[Confounding in nutritional epidemiology; is Mendelian randomization the answer?] / Het probleem met de voedingsepidemiologie.

Observational studies have reported many beneficial effects of vitamin and mineral supplements on cardiovascular and other diseases, but randomized controlled trials have failed to confirm these. This could be due to the failure of statistical adjustment to eliminate residual and unmeasured confounding by known risk factors. A Mendelian randomization study now suggests a similar problem for the observed beneficial effects of moderate alcohol intake. When 500,000 Chinese people were ranked by self-reported alcohol intake, stroke risk showed a U-shaped curve, risk being lowest at 1-2 units per day. However, when subjects were ranked by genetically conditioned intake, risk was lowest in abstainers and went up linearly with intake. Mendelian randomization may be more suitable for elucidating the effects of diet on health than conventional epidemiology.

Serum neurofilament light chain in patients with acute cerebrovascular events.

BACKGROUND AND PURPOSE: Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months. RESULTS: We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score < 7, 13.1 pg/mL [interquartile range (IQR), 5.3-27.8]; NIHSS score 7-15, 16.7 pg/mL (IQR, 7.4-34.9); and NIHSS score > 15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P < 0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors. CONCLUSIONS: In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months.

[City hall holds the key to weight control]. / De sleutel tot vetzucht ligt op het stadhuis.

Doctors can play a major role in reducing obesity in the community, but that requires an unconventional approach. Treatment of individual patients with diet or drugs is largely ineffective. In contrast, comprehensive community interventions such as one pioneered by EPODE in France have successfully reduced the prevalence of corpulence in children. Such a community approach requires simultaneously engagement by town governments, retailers, associations, restaurants, caterers, media, schools and kindergartens to cooperate in improving diets, reducing caloric intake and increasing activity. Physicians are by far the most highly trusted source of information when it comes to health matters. Therefore, a few words from a doctor at the right time and in the right place, e.g. at a city council meeting, could tip the scales. Individual doctors cannot cure patients' obesity by themselves in their offices, but a few hours per year spent on persuading key stakeholders might help to turn the tide on obesity in the community.

Proteomic discovery and verification of serum amyloid A as a predictor marker of patients at risk of post-stroke infection: a pilot study.

BACKGROUND: Post-stroke infections occur in 20-36% of stroke patients and are associated with high morbidity and mortality rates. Early identification of patients at risk of developing an infection could improve care via an earlier treatment leading to a better outcome. We used proteomic tools in order to discover biomarkers able to stratify patients at risk of post-stroke infection. METHODS: The post hoc analysis of a prospective cohort study including 40 ischemic stroke patients included 21 infected and 19 non-infected participants. A quantitative, isobaric labeling, proteomic strategy was applied to the plasma samples of 5 infected and 5 non-infected patients in order to highlight any significantly modulated proteins. A parallel reaction monitoring (PRM) assay was applied to 20 additional patients (10 infected and 10 non-infected) to verify discovery results. The most promising protein was pre-validated using an ELISA immunoassay on 40 patients and at different time points after stroke onset. RESULTS: Tandem mass analysis identified 266 proteins, of which only serum amyloid A (SAA1/2) was significantly (p = 0.007) regulated between the two groups of patients. This acute-phase protein appeared to be 2.2 times more abundant in infected patients than in non-infected ones. These results were verified and validated using PRM and ELISA immunoassays, which showed that infected patients had significantly higher concentrations of SAA1/2 than non-infected patients at hospital admission, but also at 1, 3, and 5 days after admission. CONCLUSIONS: The present study demonstrated that SAA1/2 is a promising predictor, at hospital admission, of stroke patients at risk of developing an infection. Further large, multicenter validation studies are needed to confirm these results. If confirmed, SAA1/2 concentrations could be used to identify the patients most at risk of post-stroke infections and therefore implement treatments more rapidly, thus reducing mortality.

[Fish oil in pregnancy: can it prevent asthma in children?] / Visolie tijdens de zwangerschap.

Taking fish oil supplements in the third trimester of pregnancy was associated with significantly less wheezing or asthma in the child at the age of 3-5 years, according to a randomized clinical trial by Bisgaard et al., NEJM 2017. However, the results of this study should be interpreted with caution. The primary end points were modified at a late stage in the study, and two primary end points, eczema in the first 3 years of life and allergic sensitization at 18 months of age, were demoted to secondary end points, and showed no significant effect of treatment. Furthermore, the age range for the published primary end point, persistent wheeze, differed from that in the protocol. Additional concerns include the emphasis on outcomes by omega-3 fatty acid levels in the blood, a post hoc subgroup analysis not included in the protocol. In our opinion, this study does not justify advising routine fish oil supplements in pregnancy.

Trans fatty acids and cardiovascular health: research completed?

This review asks the question if further research on trans fatty acids and cardiovascular health is needed. We therefore review the evidence from human studies on trans fatty acids and cardiovascular health, and provide a quantitative review of effects of trans fatty acid intake on lipoproteins. The results show that the effect of industrially produced trans fatty acids on heart health seen in observational studies is larger than predicted from changes in lipoprotein concentrations. There is debate on the effect of ruminant trans fatty acids and cardiovascular disease. Of special interest is conjugated linoleic acid (CLA), which is produced industrially for sale as supplements. Observational studies do not show higher risks of cardiovascular disease with higher intakes of ruminant trans fatty acids. However, CLA, industrial and ruminant trans fatty acids all raise plasma low-density lipoprotein and the total to high-density lipoprotein ratio. Gram for gram, all trans fatty acids have largely the same effect on blood lipoproteins. In conclusion, the detrimental effects of industrial trans fatty acids on heart health are beyond dispute. The exact size of effect will remain hard to determine. Further research is warranted on the effects of ruminant trans fatty acids and CLA on cardiovascular disease and its risk factors.

Why the European Food Safety Authority was right to reject health claims for probiotics.

Probiotics are microbes that are claimed to promote health and well-being when added to foods. However, the European Food Safety Authority (EFSA) has so far advised negatively about health claims for probiotics. Companies and scientists have protested against these rejections, sometimes in vigorous language. I argue that EFSA could not have acted differently, given EU regulations and the lack of convincing evidence for some of the claimed effects of probiotics on human health and well-being. One EU regulation that makes it hard to demonstrate the benefits of probiotics is the prohibition of medical claims, i.e. claims that a food prevents or cures a disease. If this prohibition did not exist, manufacturers of nutritional treatments might circumvent the costly procedures required for drugs, and market their products to ill people without thorough proof that they are effective and safe. However, the prohibition is also a legal fiction, because promotion of health and prevention of disease is largely the same thing. EFSA has recently indicated that it will allow health claims based on the ability of probiotics to reduce infections. To a certain extent, this abolishes the distinction between health claims and medical claims. It remains to be seen if probiotics producers can convince EFSA that their products prevent or cure infections and other diseases in humans.

Optimizing the risk estimation after a transient ischaemic attack - the ABCDE⊕ score.

BACKGROUND AND PURPOSE: The risk of stroke after a transient ischaemic attack (TIA) can be predicted by scores incorporating age, blood pressure, clinical features, duration (ABCD-score), and diabetes (ABCD2-score). However, some patients have strokes despite a low predicted risk according to these scores. We designed the ABCDE+ score by adding the variables 'etiology' and ischaemic lesion visible on diffusion-weighted imaging (DWI) -'DWI-positivity'- to the ABCD-score. We hypothesized that this refinement increases the predictability of recurrent ischaemic events. METHODS: We performed a prospective cohort study amongst all consecutive TIA patients in a university hospital emergency department. Area under the computed receiver-operating curves (AUCs) were used to compare the predictive values of the scores with regard to the outcome stroke or recurrent TIA within 90 days. RESULTS: Amongst 248 patients, 33 (13.3%, 95%-CI 9.3-18.2%) had a stroke (n = 13) or a recurrent TIA (n = 20). Patients with recurrent ischaemic events more often had large-artery atherosclerosis as the cause for TIA (46% vs. 14%, P < 0.001) and positive DWI (61% vs. 35%; P = 0.01) compared with patients without recurrent events. Patients with and those without events did not differ with regard to age, clinical symptoms, duration, blood pressure, risk factors, and stroke preventive treatment. The comparison of AUCs [95%CI] showed superiority of the ABCDE+ score (0.67[0.55-0.75]) compared to the ABCD(2) -score (0.48[0.37-0.58]; P = 0.04) and a trend toward superiority compared to the ABCD-score (0.50[0.40-0.61]; P = 0.07). CONCLUSION: In TIA patients, the addition of the variables 'etiology' and 'DWI-positivity' to the ABCD-score seems to enhance the predictability of subsequent cerebral ischaemic events.

Significance of microbleeds in patients with transient ischaemic attack.

BACKGROUND AND PURPOSE: The aim of this study was to determine the prognostic significance of microbleeds in TIA-patients. In patients with a transient ischaemic attack (TIA), the prognostic value of microbleeds is unknown. METHODS: In 176 consecutive TIA patients, the number, size, and location of microbleeds with or without acute ischaemic lesions were assessed. We compared microbleed-positive and microbleed-negative patients with regard to the end-point stroke within 3 months. RESULTS: Four of the seven patients with subsequent stroke had microbleeds. Microbleed-positive patients had a higher risk for stroke [odds ratios (OR) 8.91, 95% CI 1.87-42.51, P<0.01] than those without microbleeds. Microbleed-positive patients with accompanying acute ischaemic lesions had a higher stroke risk than those with neither an acute ischaemia nor a microbleed (OR 6.20, 95% CI 1.10-35.12; P=0.04). CONCLUSION: Microbleeds alone or in combination with acute ischaemic lesions may increase the risk for subsequent ischaemic stroke after TIA within 3 months.

Anterior pituitary axis hormones and outcome in acute ischaemic stroke.

BACKGROUND: Early and accurate prediction of outcome in acute stroke is important and influences risk-optimized therapeutic strategies. Endocrine alterations of the hypothalamic-pituitary axis are amongst the first measurable alterations after cerebral ischaemia. We therefore evaluated the prognostic value of cortisol, triiodothyronine (T3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and growth hormone (GH) in patients with an acute ischaemic stroke. METHODS: In an observational study including 281 patients with ischaemic stroke, anterior pituitary axis hormones (i.e. cortisol, T3, fT4, TSH and GH) were simultaneously assessed to determine their value to predict functional outcome and mortality within 90 days and 1 year. RESULTS: In receiver operating characteristic curve analysis, the prognostic accuracy of cortisol was higher compared to all measured hormones and was in the range of the National Institutes of Health Stroke Scale (NIHSS). Cortisol was an independent prognostic marker of functional outcome and death [odds ratio (OR) 1.0 (1.0-1.01) and 1.62 (1.37-1.92), respectively, P<0.0002 for both, adjusted for age and the NIHSS] in patients with ischaemic stroke, but added no significant additional predictive value to the clinical NIHSS score. CONCLUSION: Cortisol is an independent prognostic marker for death and functional outcome within 90 days and 1 year in patients with ischaemic stroke. By contrast, other anterior pituitary axis hormones such as peripheral thyroid hormones and GH are only of minor value to predict outcome in stroke.

Stress hormones predict cerebrovascular re-events after transient ischemic attacks.

BACKGROUND: TIA is a strong predictor of subsequent stroke. The hypothalamic stress hormone copeptin is an accurate prognostic marker in acute ischemic stroke. This study assessed prognostic reliability of 2 distinct stress hormones, copeptin and cortisol, for the risk stratification of re-events in patients with TIA. METHODS: We conducted a prospective study in patients admitted to the emergency department with a TIA. Clinical risk scoring using the ABCD2 score was determined and both hormones were measured in plasma on admission. The primary endpoint was a cerebrovascular re-event within 90 days. RESULTS: We included 107 consecutive patients with TIA. Re-events occurred in 10 patients (9%). Copeptin levels were higher in patients with a re-event compared with patients without re-event (p = 0.02), in contrast to cortisol (p = 0.53). Copeptin revealed a higher area under the receiver operating characteristics curve (AUC) to predict re-events compared to the ABCD2 score (AUC of 0.73 vs 0.43; p < 0.01) and improved its prognostic accuracy (AUC of combined model of 0.77; p = 0.002). CONCLUSION: Measurement of plasma copeptin but not cortisol levels in patients with TIA provides additional prognostic information beyond the ABCD2 clinical risk score alone. If confirmed in future studies, routine copeptin measurement may be an additional tool for risk stratification and targeted resource allocation after TIA.

The role of routine echocardiography in unselected patients with cerebrovascular ischaemic events.

BACKGROUND: Cardiac embolism is an important etiology of cerebrovascular ischaemic events (CIE). Echocardiography is routinely performed in patients with CIE despite guidelines recommending restriction of echocardiography to patients with clinically suspected cardioembolism. OBJECTIVE: The aim of this study was to examine the therapeutic impact and prognostic role of echocardiographic findings in an unselected population suffering from CIE. METHODS: Between November 2006 and November 2007, 319 patients with CIE underwent evaluation by transthoracic echocardiography (TTE) and in addition by transesophageal echocardiography (TEE) if deemed mandatory (n = 49). The combined clinical end-point included death or recurrent CIE, occurring during a follow-up period of 3 and 12 months, respectively. RESULTS: After 3 months of follow-up, the combined end-point was noted in 30 (9%) and after 12 months in 43 (13%) patients. In multivariate analysis, atrial fibrillation (AF) (HR 2.12, 95% CI 1.38-3.25; P < 0.001) and coronary artery disease (CAD: HR 1.85, 95% CI 1.21-2.81; P = 0.004) were predictors of events occurring during short-term follow-up. After 1 year of follow-up, AF (HR 1.67, 95% CI 1.19-2.32; P = 0.003) and CAD (HR 1.5, 95% CI 1.09-2.06; P = 0.01) were associated with the combined end-point. Echocardiographic parameters assessed at study entry were not independently related to an adverse outcome. CONCLUSION: Whereas AF and CAD appear to increase the risk of events after suffering from CIE, echocardiographic findings were not independently associated with the combined end-point of recurrent CIE or death.

The stress hormone copeptin: a new prognostic biomarker in acute illness.

Stress is defined as anything that throws the body out of homeostatic balance; for example an acute illness. Any stressor which activates the hypothalamo-pituitary-adrenal (HPA) axis leads to an increase in concentrations of the adrenal stress hormone, cortisol. One of the major hypothalamic stress hormones, which is stimulated by different stressors, is vasopressin (AVP). However, measurement of circulating AVP levels is challenging because it is released in a pulsatile pattern, it is unstable and is rapidly cleared from plasma. AVP derives from a larger precursor peptide (pre-provasopressin) along with copeptin which is released in an equimolar ratio to AVP and is more stable in the circulation and easy to determine. Copeptin levels were found to closely mirror the production of AVP. We have shown that copeptin more subtly mirrors the individual stress level compared to cortisol. Due to the positive association of copeptin with the severity of illness and outcome, copeptin has been proposed as a prognostic marker in acute illness. The prognostic accuracy of copeptin has been analysed in sepsis, pneumonia, lower respiratory tract infections, stroke and other acute illnesses. Thereby, copeptin was found to accurately mirror disease severity and to discriminate patients with unfavourable outcomes from patients with favourable outcomes. Copeptin improves the prognostic information provided by commonly used clinical scoring instruments. Importantly, interpretation of copeptin levels must always consider the clinical setting. An accurate prognostic assessment has the potential to guide interventions and effectively plan and monitor rehabilitation and, thus optimise the management of individual patients and the allocation of limited health care resources. Future intervention studies must prove the value of copeptin in clinical decision making and in improving the overall medical management of patients with acute illnesses.

Absorption, distribution, and biliary excretion of cafestol, a potent cholesterol-elevating compound in unfiltered coffees, in mice.

Cafestol is a diterpene present in unfiltered coffees. It is the most potent cholesterol-elevating compound present in the human diet. However, the precise mechanisms underlying this effect are still unclear. In contrast, cafestol is also known as a hepatoprotective compound, which is likely to be related to the induction of glutathione biosynthesis and conjugation. In the present study, we investigated whole-body distribution, biliary excretion, and portal bioavailability of cafestol in mice. First, dissection was used to study distribution. Five hours after an oral dose with (3)H-labeled cafestol, most activity was found in small intestine, liver, and bile. These results were confirmed by quantitative whole-body autoradiography in a time course study, which also showed elimination of all radioactivity within 48 h after administration. Next, radiolabeled cafestol was dosed intravenously to bile duct-cannulated mice. Five hours after the dose 20% of the radioactivity was found in bile. Bile contained several metabolites but no parent compound. After intestinal administration of radioactive cafestol to portal vein-cannulated mice, cafestol was shown to be rapidly absorbed into the portal vein as the parent compound, a glucuronide, and an unidentified metabolite. From the presence of a glucuronide in bile that can be deconjugated by a bacterial enzyme and the prolonged absorption of parent compound from the gastrointestinal tract, we hypothesized that cafestol undergoes enterohepatic cycling. Together with our earlier observation that epoxidation of the furan ring occurs in liver, these findings merit further research on the process of accumulation of this coffee ingredient in liver and intestinal tract.

A high intake of conjugated linoleic acid does not affect liver and kidney function tests in healthy human subjects.

Conjugated linoleic acid (CLA) is consumed widely as a supplement. It causes hepatomegaly in animals, but toxicological data in humans are limited. We therefore studied the effect of a high daily intake of CLA on liver and kidney function in healthy subjects. Twenty subjects received 14.6 g cis-9,trans-11 CLA and 4.7 g trans-10,cis-12 CLA isomers a day for 3 weeks. Liver and kidney function was measured at 0, 3, 7, 10, 16, and 21 days. Mean values of all tests remained within normal limits. Lactate dehydrogenase (mean+/-SD) increased from 290.9+/-43.6 to 322.5+/-60.7 U/L (p=0.04) on day 21. One subject exceeded the upper limit of normal of 450 U/L on day 21, to 472 U/L and another showed an isolated elevation to 555 U/L on day 7. Gamma-glutamyltranspeptidase increased from 12.1+/-5.9 to 13.5+/-6.2U/L (p=0.002). No one exceeded the upper limit of 50 U/L for men and 40 U/L for women. A daily intake of 19.3 g CLA for 3 weeks does not produce clinically relevant effects on markers of liver and kidney function in healthy volunteers.

Which are the greatest recent discoveries and the greatest future challenges in nutrition?

BACKGROUND: Nutrition science aims to create new knowledge, but scientists rarely sit back to reflect on what nutrition research has achieved in recent decades. METHODS: We report the outcome of a 1-day symposium at which the audience was asked to vote on the greatest discoveries in nutrition since 1976 and on the greatest challenges for the coming 30 years. Most of the 128 participants were Dutch scientists working in nutrition or related biomedical and public health fields. Candidate discoveries and challenges were nominated by five invited speakers and by members of the audience. Ballot forms were then prepared on which participants selected one discovery and one challenge. RESULTS: A total of 15 discoveries and 14 challenges were nominated. The audience elected Folic acid prevents birth defects as the greatest discovery in nutrition science since 1976. Controlling obesity and insulin resistance through activity and diet was elected as the greatest challenge for the coming 30 years. This selection was probably biased by the interests and knowledge of the speakers and the audience. For the present review, we therefore added 12 discoveries from the period 1976 to 2006 that we judged worthy of consideration, but that had not been nominated at the meeting. CONCLUSIONS: The meeting did not represent an objective selection process, but it did demonstrate that the past 30 years have yielded major new discoveries in nutrition and health.

[The role of diet in the development of type 2 diabetes mellitus: calories play the leading role]. / De rol van voeding bij het ontstaan van diabetes mellitus type 2: calorieën in de hoofdrol.

Diets high in saturated fat, trans fat and glycaemic load and low in fibre and polyunsaturated fat are associated with a 25 to 50% increase in the risk of type 2 diabetes. However, obesity increases this risk by 500 to 1000%. Effects ascribed to dietary composition might therefore be due to unmeasured effects of body size. In clinical trials, a weight loss of 3-5 kg plus twice to min of walking per day reduced the incidence of diabetes by 58%. The size of this effect is remarkable. It points to the solution to the diabetes epidemic, which is to reconstruct cities so as to make people eat less and move more. There is an analogy here with the cholera epidemics, which also could be solved only by changing the urban environment.

[Fish fatty acids and cardiovascular diseases--an update]. / Visvetzuren en hart-en vaatziekten--een update.

Epidemiologic observational research shows that higher intake of fish fatty acids is associated with a lower risk of fatal heart disease and sudden death, but this effect is not observed with non-fatal heart disease. Currently available trials with clinical endpoints provide no convincing evidence that supplementation with fish oil prevents cardiovascular disease. The theory that fish fatty acids can prevent cardiac arrhythmias is not supported by the trials performed in patients with life-threatening cardiac arrhythmias. For the specific group of patients who have previously experienced a ventricular tachycardia and who have not been prescribed an anti-arrhythmia medication for this, there are indications that the intake of fish oil might even lead to a slightly increased risk ofsevere cardiac arrhythmias. However, other subgroups of patients, such as patients with a recent myocardial infarction may benefit from taking fish oil to prevent cardiac arrhythmias. The advice of the Health Council of the Netherlands to eat fish twice per week, of which fatty fish once per week, or to take 450 mg of the combination eicosapentaenic acid (EPA) and docosahexaenic acid (DHA) per day remains justifiable until the results from current studies become available. However, patients with a ventricular arrhythmia who do not receive specific anti-arrhythmic medication should be careful about taking fish oil capsules.

[The probiotic yogurt Activia shortens intestinal transit, but has not been shown to promote defecation]. / De probiotische yoghurt Activia: versnelde darmpassage wel aangetoond, maar bevordering van de stoelgang niet.

Activia is a yogurt product containing the probiotic bacterium Bifidobacterium animalis DN-173 010. Five clinical trials have been carried out. Four of these show that dairy products containing this bacterium shorten intestinal transit in volunteers. However, except in a subgroup of 19 out of 267 patients in one study, no significant effect of Activia was reported on the frequency, quantity or consistency of stools. In its marketing in the Netherlands, the company that produces Activia, Danone, claims that Activia promotes defecation. There is insufficient scientific evidence to support this claim.

[Elimination of all trans fatty acids]. / Alle transvetzuren de wereld uit.

At the start of the 20th century, the production of trans fatty acids was originally largely driven by the increasing demand for margarine. The two Dutch margarine firms Van den Bergh and Jurgens played an important role in this early development. In the early 1990s it was shown that trans fatty acids increase the risk of heart disease. Unilever, the successor to Van den Bergh and Jurgens, then took the lead in eliminating trans fatty acids from retail foods worldwide. As a result, intake in The Netherlands fell from 15 g per day in 1980 to 3 g per day in 2003. Dairy products and meat are now the major source of trans fatty acids. The effects on health of these ruminant trans fatty acids are unclear. There are three lessons to be learned from the rise and fall of trans fatty acids. First, a history of safe use does not guarantee safety of food components, because routine surveillance will fail to detect adverse effects on common illnesses with long incubation periods. Second, it shows that it is more effective and easier to change the composition of foods than to change consumer behaviour. And third, governments can have a major impact on consumers' health by mandating the use of healthier food ingredients.