameters occurred in 7 of the 12 patients with anaphylactic symptoms after challenge. Peak levels of either C1-inhibitor complex were found 5 minutes after the onset of anaphylactic symptoms. The increase in C1-inhibitor was most pronounced in the 4 patients with angioedema, 2 of which also developed shock. However, activation of HK was observed in all four patients with angioedema, the two patients with shock but no angioedema, as well as in 1 of the remaining 6 patients with anaphylactic symptoms other than angioedema or shock. Thus, activation products of the contact system may be involved in the pathogenesis of angioedema and shock in insect-sting anaphylaxis.

Anaphylactic shock after insect-sting challenge in 138 persons with a previous insect-sting reaction.

OBJECTIVE: To study the rate and severity of anaphylactic reaction in relation to plasma levels of cardiovascular mediators in persons with a history of insect-sting anaphylactic shock who were rechallenged with a sting by the same insect. DESIGN: A cohort study with measurements before and after intentional sting challenge. SETTING: Intensive care unit of an 830-bed general hospital, a national center of insect-sting anaphylaxis in The Netherlands. PATIENTS: A total of 138 patients referred after a previous anaphylactic reaction to a Hymenoptera sting; and 8 volunteers. MEASUREMENTS: Signs of anaphylaxis and plasma levels of catecholamines and angiotensins. MAIN RESULTS: Only 39 of 138 (28%) of patients with a previous insect-sting anaphylactic reaction developed anaphylactic symptoms after sting challenge. Values of cardiovascular mediators and mean arterial pressure did not differ after the challenge from initial values in the volunteers or in the patients with a mild or no reaction after challenge. In the 17 patients with anaphylactic shock, mean arterial pressure decreased from 97 +/- 11 (mean +/- SD) to 65 +/- 17 mm Hg (P < 0.001), epinephrine levels rose from a median of 0.3 nmol/L (range, 0.2 to 2.3 nmol/L) to 2.5 nmol/L (0.2 to 35.7 nmol/L; P < 0.05), norepinephrine from 1.5 nmol/L (0.5 to 6.7) to 5.9 nmol/L (1.6 to 30.9 nmol/L; P < 0.01), and angiotensin II from 61 pmol/L (7 to 217 pmol/L) to 105 pmol/L (11 to 286 pmol/L; P < 0.01), all within 5 minutes after the onset of anaphylactic symptoms. The rise of these mediators correlated with the drop in blood pressure (P < 0.001). Dopamine and angiotensin I levels did not change in any participants. CONCLUSIONS: A recurrent insect-sting anaphylactic reaction occurred in only 28% of patients with a previous reaction. During this recurrent reaction, plasma levels of endogenous epinephrine, norepinephrine, and angiotensin II rose in relation to hypotension.

Insect-sting challenge in 138 patients: relation between clinical severity of anaphylaxis and mast cell activation.

One hundred thirty-eight patients with a previous anaphylactic reaction to a yellow jacket or a honeybee sting, as well as eight volunteers, were subjected to an in-hospital sting challenge. Plasma levels of histamine, tryptase, and prostaglandin D2 (PGD2) during sting challenge were studied in relation to clinical symptoms. Prechallenge levels (mean +/- SD) of histamine, tryptase, and PGD2 were 2 +/- 1 nmol/L, 0.3 +/- 0.3 U/L, and 320 +/- 223 ng/L, respectively. In the volunteers and in none except for one of the nonreacting patients, these levels did not change significantly after challenge. In contrast, mean increases in the group of 18 patients with a mild reaction were significant for histamine and tryptase at one or more time points after the challenge. (Five patients demonstrated no increase in histamine; nine demonstrated no increase in tryptase.) Except for histamine levels in one patient, these increases were considerably more in all 17 patients with a severe reaction, starting from the first anaphylactic symptoms. Fifteen minutes later, peak values were reached of 1275 +/- 2994 nmol of histamine per liter (range, 3 to 12800 nmol/L; median, 11 nmol/L) and 406 +/- 1062 U of tryptase per liter (range, 1.8 to 4400 U/L; median, 17 U/L). This rise in levels inversely correlated with the mean arterial pressure. Plasma levels of PGD2 in severely reacting patients did not differ significantly from those in patients with a mild or no reaction. In conclusion, only 28% of patients with a history of Hymenoptera anaphylaxis developed an anaphylactic reaction after an in-hospital challenge.(ABSTRACT TRUNCATED AT 250 WORDS)