[Good clinical practice and the maintenance of ethical standards in medical research: advice for junior researchers working in mental health care]. / Good clinical practice en medisch-ethische toetsing: handvatten voor (beginnend) onderzoekers in de ggz.

BACKGROUND: In mental health care, more and more research is being done, particularly in the field of educational programmes. Unfortunately, junior researchers are often not fully informed about the rules and regulations relating to research and about medical ethics. Therefore, they are not in a position to make considered judgements that conform to good clinical practice and acceptable medical ethics.
AIM: To give practical advice to trainees, stimulating them to think carefully about ethical standards in patient-related research in mental health care. METHODS The article provides a practice-based overview of practical advice and ethical considerations.
RESULTS: We stress that before beginning their research, researchers should think very carefully about the ethics of medical research. Instructions and guidelines relating to medical and ethical standards are to be found in: directive for good clinical practice compiled by the central committee for human research (CCMO) with the accompanying e-learning module and in the basic course 'rules and organisation for clinical researchers' (BROK). Practical tips, illustrated with examples, provide a framework for stimulating thoughts on medical ethics. Finally, it is important to improve the ways in which research is embedded in the organisational structure of teaching programmes.
CONCLUSION: Basic information about GCP and the upholding of medical and ethical standards in patient-related research can be obtained from various sources. The main challenge is to ensure that GCP is firmly embedded in patient-related research undertaken by junior researchers.

Phenotype-genotype correlation in a familial IGF1R microdeletion case.

BACKGROUND: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. METHODS AND RESULTS: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. CONCLUSION: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

Value judgements that matter to patients remain implicit in oncology guidelines: an observational study.

BACKGROUND: Clinical practice guidelines are often evidence-based. However, it is inevitable that there are value judgements in the practical recommendations contained in the guidelines. In order to see if patients are ultimately being supplied with sufficient information to help them make treatment decision, we determined 1) which value judgements influence the process of developing guidelines for palliative chemotherapy, and 2) whether these value judgements were made explicit in the final guideline report. METHODS: We studied the development process of six Dutch oncology guidelines in which palliative chemotherapy plays a substantial role. We observed the guideline development groups (GDGs), conducted semi-structured interviews with individual GDG members (including the chairs), and analysed the minutes of GDG meetings and subsequent versions of the guidelines. A value judgement was defined as a statement about the value of a patient outcome with regard to palliative chemotherapy. RESULTS: We identified the following value judgements in the process of guideline development: 1) consensus on what should be considered as valuable minimum patient outcomes, 2) preference for tailored treatment in situations where there is no evidence of treatment effect, 3) preference for 'doing something' even when there is sufficient evidence of no effect, and 4) the patient outcome of 'prolonging life'. These value judgements, however, were not reported in the final guideline. CONCLUSION: At least the last two value judgements mentioned are relevant for patients with incurable metastatic cancer in making decisions whether to undergo chemotherapy and what kind. Value judgements should be made explicit in guidelines, so that clinicians can transparently discuss treatment options with individual patients.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment.

CONTEXT: Disturbances in thyroid function have been described in small-for-gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children. OBJECTIVES: To determine whether short SGA children have higher TSH levels compared to age-matched controls and evaluate the influence of gestational age. To investigate whether GH treatment alters thyroid function. PATIENTS: A total of 264 short SGA children (116 preterm), prepubertal and non-GH deficient. MEASUREMENTS: Serum FT4 and TSH at baseline and after 6, 12 and 24 months of GH treatment. RESULTS: Baseline mean TSH was higher in preterm short SGA children than in age-matched controls (P < 0.05). Mean FT4 was not significantly different between short SGA children and controls. Baseline FT4 or TSH did not correlate with gestational age, or SDS for birth weight, birth length, height, body mass index, IGF-I or IGFBP-3. Mean FT4 decreased significantly during the first 6 months of GH treatment, but remained within the normal range. TSH did not change during treatment. The change in FT4 did not correlate with the change in height SDS during 24 months of GH treatment. CONCLUSION: Preterm short SGA children have higher, although within the normal range, TSH levels than controls. The level of TSH does not correlate with gestational age, birth weight SDS or birth length SDS. FT4 decreases during GH treatment, but is neither associated with an increase in TSH nor does it affect the response to GH treatment. As these mild alterations in thyroid function do not appear clinically relevant, frequent monitoring of thyroid function during GH therapy is not warranted in short SGA children.

Impact of detection bias on the risk of gastrointestinal cancer and its subsites in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) may be a risk factor for gastrointestinal (GI) cancers, but variations in study designs of observational studies may have yielded biased results due to detection bias. Furthermore, differences in risk for GI cancer subsites have not been extensively evaluated. We aimed to determine the risk of GI cancer and its subsites in patients with T2DM and how it is affected by detection bias. METHODS: A matched cohort study was performed using the NCR-PHARMO database. New-users of ≥1 non-insulin anti-diabetic drug during 1998-2011 were matched with non-diabetic controls by year of birth, sex, and time between database entry and index. Cox regression analyses were performed with and without lag-period to estimate hazard ratios (HRs) for GI cancer and its subsites. Covariables included age, sex, use of other drugs and history of hospitalisation. RESULTS: An increased risk of GI cancer was observed in T2DM patients (HR 1.5, 95% confidence interval [CI] 1.3-1.7) compared with controls, which was attenuated in the 1-year lagged analysis (HR 1.4, 95% CI 1.2-1.7). Stratified by subsite, statistically significant increased risks of pancreatic (HR 4.7, 95% CI 3.1-7.2), extrahepatic bile duct (HR 4.2, 95% CI 1.5-11.8) and distal colon cancer (HR 1.5, 95% CI 1.1-2.1) were found, which remained statistically significantly increased in the lagged analysis. CONCLUSIONS: T2DM patients had a 40% increased risk of GI cancer. Increased GI cancer risks tended to be weaker when reducing detection bias by applying a 1-year lag-period. Future observational studies should therefore include sensitivity analyses in which this bias is minimised.

Trill performance components vary with age, season, and motivation in the banded wren.

Acoustic displays with difficult-to-execute sounds are often subject to strong sexual selection, because performance levels are related to the sender's condition or genetic quality. Performance may also vary with age, breeding stage, and motivation related to social context. We focused on within-male variation in four components of trill performance in banded wren (Thryophilus pleurostictus) songs: note consistency, frequency bandwidth, note rate and vocal deviation. The latter is a composite measure reflecting deviation from the performance limit on simultaneously maximizing both frequency bandwidth and note rate. We compared the changes in these song parameters at three time scales: over the course of years, across the breeding season, and at different times of the day with contrasting agonistic contexts. Vocal deviation decreased and note consistency increased over years, suggesting that experience may improve individual proficiency at singing trills. Consistency also increased across the season, confirming that practice is important for this parameter. Although there was no significant seasonal change in vocal deviation, one of its components, note rate, increased during the season. Neither vocal deviation nor consistency varied with agonistic context. However, note rate increased during playback experiments simulating territorial intrusions compared to dawn chorus singing. The magnitude of a male's increase in note rate was positively correlated with his aggressive behavior during the playback experiment. Thus consistency, bandwidth, and vocal deviation indicate age, whereas trill rate flexibly indicates the singer's aggressive motivation. We also found evidence of a within-male trade-off between vocal deviation and consistency.

Leaky gut and diabetes mellitus: what is the link?

Diabetes mellitus is a chronic disease requiring lifelong medical attention. With hundreds of millions suffering worldwide, and a rapidly rising incidence, diabetes mellitus poses a great burden on healthcare systems. Recent studies investigating the underlying mechanisms involved in disease development in diabetes point to the role of the dys-regulation of the intestinal barrier. Via alterations in the intestinal permeability, intestinal barrier function becomes compromised whereby access of infectious agents and dietary antigens to mucosal immune elements is facilitated, which may eventually lead to immune reactions with damage to pancreatic beta cells and can lead to increased cytokine production with consequent insulin resistance. Understanding the factors regulating the intestinal barrier function will provide important insight into the interactions between luminal antigens and immune response elements. This review analyses recent advances in the mechanistic understanding of the role of the intestinal epithelial barrier function in the development of type 1 and type 2 diabetes. Given our current knowledge, we may assume that reinforcing the intestinal barrier can offer and open new therapeutic horizons in the treatment of type 1 and type 2 diabetes.

Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study.

BACKGROUND: Microscopic colitis causes chronic watery diarrhoea. Recent studies have suggested an aetiological role for various medications, including proton pump inhibitors, in the pathogenesis of microscopic colitis. AIM: To determine whether an association exists between microscopic colitis and proton pump inhibitor use in patients with documented microscopic colitis vs. age- and gender-matched controls. METHODS: In this retrospective case-control study, cases of microscopic colitis from a secondary and tertiary referral medical centre diagnosed in the last 5 years were reviewed. Demographic characteristics, clinical, histological and endoscopic records, as well as exposure to PPIs and NSAIDs were assessed. Controls from the population were matched to cases by gender and by age. RESULTS: During the investigated period, 136 cases were identified in both hospitals. Of these, 95 cases of microscopic colitis were retrieved for detailed analysis. Exposure to proton pump inhibitors at the time of the histological diagnosis was significantly higher in patients with collagenous colitis than in controls [38% vs. 13%, P < 0.001; adjusted OR of 4.5 (95% CI 2.0-9.5)]. CONCLUSIONS: This observation confirms the presumed association between microscopic colitis and PPI use, and it supports the possible aetiological role of PPI exposure in the development of microscopic colitis.

Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age.

CONTEXT: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. OBJECTIVE: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. PATIENTS: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. INTERVENTION: Short prepubertal SGA children received GH 1mg/m(2)/day. OUTCOME MEASURES: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. RESULTS: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P<0.001). Children with C(-202)/C(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. CONCLUSION: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.

Storage proteins are present in the hemolymph from larvae and adults of the Colorado potato beetle.

The protein composition of larval and adult hemolymph from the Colorado potato beetle, Leptinotarsa decemlineata, was investigated and some abundant, high molecular weight proteins were identified and characterized. Diapause protein 1, which occurs in the hemolymph of last instar larvae and short-day adults, appeared to be a storage protein. This protein dissociated into two bands due to the high pH used in nondenaturing gels. Its quaternary structure was established by chemical crosslinking. It appeared to be a hexamer. Diapause protein 1 is composed of approximately 82,000 subunits. The amino acid composition and N-terminal sequence of this protein has been determined. Specific antibodies against diapause protein 1 have been developed. Topical application of 1 microgram pyriproxyfen, a juvenile hormone analog, to last instar larvae and short-day adults suppressed the appearance of this protein in the hemolymph. Pyriproxyfen prematurely induced vitellogenin, when applied to last instar larvae. A larval specific protein was also identified in the hemolymph. Its temporary appearance in the hemolymph of last instar larvae, its subunit composition (M(r) approximately 82,000) and its suppression by pyriproxyfen suggests that this protein is a storage protein as well.

Structure of Colorado potato beetle lipophorin: differential scanning calorimetric and small-angle X-ray scattering studies.

The structure of lipophorin, isolated from hemolymph of the Colorado potato beetle, was investigated by differential scanning calorimetry (DSC) and small-angle X-ray scattering. The DSC heating curves of intact lipophorin showed endothermic peaks that were similar to peaks obtained with the hydrocarbon fraction isolated from this lipophorin. The observed peaks correlated with the transition of the hydrocarbons from an ordered into a more disordered state. Changes in structure of the lipophorin particles with increasing temperature were also observed by small-angle X-ray scattering studies. The structural organization of lipophorin was further elucidated by simulation analysis, using a three-layered symmetrical sphere as a model. These studies revealed that lipophorin from the Colorado potato beetle is a sphere with a maximum diameter of 175 A. The sphere is composed of three radially symmetrical layers of different electron densities. The outer layer (37.5-39.5 A in thickness) is composed of phospholipid, apolipophorin I, and part of apolipophorin II. The middle layer (5-10 A) contains diacylglycerol, the rest of apolipophorin II, and probably beta-carotene. The core of the particle (40-45 A) only contains hydrocarbons. This structure differs from another model, previously proposed for cockroach and locust lipophorins [Katagiri, C., Sato, M., & Tanaka N. (1987) J. Biol. Chem. 262, 15857-15861], in the small size of the middle layer. The volume of the middle layer correlated well with the low diacylglycerol content of this lipophorin.