Denialism Preserves Scientific Controversies: a Case Study of Abusive Head Trauma Research

The traditional theory of abusive head trauma requires scientific scrutiny. Those who question the validity of this theory have been accused of denialism for the purpose of obfuscating evidence in legal settings and supporting abusive caregivers. The tradi­tional theory holds that abusive head trauma results from “shaken baby syndrome”. In reference to abusive head trauma in the absence of external signs of trauma, we argue that it is the child-protection clinicians and concerned researchers who represent denialism. We have identified three types of denialism in this area: (i) denialism of the presence of a scientific controversy; (ii) denialism of relevant scientific distinctions between abusive head trauma cases with versus without external signs of trauma; and (iii) denialism of circular reasoning as a major risk of bias. The analysis discloses that the scientific controversy pertaining to abusive head trauma is real and that it is problematic to lump together all alleged abusive head trauma, with and without exter­nal signs of trauma. Further, it has been ignored that circular reasoning results in a high risk of bias. We conclude that denialism preserves rather than promotes scientific developments on abusive head trauma research.

A Systematic Review of Clinical Trials Testing CETP and PCSK9 Inhibitors: The Cholesterol-Heart Theory—Time for a Requiem?

There is an ongoing intense controversy around cholesterol lowering using statins, questioning the reality of the benefits and the safety of this treatment. Going even further, this has led to a growing questioning of the robustness of the well-established cholesterol-heart theory, stating that high cholesterol levels ineluctably and strongly increase the risk of coronary artery obstruction and acute myocardial infarction. In the same way, many scientists no longer agree with the theory that high cholesterol increases the risk of ischemic stroke. To test the cholesterol-heart theory, the present systematic review aimed at examining whether the most recent clinical trials testing powerful cholesterol-lowering interventions (such as anti-CETP and anti-PCSK9) report effective reduction of fatal cardiovascular complications and improved survival. Because of high heterogeneity between studies, a meta-analysis was not feasible. The review did show that neither anti-CETP nor anti-PCSK9 treatment can significantly reduce the risk of cardiovascular death, thereby giving credit to the questioning of the cholesterol-heart theory. Our review also shows that the quality of the included trials is generally poor with suspicion of inefficient blinding. This undermines the validity of the reported nonfatal events and thereby increases the importance of comparing fatal endpoints in both groups to test the cholesterol-heart theory.

A Milestone for the Journal of Controversies in Biomedical Research

If every positive result published in peer-reviewed, biomedical journals were true, the world would be disease-free. On the contrary, the disease burden and the associated economic burden are on the rise. With unprecedented advances in technology, we have been able to manipulate genes and biological pathways and experimentally demonstrate that diseases can be cured by such approaches. We read these success stories in peer-reviewed journals. However, it is not an understatement that more than 95% of these experimental findings never translate to any useful clinical outcome. One of the reasons for this is that when one gene or biological pathway is manipulated, compensatory mechanisms come into play, causing or sustaining the same disease through alternate pathways or inducing adverse events that are worse than the disease itself. These results usually do not get published. Unless we choose to publish negative, null, and contradictory findings along with positive results, and challenge the existing paradigm, false science will flourish. The Journal of Controversies in Biomedical Research is a dedicated journal for the publication of negative, null, and controversial findings. The current issue of the journal contains a review article questioning the validity of the cholesterol-heart theory, which claims that high cholesterol levels lead to coronary artery obstruction and acute myocardial infarction and that lipid-lowering drugs would offer protection against such pathologies. I hope the journal and the article will stimulate intellectual scientific conversation and encourage researchers to publish their negative, null, and controversial research findings and views.

Immortalized HEK 293 Kidney Cell Lines as Models of Renal Cells: Friends or Foes?

The immortalized cell lines derived from human embryonic kidney, named HEK 293, are extensively used as models of human renal cells in in vitro studies. Nevertheless, ample evidence in the literature shows that HEK 293 cells display genotypic and phenotypic characteristics that differ substantially from primary kidney cells, with potential detrimental effects on the quality of the experimental results. Among the differences documented between HEK 293 and renal cells, there is an altered pattern of expression of many proteins involved in the development and physiological functions of the kidney. Methionine sulfoxide reductase (Msr) enzymes are ubiquitous components of the cellular machinery, evolved to counteract the damages inflicted to methionine residues by oxidative stress, particularly intense in kidney tissues. In this article, we have compared the levels of expression of several different Msr enzymes in human kidney and in a HEK 293 strain and have observed significant differences between the two cell types.

Lack of association in acne and salivary testosterone

The pathogenesis of acne vulgaris has only been partially elucidated. Various hormones, especially androgens, are likely to play a role, but results of studies are still inconclusive. The objective of the current study was to investigate whether day to day variation in salivary testosterone correlates with acne in males. Saliva samples were collected for 120 consecutive days from each of the 40 males. Salivary testosterone concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Facial acne lesions were assessed on a daily basis by photography by the participating males. Potential confounders’ (sexual intercourse, masturbation, physical exercise and disease) were also registered every day by the participants. A significant but weak association between salivary testosterone and acne was found (n = 4602, r = 0.031, P = 0.034). Elevated testosterone concentrations were associated with an increase in acne, but when testosterone concentrations were above twice the individual average, acne lesions paradoxically decreased. The current results indicate that daily fluctuations in salivary testosterone levels in males are associated with acne patterns, but the weak correlation suggests that the effect is too small to be of clinical significance. The analysis in the current study was complicated by a large number of days on which the participants had no acne, as well as the seemingly non-monotonic relation between testosterone and acne. This may indicate that the actual relation is stronger than concluded here.

Does Oxidative Stress Change During Orthotopic Liver Transplantation?

In clinical ischemia/reperfusion injury, damage resulting from oxidative and nitrosative stress is generally considered crucial for graft functioning. Yet, there is increasing evidence that modern clinical transplantation including orthotopic liver transplantation (OLT) is not associated with elevation of oxidative and nitrosative stress upon organ reoxygenation. We measured two currently used biomarkers of oxidative stress, i.e., 15(S)-8-iso-prostaglandin F2a (15(S)-8-iso-PGF2a) and cis-epoxyoctadecanoic acid (cis-EpOA), in human plasma during the entire time duration of OLT in eight patients suffering from end-stage liver disease. No considerable concentration changes of 15(S)-8-iso-PGF2a and cis-EpOA were observed, indicating lack of oxidative stress. Previously, we found in the same patients that nitrosative stress, measured as 3-nitrotyrosine and 3-nitrotyrosinoalbumin. Yet, as 15(S)-8-iso-PGF2a, cis-EpOA and 3-nitrotyrosine are produced both by chemical and enzymatic reactions, the current concepts of oxidative and nitrosative stress require reconsideration.

Does the Inhibitory Action of Asymmetric Dimethylarginine (ADMA) on the Endothelial Nitric Oxide Synthase Activity Explain Its Importance in the Cardiovascular System? The ADMA Paradox

Asymmetric dimethylarginine (ADMA, NG, NG-dimethyl-L-arginine) is endogenously produced by asymmetric dimethylation of the guanidine group of L-arginine residues. ADMA is generally considered a powerful cardiovascular risk factor, an Übermarker, due to its inhibitory action on the activity of nitric oxide synthase (NOS) isoforms. In the endothelium, the constitutively expressed and Ca2+/calmodulin-dependent NOS (eNOS) catalyzes the conversion of L-arginine to nitric oxide (NO). NO is one of the most potent endogenous activators of soluble guanylyl cyclase which produces the second messenger cyclic guanosine monophosphate (cGMP). There is experimental evidence from in vitro and in vivo experiments that challenges the extraordinary importance of ADMA as the culprit of NO-related cardiovascular diseases in the human circulation. Most notably, we present data showing that ADMA is a weak competitive inhibitor of recombinant endothelial NOS (eNOS) activity (Ki 3.9 μM, IC50 12 μM). Thus, at its relatively low concentrations of 0.4 to 0.5 μM in the human blood, ADMA is unlikely to inhibit NO synthesis in the endothelium to an extent sufficient enough to cause endothelium dysfunction. Furthermore, ADMA does not “uncouple” eNOS and does not diminish the bioavailability of NO through its reaction with superoxide radical anions produced by “uncoupled” eNOS. Consequently, the particular importance assigned to ADMA in the human circulation is likely to be due to other not yet recognized biological actions beyond inhibition of eNOS activity. This “ADMA paradox” remains to be solved.

The dilemma of oxidative stress personified by the diprosopus 8-iso-prostaglandin F2α and prostaglandin F2α

In general, the term “oxidative stress” describes an imbalance between oxidants and antioxidants in favor of the oxidants. While antioxidant defense is widely accepted to involve both enzymatic and non-enzymatic reactions, oxidants are generally assumed to be produced by non-enzymatic processes involving chemically produced free radicals. However, many oxidants are also formed by numerous enzymes and proteins. The F2-isoprostane 8-iso-prostaglandin F2α (8-iso-PGF2α) and malondialdehyde (MDA) are widely used as biomarkers of oxidative stress, although there is evidence that both 8-iso-PGF2α and MDA are also produced enzymatically from arachidonic acid by the action of cyclooxygenase (COX). On the contrary, there is also evidence that PGF2α is produced from arachidonic acid both by the action of COX and non-enzymatically. The duality of oxidative stress, personified by 8-iso-PGF2α and PGF2α, is a serious dilemma and demands new definitions and strategies from the scientists.

Recent flaws in Evidence Based Medicine: statin effects in primary prevention and consequences of suspending the treatment.

Statin therapy is presented as a protection against ischemic heart disease (IHD) complications. As IHD is often a fatal disease, statins are thereby supposed to decrease cardiovascular mortality and increase life expectancy. However, these benefits are increasingly challenged in the medical community, the controversy being particularly intense when discussing the effects of statins in primary prevention and the consequences of statin discontinuation. Both primary prevention and treatment discontinuation have been recently used by investigators linked to the pharmaceutical industry to justify and boost prescription and consumption of statins and other cholesterol-lowering medications. We herein review some recent commercial data related to primary prevention with rosuvastatin and statin discontinuation and their respective effects on IHD and overall mortality rate. We conclude that (1) despite the recent hype raised by HOPE-3, the cholesterol-lowering rosuvastatin is likely not beneficial in intermediate-risk individuals without cardiovascular disease (primary prevention). This trial may even represent a typical example of how evidence-based medicine has been flawed in commercial studies. (2) Statin discontinuation does not lead to increased IHD and overall mortality, at least in the months following interruption of treatment. On the contrary, one might even conclude that statin discontinuation could save lives. One possible explanation of this apparently paradoxical finding is that statin discontinuers, in the same time they stop statin therapy, likely try to adopt a healthy lifestyle. Further studies are needed to confirm the real effects of statin discontinuation in various clinical conditions. In the meantime, it is not evidence based to claim that statin discontinuation increases mortality or saves lives.

Is Aristolochic Acid Really the Cause of the Balkan Endemic Nephropathy?

In recent years, aristolochic acid has been promoted vigorously as the causal agent of the Balkan endemic nephropathy because of similarities to some other nephropathies, association with DNA adducts and a perception of human exposure via bread. Critical evaluation of the literature exposes flaws in these aspects, and there has been consistent failure of experimental toxicology to mimic either the slow silent bilateral atrophy of the Balkan disease or the transitional cell carcinomas in the upper urothelium. It seems yet premature to promote the curious Balkan disease as aristolochic acid nephropathy without the epidemiological rigour necessary in biomedical research.