Medical Hypotheses - Articles in Press

Hypothesis for resolution of diabetes after sleeve gastrectomy - Corrected Proof

Wei Zhang, Da-qiao Zhu, Ming Qiu — 2012-05-16

Abstract: Sleeve gastrectomy improves glucose metabolism as effective as Roux-en Y gastric bypass. The underlying mechanism is still not clear. We hypothesized that inhibition of GOAT activity was one therapeutic consequence of SG, and a status of low ghrelin level with low AG: UAG ratio might be an optimal gastrointestinal hormone profile for the remission of T2DM.

Chromosomally-integrated human herpesvirus 6 in familial glioma etiology - Corrected Proof

E. Susan Amirian, Michael E. Scheurer — 2012-05-16

Abstract: Human herpesvirus 6 (HHV-6) is a highly neurotropic beta-herpesvirus with demonstrated transformative properties. HHV-6 infection has been implicated in the etiologies of cancers, including lymphoma and leukemia; conditions with brain involvement, including epilepsy and encephalitis; and other disorders. HHV-6 is also the only human herpesvirus that has been proven to integrate into the chromosomes of a proportion (1–12%) of infected individuals. Because several traditional genetic association studies have failed to identify a variant that can account for the established relationship between family history and glioma risk, the possibility that chromosomally-integrated HHV-6 (CI-HHV-6), as a heritable factor, may explain a proportion of familial glioma cases warrants evaluation. To test this hypothesis, the prevalence of CI-HHV-6 in familial glioma cases and related and unrelated cancer-free control groups should be compared. Among glioma-affected families, the inheritance pattern of CI-HHV-6 could be evaluated by constructing pedigrees. If CI-HHV-6 is found to be associated with familial glioma risk, this knowledge could potentially lead to the future development of novel therapeutic and preventive approaches, including vaccines and immunotherapies targeted at the HHV-6 sequences.

The world epidemic of sleep disorders is linked to vitamin D deficiency - Corrected Proof

S.C. Gominak, W.E. Stumpf — 2012-05-14

Abstract: An observation of sleep improvement with vitamin D supplementation led to a 2year uncontrolled trial of vitamin D supplementation in 1500 patients with neurologic complaints who also had evidence of abnormal sleep. Most patients had improvement in neurologic symptoms and sleep but only through maintaining a narrow range of 25(OH) vitamin D3 blood levels of 60–80ng/ml. Comparisons of brain regions associated with sleep–wake regulation and vitamin D target neurons in the diencephalon and several brainstem nuclei suggest direct central effects of vitamin D on sleep. We propose the hypothesis that sleep disorders have become epidemic because of widespread vitamin D deficiency. The therapeutic effects together with the anatomic–functional correspondence warrant further investigation and consideration of vitamin D in the etiology and therapy of sleep disorders.

Still’s disease and the mitochondrion: The other face of an old friend? - Corrected Proof

François Hayem, Gilles Hayem — 2012-05-14

Abstract: Although Still’s disease has been first described more than one century ago, it still appears as an orphan entity, which should be separated from the other auto-inflammatory diseases (AID). The main reason to individualize Still’s disease among the AID is the absence of any genetic predisposition. Recently, the human mitochondria have been clearly implicated in the systemic inflammation that is observed during the innate immune response. After various types of cellular injuries, including infections, the release of “Damage-Associated Molecular Patterns” (DAMPs) from mitochondria can recruit circulating polymorphonuclear neutrophils (PMNs), monocytes and macrophages, along with the activation of NLRP3 inflammasome. Flares of Still’s disease usually mimic systemic bacterial infections, with high levels of PMNs, but no evidence of circulating bacteria. Ubiquitous and usually benign viruses, such as human herpes virus 6 (HHV-6), appear capable of inducing mitochondrial damages. Such a phenomenon could in turn initiate the flares of Still’s disease, thereafter persisting as an inappropriate and self-perpetuating reaction to an endogenous bacterial vestige, the mitochondrion itself.

Familiar acute myocardial infarction: A genetic disease? - Corrected Proof

Iván J. Núñez-Gil, Gisela I. Feltes Guzmán, Antonio Fernández Ortiz — 2012-05-14

The familiar influence represents an important cardiovascular risk factor related to the development of coronary artery disease (CAD). This point has been partially explained by several hereditary biochemical abnormalities (i.e. hyperlipidemia, metabolic syndrome, c-reactive protein, hyperhomocysteinemia), deleterious family-influenced way of life patterns (diet, character, smoking, exercise), together with other features (hypertension, obesity, gender, depression and mental stress) .

Diacerein: A potential therapeutic drug for periodontal disease - Corrected Proof

2012-05-14

Abstract: Periodontal diseases are chronic inflammatory diseases characterized by the destruction of the tooth-supporting structures. They are the most prevalent form of bone pathology in humans and act as a modifying factor of the systemic health of patients. Accumulating evidence has provided insight into mechanisms of periodontal inflammation revealing that oral pathogens induce inflammatory cascades, including a variety of cytokines produced by different cell types, which promotes host-mediated tissue destruction. Cytokine networks established in diseased periodontal tissues are extremely complex, and substances regulating immuno-inflammatory reactions and signaling pathways, in addition to traditional periodontal treatment, could potentially be targeted as an approach for prevention and treatment of periodontal diseases. Diacerein, a purified anthraquinone derivative, was derived originally from plants with profound anti-inflammatory and analgesic activities. Its wide range of biological activities have been applied and discussed for several decades; however, studies of diacerein have mainly concentrated on effects on joint-derived tissues/cells, which suggest a beneficial role in osteoarthritis treatment. Diacerein reduces association of the IL-1 receptor to form heterodimer complexes, repressing IL-1 and its related downstream events and impairing active IL-1 release due to the inhibition of the IL-1-converting enzyme (ICE). To date, there are no reports describing the therapeutic effect of diacerein for treatment of periodontitis. Given the involvement of inflammation and occurrence of tissue destruction in periodontal disease, we propose that diacerein might be a promising biological drug for periodontal disease due to its therapeutic advantages. In addition, we hypothesize that the underlying mechanisms might involve the capacity of diacerein to selectively inhibit signal transduction to affect the cytokine profiles and, consequently, produce the outcome of ameliorating disease breakdown.

How metabolic acidosis and oxidative stress alone and interacting may increase the risk of fracture in diabetic subjects - Corrected Proof

L.A. Frassetto, A. Sebastian — 2012-05-14

Abstract: Subjects with either type 1 or type 2 diabetes are at higher risk for having fractures, a risk not necessarily improved by better glucose control. In this article, we argue that low grade metabolic acidosis and increased oxidative stress occurring in bone disease in part as a result of complications of diabetes, reinforce each other, and together constitute a double jeopardy for the development of bone fractures in diabetic subjects.

Finegoldia magna (formerly Peptostreptococcus magnus): An overlooked etiology for toxic shock syndrome? - Corrected Proof

Marnie E. Rosenthal, Albert D. Rojtman, Elliot Frank — 2012-05-09

Abstract: Finegoldia magna is an anaerobic Gram positive coccus, previously classified as Peptostreoptococcus magnus. It is normal flora of the gastrointestinal and genitourinary tract, and can be isolated from skin and the oral cavity and is often regarded as a contaminant in cultures. As the most frequently isolated anaerobic coccus, it is implicated in a range of mono- and polymicrobial infections, including skin and skin structure, bone and joint (native and prosthetic joints), infective endocarditis (native and prosthetic valves), necrotizing pneumonia, mediastinitis and meningitis. Recently, whole genome sequencing furthered the understanding of the pathogenicity of this organism by elucidating both chromosomally encoded and mobile plasmid mediated virulence factors. Although no cases of toxic shock syndrome have been attributed to F. magna, we present a case of a fatal monomicrobial F. magna bacteremia and hypothesize that superantigen activity, mediated via Protein L binding the variable domain of the κ light chains of IgG, resulted in the syndrome observed in our patient. Additionally, we suspect the overall significance of this pathogen is underestimated and with more sensitive detection methods, this organism will be identified more frequently in clinical cultures and associated with true infection.

A hypothesis: Edaravone exert cardioprotection partly via modulation of adiponectin - Corrected Proof

Haifeng Pei, Min Jia, Lu Sun, Xiaohui Zheng, Haiyan Zhou — 2012-05-09

Abstract: Edaravone has been recognized as a potential protective agent for cardiovascular diseases. It is well known that edaravone can attenuate oxidative stress and inhibit the production of proinflammatory cytokines such as TNF-α. However, the mechanisms behind the cardioprotection of edaravone are still incompletely understood yet. As a primary adipose-derived protein, adiponectin exhibits protective properties on the heart and blood vessels. Accumulative studies have shown that there exists a reciprocal relationship between adiponectin and TNF-α, i.e., adiponectin negatively regulates TNF-α expression, whereas adiponectin expression is inhibited by TNF-α. So we hypothesize that edaravone plays a role in cardioprotection partly through modulation of adiponectin level by suppression of TNF-α.

Effects of contrast material on the metabolite ratios in single-voxel MR Spectroscopy of intraaxial brain tumors - Corrected Proof

2012-05-07

Abstract: Aim: The purpose of our study was to determine whether the administration of contrast material affects the results of MR Spectroscopy (MRS) in different intraaxial brain tumors.Materials and methods: Thirty-three patients (median range 46.72±2.95, range 9–77) with intraaxial brain tumors underwent MRS before and 5min after intravenous administration of gadolinium based contrast material at the standard dose of 0.1mmol/kg (Gadodiamide or Gd-DOTA). Metabolite ratios (N-acetyl aspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, and NAA/Cho) were calculated.Results: There was no significant difference between the pre and postcontrast MRS spectra as regards to NAA/Cr (p:0.4), Cho/Cr (p:0.2), and NAA/Cho (p:0.2) ratios obtained from the intraaxial brain tumors.Conclusion: Contrast material administration did not change the metabolite ratios of MRS. Contrast administration would be useful in guiding voxel localization in MRS evaluation of intraaxial brain tumors.

Regeneration of tooth-like hydroxyapatite depended on amelogenin functional section monolayer: A new approach for tooth repair - Corrected Proof

Kun Tian, Min Peng, Xiaohua Ren, Chuhang Liao, Wei Fei — 2012-05-07

Abstract: Tooth defect due to caries, trauma, or acid corrosion are common in mankind. Ceramics, metal and resin were used to repaired tooth defect in the past hundred years, but they cannot instead enamel and dentin in depth in clinic usage for the difference in structure and element. So the formation of organized nanocrystals that resemble enamel is crucial for successful enamel remineralization. Now synthesizing a mimicking structure of human enamel using acellular methods has attracted much interest from research groups who have tried using recombinant enamel making proteins like amelogenin, surfactants, to mimic the biomineralization process to restore the enamel layer. Since amelogenin can be used in the assembly of functional nanostructures, we hypothesis that rationally designed β-sheet-forming peptides that spontaneously form three-dimensional fibrillar scaffolds in response to specific environmental triggers may potentially be used in inducing tooth-like hydroxyapatite crystal ex vivo which important to treatment/prevention of dental caries, via bioactive surface groups.

Nomenclature for drugs in targeted therapies - Corrected Proof

A. Venniyoor — 2012-05-03

Abstract: A proposal for denoting the new drugs used in targeted therapy of cancer is submitted. This would simplify both the writing of regimen acronyms in scientific papers, and be more informative than the current system.

N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for? - Corrected Proof

Marcos Arturo Martínez-Banaclocha — 2012-04-30

Abstract: Parkinson’s disease is an age-related neurodegenerative disorder that is ameliorated with levodopa. However, long-term use of this drug is limited by motor complications, postural instability and dementia resulting in the progression of the disease. Insights into the organization of the basal ganglia and knowledge of the mechanisms responsible for cell death in Parkinson’s disease has permitted the development of putative neuro-protective drugs that might slow the disease progression. Although no drug has yet been established to alter the rate of disease progression, recent publications have confirmed previous results and hypotheses about the probable role of thiolic antioxidants on Parkinson’s disease, demonstrating a significant reduction of dopaminergic neuronal degeneration in α-synuclein over expressing mice treated with oral N-acetyl-cysteine. This thiolic antioxidant is a modified form of the natural amino acid cysteine, which is the precursor of the most potent intracellular antioxidant glutathione. Besides, increasing evidence has been accumulated in the last 10years about the beneficial effects of this thiolic antioxidant in experimental and pathologic states of the nervous system, including against neurotoxic substances. The present paper put forward the existing rationale evidence for the use of N-acetyl-cysteine alone or in combination with levodopa in the clinical management of this neurodegenerative disorder.

Antipsychotic drugs: Pro-cancer or anti-cancer? A systematic review - Corrected Proof

2012-04-30

Abstract: Introduction: Important data was recently published on the potential genotoxic or carcinogenic effects of antipsychotics, as well as on their cytotoxic properties on cancer cells, that must be considered by psychiatrists in the benefit/risk ratio of their prescriptions.Aim of the study: To answer whether or not antipsychotics, as a class or only some specific molecules, may influence cancer risk among treated patients.Methods eligibility criteria: All studies (in vitro, animal studies and human studies) concerning effects of antipsychotic drugs on cancer development were included. The search paradigm [neoplasms AND (antipsychotic agents OR neuroleptic OR phenothiazine)] was applied to Medline (1966–present) and Web of Science (1975–present).Results: Ninety-three studies were included in the qualitative synthesis. Results can be summarized as follows: (1) patients with schizophrenia may be less likely to develop cancer than the general population, (2) antipsychotics as a class cannot be considered at the moment as at risk for cancer, even if some antipsychotics have shown carcinogenic properties among rodents, (3) phenothiazines seem to have antiproliferative properties that may be useful in multidrug augmentation strategies in various cancer treatments, but their bad tolerance may decrease usage amongst non-psychotic patients, and (4) clozapine appears to have a separate status given that this molecule shows antiproliferative effects implied in agranulocytosis as well as a potential increased risk for leukemia.Conclusion: Benefit/risk ratio regarding cancer risk is in favor of treating patients with schizophrenia with antipsychotic drugs. The practicing clinician should be reassuring on the subject of cancer risk due to antipsychotic drugs.

Increased membrane turnover in the brain in cutaneous anthrax without central nervous system disorder: A magnetic resonance spectroscopy study - Corrected Proof

2012-04-30

Abstract: Cutaneous anthrax, caused by Bacillus anthracis contacting the skin, is the most common form of human anthrax. Recent studies implicate the presence of additional, possibly toxin-related subtle changes, even in patients without neurological or radiological findings. In this study, the presence of subtle changes in cutaneous anthrax was investigated at the metabolite level using magnetic resonance spectroscopy. Study subjects were consisted of 10 patients with cutaneous anthrax without co-morbid disease and/or neurological findings, and 13 healthy controls. There were no statistical differences in age and gender between two groups. The diagnosis of cutaneous anthrax was based on medical history, presence of a typical cutaneous lesion, large gram positive bacilli on gram staining and/or positive culture for B. anthracis from cutaneous samples. Brain magnetic resonance imaging examination consisted of conventional imaging and single-voxel magnetic resonance spectroscopy. Magnetic resonance spectroscopy was performed by using point-resolved spectroscopy sequence (TR: 2000ms, TE: 136ms, 128 averages). Voxels of 20mm×20mm×20mm were placed in normal-appearing parietal white matter to detect metabolite levels. Cerebral metabolite peaks were measured in normal appearing parietal white matter. N-acetyl aspartate/creatine and choline/creatine ratios were calculated using standard analytical procedures. Patients and controls were not statistically different regarding parietal white matter N-acetyl aspartate/creatine ratios (p=0.902), a finding that implicates the conservation of neuronal and axonal integrity and neuronal functions. However, choline/creatine ratios were significantly higher in patient groups (p=0.001), a finding implicating an increased membrane turnover. In conclusion, these two findings point to a possibly anthrax toxins-related subtle inflammatory reaction of the central nervous system at the cellular level.

Hypothesis about brilliant lights by bioluminescent photons in near death experiences - Corrected Proof

István Bókkon, Vahid Salari — 2012-04-30

Abstract: In near death experiences (NDEs), seeing a brilliant light may arise in the recovery period following cardiac arrest, but the subjects can think that these experiences had happened during the actual period itself. Here we hypothesize a biophysical explanation about the encounter with a brilliant light in NDEs. Accordingly, meeting brilliant light in NDEs is due to the reperfusion that induces unregulated overproduction of free radicals and excited biomolecules among them in numerous parts in the visual system. Unregulated free radicals and excited species can produce a transient increase of bioluminescent photons in different areas of the visual system. If this excess of bioluminescent photon emission exceeds a threshold, they can appear as (phosphene) lights in our mind. In other words, seeing a brilliant light in NDEs may due to bioluminescent photons simultaneously generated in the recovery phase of numerous areas of the visual system and the brain interprets these intrinsic bioluminescent photons as if they were originated from the external visual world. Although our biophysical explanation about brilliant light phenomenon in NDEs can be promising, we do not reject further potential notions.

The schizoictal syndrome - Corrected Proof

Teresa Biermann, Wolfgang Sperling — 2012-04-30

Abstract: There are several common denominators of schizophrenia and epilepsy including models of pathogenesis as well as their clinical occurence mainly referring to schizophrenia-like syndrome in epilepsy or similar clinical entities . Up to now it has not been emphasized that a process of synchronization or desynchronization of neuronal cell structures within the context of neuronal plasticity might be a plausible pathogenetic mechanism of epilepsy as well as schizophrenia. Clinical as well as therapeutical implications of this hypothesis on the basis of scientific evidence are discussed.

Translating whole-body cryotherapy into geriatric psychiatry – A proposed strategy for the prevention of Alzheimer’s disease - Corrected Proof

Blazej Misiak, Andrzej Kiejna — 2012-04-30

Abstract: Alzheimer’s disease (AD), which is the most common form of dementia, constitutes one of the leading causes of disability and mortality in aging societies. Currently recommended medications used in treating AD include cholinesterase inhibitors and the NMDA antagonist – memantine, but poorly counteract progression of the disease. According to current knowledge, the neuropathological process underlying the etiology of AD begins many years, if not decades, before the development of overt symptoms of dementia. Mild cognitive impairment (MCI) is regarded as the first detectable manifestation of cognitive decline. Nowadays, there is a general consensus that vascular alterations, oxidative stress and inflammatory response contribute to the development of AD. Following these mechanisms and tracing the anti-inflammatory and anti-oxidative effects of cryostimulation, we postulate that whole-body cryotherapy (WBCT) might be utilized as a means of preventing AD. WBCT is a relatively safe and cost-effective procedure, which is widely applied in various medical specialties. Thus, there is an urgent necessity to evaluate the long-term effectiveness of WBCT in the prevention of AD in patients with MCI and healthy individuals.

Is premature ejaculation an impulse control disorder? - Corrected Proof

Osman Özdemir — 2012-04-30

Abstract: Premature ejaculation (PE) is defined as persistent or recurrent ejaculation with minimal sexual stimulation that occurs before the participant wishes to ejaculate and is associated with marked distress or interpersonal difficulty. Impulse control disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a “failure to resist” impulses to engage in harmful, disturbing or distressing behaviours. I hypothesise that premature ejaculation is an impulse control disorder. ICDs share features with PE aspects of impaired control, rapid responses to stimuli and hypersensitivity. These disorders often occur with subjective and social distress for patients. In addition to these features, the neurotransmitter systems have been similarly implicated in ICDs and PE. The same treatment options further support a relationship between ICDs and PE. The behaviours likely exist on a spectrum.

The membrane interaction of drugs as one of mechanisms for their enantioselective effects - Corrected Proof

Hironori Tsuchiya, Maki Mizogami — 2012-04-30

Abstract: The discrimination between different enantiomers of chiral compounds by the biological system is medically important as the pharmacological and toxicological effects of enantiomeric drugs significantly differ depending on their stereostructures. One enantiomer is preferred over its enantiomeric counterpart and a racemic mixture for higher activity or lower toxicity. Such enantioselectivity has been exclusively explained by the stereostructure-specific interactions with receptors, channels and enzymes of drugs including general and local anesthetics, sedatives, hypnotics, anti-inflammatory drugs, analgesics and β-adrenergic antagonists. These drugs can act on not only protein targets but also lipid biomembranes. Almost all of the relevant proteins are embedded in or associated with membrane lipid bilayers. Therefore, we propose one of possible mechanisms that drugs might enantioselectively interact with membrane lipids and induce changes in membrane property like fluidity which are discriminable between enantiomers. If the induced changes are different between enantiomers, enantiomeric drugs would differently influence the membrane lipid environments for receptors, channels and enzymes, resulting in the enantioselectivity of drug effects. The enantioselective membrane interactions of drugs could be mediated by membrane component cholesterol and phospholipids, both of which have chiral centers in structure as well as drug enantiomers. Chiral membrane lipids possibly exhibit the preference for the interactions with drug molecules of either the same chirality or the different chirality, producing the selectivity to one drug enantiomer. The proposed hypothesis may be available to investigate more useful medicines based on the novel concept of drug enantioselectivity.

Geometrical factors as predictors of increased growth rate or increased rupture risk in small aortic aneurysms - Corrected Proof

Efstratios Georgakarakos, Christos V. Ioannou — 2012-04-30

Abstract: Abdominal Aortic Aneurysms (AAAs) are focal dilation of the aorta that can lead to excessive enlargement and rupture over time. Current practice suggests intervention when the maximum diameter exceeds 5.5cm, since in this diameter range the annual rupture risk outweighs the operative mortality. However, small AAA (<5.5cm), though infrequently, may rupture or produce symptoms. Evidence from large randomized studies of small AAAs support the heterogeneity in patterns of growth and rupture potential among small AAAs. Elevated wall stress values have been implicated in AAAs rupture and rapid enlargement. Additionally, many studies have identified a strong correlation between certain geometric factors and elevated stress values. In this article we discuss the possibility that geometrical factors may have a predictive value to identify those small AAAs that have an increased risk of rupture or growth rate either during initial examination or during follow-up, making them amenable for early repair.

Sistemic calciphylaxis and thrombotic microangiopathy in a kidney transplant patient: Two mixing fatal syndromes? - Corrected Proof

2012-04-30

Abstract: Abnormalities in calcium and phosphorus metabolism are common and metabolic bone diseases develop often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions, however, appear to increase the risk of soft tissue and vascular calcification in patients with End Stage Renal Disease (ESRD), so current therapeutic approaches are thus being re-evaluated in an effort to limit these risks.Patients with calciphylaxis have an extremely high mortality rate, diagnosis requires a high degree of clinical suspicion and the role and extent of parathyroidectomy in the management of this condition remain controversial.In some cases renal transplant patients could suffer from a comorbidity in which vascular function is compromised not only by secondary hyperparathyroidism-related calcification but also by other pathological condition as haemolytic uremic syndrome (HUS), leading to a fatal clinical outcome.We postulate that in these cases a secondary hyperparathyroidism not properly diagnosed in an early phase of the renal disease (probably before the kidney transplant) could cause a vascular calcification which, adding to the pre-existing HUS-related vascular compromission, gave rise to catastrophic clinical consequences.In the management of ESRD patients, in particular in the cases of pre-existing angiopathies, could be therefore crucial the early and proper diagnosis of an alteration of calcium–posphorus metabolism and effort of medicine could be oriented in these cases also towards identification of screening methodologies to undoubtedly assess such a diagnosis.

An in-silico strategy to explore neuroprotection by quercetin in cerebral ischemia: A novel hypothesis based on inhibition of matrix metalloproteinase (MMPs) and acid sensing ion channel 1a (ASIC1a) - Corrected Proof

2012-04-30

Abstract: Cerebral ischemia are caused by acute interruption of the brain arterial blood supply, typically by a thrombus or embolus, leading to neuronal insult and the remainder damage are caused by blood vessel rupture, leading to hemorrhage. Acidosis and matrix metalloproteinase activation are the central and prominent metabolic feature of ischemic brain. The combined inhibition of MMPs and ASIC1a channels can offer a new therapeutic approach in cerebral stroke management. Moreover, the combined inhibition of MMPs and ASIC1a with flavonoids remains unknown against neuroprotection in animal models of cerebral ischemia. Flavonoids are believed to act as health-promoting substances and some of them have antioxidant and anti-inflammatory properties. Therefore, the target of the present study was in-silico evaluation of the neuroprotective efficacy of quercetin in rat model of focal cerebral ischemia/reperfusion (I/R) injury and efforts were made to analyze its inhibitory effects on MMPs activation and ASIC1a channels mediated downstream survival/damage mechanisms. Thus on the basis of our in-silico studies we hypothesize that quercetin can be a neuroprotective agent in rat model of focal cerebral ischemia/reperfusion (I/R) injury due to its inhibitory effects on MMPs activation and ASIC1a channels mediated downstream survival/damage mechanisms.

HIF-1α/VEGF signaling pathway may play a dual role in secondary pathogenesis of cervical myelopathy - Corrected Proof

Hou-Qing Long, Guang-Sheng Li, Yong Hu, Chun-Yi Wen, Wen-Han Xie — 2012-04-30

Abstract: Cervical spondylotic myelopathy (CSM) is one of the most common spinal cord disorders affecting the elderly. Yet the exact pathophysiology of CSM remains unclear. Vascular response to initial mechanical compression and associated ischemia may involve in secondary pathophysiology. Chronic compressive lesions to cervical cord resulting in lack of perfusion have established considerable evidences to support ischemia as an important pathogenesis both in patients and animal models, a similarity as that of acute spinal cord injury (SCI). In hypoxic condition following SCI, the up-regulation of vascular endothelial growth factor (VEGF), is consistent with increasing hypoxia induced factor-1α (HIF-1α) in acute periods. HIF-1α/VEGF signaling pathway is thought to play a dual role following SCI. In one hand, VEGF was demonstrated to be correlated with angiogenesis (protecting vascular endothelial cells, increasing blood vessel density and improving regional blood flow), neurogenesis (antiapoptotic, neurotrophic, attenuate axonal degradation), and locomotor ability improvement. In other hand, some studies revealed that VEGF have limited therapeutic effect, even exacerbate the secondary damage following SCI. VEGF administrations in acute or subacute periods result in elevation of blood-spinal cord barrier (BSCB) permeability even last for chronic course. BSCB permeability elevation initiates a secondary cascade of events involving excitotoxicity, infiltration of leukocytes and tissue edema. With comprehensive understanding of temporal and spatial of HIF-1α/VEGF signaling pathway, development of therapeutic strategies to promote new vessel growth while minimize the deleterious effects of VEGF-induced microvascular permeability, and thereby improve neurologic function, seems to be feasible and promising.

Fast-spiking interneurons and gamma oscillations may be involved in the antidepressant effects of ketamine - Corrected Proof

Zhi-qiang Zhou, Guang-fen Zhang, Xiao-min Li, Chun Yang, Jian-jun Yang — 2012-04-30

Abstract: Accumulating lines of evidence have indicated that a non-selective N-methyl-d-aspartate (NMDA) receptor antagonist ketamine exerts fast and robust antidepressant effects via stimulating glutamate transmission and activating the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Moreover, NMDA receptor antagonist has the ability to reduce the activity of fast-spiking (FS) interneurons which results in the disinhibition of pyramidal neurons and increases the glutamate transmission. We therefore hypothesize that FS interneurons may play an important role in the antidepressant effects of ketamine. Quantification of FS interneurons function via analyzing gamma oscillations may guide the antidepressant therapy of ketamine in clinical practice.

The extracellular signal-regulated kinase pathway may play an important role in mediating antidepressant-stimulated hippocampus neurogenesis in depression - Corrected Proof

Lingxiao Wang, Daihui Peng, Bin Xie, Kaida Jiang, Yiru Fang — 2012-04-30

Abstract: Understanding the reasons for the delayed action of antidepressants in patients with depression is an important step in the effort to understand the etiology and course of this disabling condition. Researches using animal models of depression find that depression is associated with impaired neurogenesis and structural plasticity in specific regions of the brain. Chronic treatment with antidepressants increases neurogenesis and reduces animal behaviors that are associated with depression. Other studies suggests that neurogenesis is an important component of the mechanism of action of both antidepressants and mood stabilizers. Moreover, the time course of increased neurogenesis is parallel to that of the behavioral effects, and animals with higher baseline hippocampus neurogenesis have a more rapid response to antidepressants. However, the molecular mechanisms that link antidepressants, neurogenesis and behavioral changes remain unknown. Previous research has shown that the extracellular signal-regulated kinase (ERK) signaling pathway plays an important role in regulating neurogenesis and synaptic plasticity in the brain and is activated by antidepressants and mood stabilizers. We hypothesize that the ERK pathway is the mechanism by which antidepressants regulate neurogenesis in the hippocampus and, thus, should be considered a potential target for the development of new antidepressants.

Lipoxin receptor agonist, may be a potential treatment for hemorrhagic shock-induced acute lung injury - Corrected Proof

Jie Gong, Hong-Bin Li, Si Guo, You Shang, Shang-Long Yao — 2012-04-30

Abstract: The main pathogenesis of acute lung injury induced by hemorrhagic shock is increasingly recognized as an inflammatory process. BML-111, a lipoxin receptor agonist, has been demonstrated to promote acute inflammatory resolution by reduction of pro-inflammatory cytokines, attenuation of neutrophilic infiltration, and increasing macrophage phagocytosis of apoptotic neutrophils. Meanwhile, lipoxins and lipoxin analogues have been reported to play pro-resolving and anti-inflammatory effects in many disease models including cerebral ischemia, dorsal air pouch, peritonitis, and so on. Therefore, we hypothesize that BML-111 may be implicated in pathogenesis of hemorrhagic shock-induced acute lung injury.

CREG mediated adventitial fibroblast phenotype modulation: A possible therapeutic target for proliferative vascular disease - Corrected Proof

Yang Li, Cheng-Hui Yan, Ya-Ling Han — 2012-04-30

Abstract: Proliferative vascular diseases, of which neointimal formation is a key pathological feature, cause significant morbidity and mortality worldwide. Adventitia is the outermost connective tissue that surrounds an artery. In recent years, accumulating data indicate that adventitial fibroblasts participate in the formation of neointimal lesions. Our previous studies have demonstrated that cellular repressor of E1A-stimulated genes (CREG) plays critical roles in reducing neointimal hyperplasia by promoting vascular smooth muscle cell (VSMC) differentiation and grow arrest and inhibiting migration. Hence, it is plausible that genetical modification with CREG gene in adventitial fibroblasts might inhibit angiotensin II-induced transdifferentiation to myofibroblasts, proliferation and migration, as well as adventitial thickening, finally decreasing neointimal formation. Possible mechanisms may include CREG direct attenuation of reactive oxygen species derived from reduced cathepsin-dependent activation of NADPH oxidase and indirect suppression of the downstream of NADPH oxidase including ERK1/2, JNK and p38 MAPK pathways in adventitial fibroblasts. Therefore, CREG may be a potential therapeutic target for proliferative vascular diseases.

Cyclooxygenase-2 inhibitors induce anoikis in osteosarcoma via PI3K/Akt pathway - Corrected Proof

Bing Liu, Liyan Qu, Zhengming Yang, Huimin Tao — 2012-04-30

Abstract: COX-2, an inducible enzyme, is associated with inflammatory diseases and carcinogenesis. Overexpression of COX-2 occurs in many human malignancies, including osteosarcoma. In our study, we reported that Celecoxib, a cyclooxygenase-2 inhibitor, induces apoptosis in human osteosarcoma cell line MG-63 via down-regulation of PI3K/Akt. PI3K/Akt plays an essential role in the cell/extracellar matrix (ECM) and cell/cell adhesion. We hypothesize that COX-2 inhibitors induce anoikis in osteosarcoma via PI3K/Akt, resulted in lack of correct attachment and the down-regulations of β-catenin, TrkB and E-cadherin, which play an essential role in the cell/extracellar matrix (ECM) and cell/cell adhesion. Meanwhile, apoptosis also be disclosed, such as DNA fragments and apoptotic bodies, activation of caspase-8, 9 and cleavage of PARP. With wortmannin, a specific PI3K inhibitor can simulate the effect of COX-2 inhibitors. If our hypothesis is correct, COX-2 inhibitors could cut down the occurrence of metastasis and facilitate the patient who may benefit from addition of COX-2 inhibitors to standard cytotoxic therapy.

Leukocyte chemoattractant receptor FPR2 may accelerate atherogenesis - Corrected Proof

Wuzhou Wan, Ji-Liang Gao — 2012-04-30

Abstract: Atherosclerosis is a chronic inflammatory disease and the number one cause of mortality worldwide. The fundamental causes of atherosclerosis have not been precisely delineated, although pathogenesis clearly involves endothelial dysfunction and both innate and adaptive immunity. Recent evidence suggests that formyl peptide receptor 2 (FPR2), a G protein-coupled receptor (GPCR), mediates a range of inflammatory responses including superoxide production in neutrophils, chemotaxis of monocytes and neutrophils, CCL2 production in endothelial cells (ECs) and monocytes, and increased CXCL8 expression in neutrophils, which are all related with atherogenesis. Therefore, we propose that FPR2 may play a pathogenic role in atherogenesis.

Dysbiosis of Gut Microbiota (DOGMA) – A novel theory for the development of Polycystic Ovarian Syndrome - Corrected Proof

Kelton Tremellen, Karma Pearce — 2012-04-30

Abstract: Polycystic Ovarian Syndrome (PCOS) is the most common cause for menstrual disturbance and impaired ovulation, effecting one in twenty women of reproductive age. As the majority of women with PCOS are either overweight or obese, a dietary or adipose tissue related trigger for the development of the syndrome is quite possible. It has now well established that PCOS is characterised by a chronic state of inflammation and insulin resistance, but the precise underlying triggers for these two key biochemical disturbances is presently unknown. In this paper we present support for a microbiological hypothesis for the development of PCOS. This novel paradigm in PCOS aetiology suggests that disturbances in bowel bacterial flora (“Dysbiosis of Gut Microbiota”) brought about by a poor diet creates an increase in gut mucosal permeability, with a resultant increase in the passage of lipopolysaccaride (LPS) from Gram negative colonic bacteria into the systemic circulation. The resultant activation of the immune system interferes with insulin receptor function, driving up serum insulin levels, which in turn increases the ovaries production of androgens and interferes with normal follicle development. Thus, the Dysbiosis of Gut Microbiota (DOGMA) theory of PCOS can account for all three components of the syndrome-anovulation/menstrual irregularity, hyper-androgenism (acne, hirsutism) and the development of multiple small ovarian cysts.

Allocentric lock in anorexia nervosa: New evidences from neuroimaging studies - Corrected Proof

Giuseppe Riva, Santino Gaudio — 2012-04-30

Abstract: Individuals with anorexia nervosa (AN) have a disturbance in the way in which their body is experienced and tend to evaluate negatively their own body and body parts. It is controversial whether these symptoms are secondary to dysfunctions in the neuronal processes related to appetite and emotional regulation or reflect a primary disturbance in the way the body is experienced and remembered.According to the “Allocentric Lock Hypothesis – ALH” (http://dx.doi.org/10.1016/j.mehy.2011.10.039) individuals with AN may be locked to an allocentric (observer view) negative memory of the body that is no more updated by contrasting egocentric representations driven by perception. Recent neuroimaging studies are showing several structural and functional alterations in frame- and memory-related body-image-processing brain circuits that may support ALH.

Preeclampsia and gestational diabetes mellitus: Pre-conception origins? - Corrected Proof

S.W. Wen, R.-H. Xie, H. Tan, M.C. Walker, G.N. Smith, R. Retnakaran — 2012-04-30

Abstract: Preeclampsia (PE) and gestational diabetes mellitus (GDM) are two of the most common medical complications of pregnancy, with risks for both mother and child. Like many other antepartum complications, PE and GDM occur only in pregnancy. However, it is not clear if pregnancy itself is the cause of these complications or it these conditions are caused by factors that existed prior to gestation. In this paper, we hypothesize that although the clinical findings of PE and GDM are first noted during pregnancy, the origins of both conditions may actually precede pregnancy. We further hypothesize that pathophysiologic changes underlying PE and GDM are present prior to pregnancy, but remain undetected in the non-gravid state either because pregnancy is the trigger that makes these pathologies become clinically detectable or because there has been limited prospective longitudinal data comparing the pre-gravid and antepartum status of women that go on to develop these conditions. Rigorous prospective cohort studies in which women undergo serial systematic evaluation in the pre-conception period, throughout pregnancy and into the postpartum are ideally needed to test this hypothesis of pre-conception origins of PE and GDM. In this context, we are creating a pre-conception cohort, involving about 5000 couples who plan to have a baby within six months in Liuyang county in the Chinese province of Hunan. Results from this pre-conception cohort program should be able to provide definitive answer to the question of whether the underpinnings of PE and GDM originate prior to pregnancy. Ultimately, the significance of addressing this hypothesis is underscored by its potential implications for targeted interventions that could be designed to (i) prevent the deleterious effects of PE/GDM and (ii) thereby interrupt the vicious cycle of disease that links affected women and their offspring.

Potential of calcium to scaffold an endodontic biofilm, thus protecting the micro-organisms from disinfection - Corrected Proof

Suzette V. van der Waal, Lucas W.M. van der Sluis — 2012-04-27

Abstract: Biofilms in the root canal of a tooth (endodontic biofilm) can induce and sustain apical periodontitis which is an oral inflammatory disease. Still, little is known about the composition of the endodontic biofilm. Studies on biofilms in root canals focus on the identification of the microbial species, but the majority of the biofilm consists of matrix material. Environmental aspects determine the structure of the biofilm and extracellular matrix.Calcium is involved in biofilm formation and activity at three levels. Firstly in cell-environment; calcium may ‘condition’ the surfaces of support and bacterial cells. Secondly, in cell–cell interaction; calcium plays a role in build up of biofilm structures. Typically, calcium ions act as ‘cation bridges’ between polysaccharides originating from different cells. Thirdly, within cells, calcium is required for certain biochemical reactions in bacteria and some bacterial physiological activities. Because calcium is present in the root canal, it could play a significant role in the organization of the biofilm.Chelators, already used in endodontics to remove the smear layer by disintegration of the structural cohesion calcium bonds, could weaken the biofilm matrix by removing calcium from the extracellular matrix thus disturbing its coherence. Subsequently, this disruption could increase the efficacy of disinfecting agents.

Vascularized the greater trochanter grafting treatment cysts of the femoral neck - Corrected Proof

Hui Xie, Dewei Zhao — 2012-04-26

Abstract: Bone cyst is a common benign bone tumor lesion, it is characterized by a clear boundary appearing round or oval osteolytic area, cortical bone thinning, and sometimes it can be visible sclerotic margin. Limb long bone cysts occur more common shares, the current jaw bone cysts are also relatively common, and most patients are asymptomatic. Femoral neck bone cyst can lead to pain and pathologic fractures, which is one of the main reasons why patients are in treatment. Due to the lesion site and patients age specificity of femoral proximal bone cysts especially femoral neck bone cysts in young adults, treatment is necessary to completely remove the lesion to prevent cyst recurrence, but also as far as possible to restore function in patients with hip joint.

A muscle spindle abnormity in one laryngeal muscle would be sufficient to cause stuttering - Corrected Proof

Steffen H. Schuster, Frank M. Schuster — 2012-04-26

Abstract: Muscle spindles are increasingly recognized as playing a pivotal role in the cause of dystonia. This development and own laryngeal observations that support the idea of causally “well-intentioned” stuttering motivated us to present the following hypothesis: stuttering events compensate for a sensory problem that arises when the abductor/adductor ratio of afferent impulse rates from the posterior cricoarytenoid and lateral cricoarytenoid muscle spindles is abnormally reduced and processed for the occasional determination of the vocal fold position. This hypothesis implies that functional and structural brain abnormalities might be interpreted as secondary compensatory reactions. Verification of this hypothesis (using technologies such as microneurography, dissection and muscle afferent block) is important because its confirmation could relink dystonia and stuttering research, change the direction of stuttering therapy and destigmatize stuttering radically.

The cardiorenal link in advanced cirrhosis - Corrected Proof

Aleksander Krag, Flemming Bendtsen, Andrew K. Burroughs, Søren Møller — 2012-04-26

Abstract: A considerable number of patients with advanced cirrhosis develop a hepatorenal syndrome. The pathogenesis involves liver dysfunction, splanchnic vasodilatation, and activation of vasoconstrictive systems. There are now several observations that indicate a relation between the renal failure and impaired cardiac function in patients with advanced cirrhosis. Cirrhotic cardiomyopathy has been described as a condition with impaired contractile responsiveness to stress and altered diastolic relaxation. We propose a cardiorenal interaction in patients with advanced cirrhosis and renal dysfunction that refers to a condition where cardiac dysfunction in cirrhosis is a major determinant of kidney function and survival. Thus, the relation between cardiac dysfunction and renal insufficiency should be target for future studies and development of new treatments should focus on ameliorating the cardiac dysfunction.

Can a school based programme in a natural environment reduce BMI in overweight adolescents? - Corrected Proof

Graham Slaney, Jo Salmon, Philip Weinstein — 2012-04-26

Abstract: Current levels of obesity amongst adolescents may be largely attributed to changes in environmental exposures that place vulnerable youth at risk, yet few studies have incorporated environmental approaches to normalising Body Mass Index (BMI). Our hypothesis is that a live-in school based programme in a natural environment can reduce the BMI of overweight children. The pilot study therefore explores the effects of such a programme on the BMI of adolescents in rural Victoria, Australia. Year 9 students (15year olds, N=1021) at a rural school with a physically demanding, 10-month, live-in outdoor programme had their BMIs measured at the beginning and end of the programme. Their observed BMI at the end of the programme was compared to expected BMI (based on adjustment of their initial BMI to account for normal growth using international standards). Participation in the programme reduced the BMI of boys who were in the normal to obese range (χ2=8.57, p=0.014), but not in girls. For the overweight and obese boys BMI decreased by up to 2.5kg/m2. These results suggests that school based environmental interventions may be effective in reducing obesity in adolescents, supporting our hypothesis. Our study is limited by its opportunistic observational nature, but it nevertheless suggests that such a live-in school programme in a natural environment may provide a valuable addition to the list of interventions available to combat the obesity epidemic. Although the programme reduced BMI in boys, the equivocal data for girls means that even an intensive programme such as this struggles to achieve a significant change in BMI across all obese adolescents. Our study nevertheless supports the need for further investigation of the possible contribution of school based programmes in natural environments to interventions to fight the obesity epidemic – because there is no magic bullet.

Middle cerebral artery preponderance in ischemic stroke: A coincidence or fate? - Corrected Proof

Sadip Pant, Abhishek Deshmukh, Pritam Neupane — 2012-04-25

Abstract: Stroke is the leading cause of disability and the third leading cause of death in the United States. More than 700,000 persons per year suffer a first-time stroke in the United States, with 20% of these individuals dying within the first year after the stroke. Ischemic stroke accounts for majority of cases of stroke and within this subgroup also, anterior circulation stroke involving the middle cerebral artery (MCA) is the commonest one. There has been no speculation so far as to why this anatomical preponderance to middle cerebral artery exists in thrombotic stroke. While the role of nitric oxide (NO) as a vasculoprotective molecule has been well established, understanding the stimulus for its release and anatomical course of middle cerebral artery can provide a good justification for the clinical finding mentioned above. This bench to bedside correlation not only explains the predilection of ischemic thrombotic stroke to MCA but also highlights the significance of NO as a vasculoprotective molecule in cerebrovascular disease which has not been emphasized earlier.

Mercury chronic toxicity might be associated to some cases of hydrocephalus in adult humans? - Corrected Proof

2012-04-23

Abstract: Mercury accumulates in nervous tissue causing neurological and psychiatric manifestations. Numerous clinical findings have been described in patients that suffered chronic mercury intoxication. Some findings, such as hydrocephalus, have been described only in experimental studies. Following, we present a case of 50year-old man with a 3-month history of severe frontal headache episodes and vision loss together with a history of asthenia, anorexia, muscle pain, fatigue and neuropsychiatric symptoms. The magnetic resonance imaging showed hydrocephalus and stenosis of aqueduct of Sylvius. This patient reported that he worked as laboratory metallurgic auxiliary for over 30years. During this time, he had been chronically exposed to elemental mercury. The metals whole blood test was normal, except by his blood mercury level that was 61.5μg/L (normal ⩽1μg/L). In our best knowledge, hydrocephalus and stenosis of aqueduct of Sylvius have been described only in animals exposed to methylmercury during their gestation. We think that this case of hydrocephalus might be associated with the chronic mercury exposure and therefore this etiology must be taken in account in a patient with hydrocephalus of unknown etiology.

Circadian regulation of cellular homeostasis – Implications for cell metabolism and clinical diseases - Corrected Proof

N. Meermeier, N. Krishnan — 2012-04-23

Abstract: The major pathways involving nutrient and energy metabolism including cellular homeostasis are profoundly impacted by the circadian clock, which orchestrates diurnal rhythms in physiology and behavior. While the links between circadian and metabolic rhythms are unclear, recent studies imply a close link between the two with one feeding back on the other. In this discussion, we present the hypothesis that circadian clocks likely contribute to cellular homeostasis, especially proteostasis, through regulation of metabolic rhythms, which in turn feed-back on circadian oscillators. The disruption of circadian clocks leads to altered metabolic rhythms and metabolic disease states as a result of altered cellular homeostasis.

Inter-hemispheric competition relieved in both: Hypotheses for autism and schizophrenia from problem theory - Corrected Proof

Gordon Burnand — 2012-04-23

Abstract: A logical relationship exists among six general problems that people face in life. Using hope about something for its subjective probability, its expected likelihood, the problems form a series where the method of assessing hope changes in a simple manner from one problem to the next. The central hypothesis is that human beings exploit this. Brain structures and predispositions have evolved accordingly, leading to the hemispheres having different predispositions. The hemispheres are effectively joined at 5months. Infants will then find that they engage in two unrelated activities. Typical infants label the activities in detail, using visual images, as part of gaining control over them. Hypotheses are: (a) autistic children fail labelling at the start, and hence they encounter uncontrolled competition between the hemispheres; (b) with some, serotonin abnormality impairs sensory information processing and hence the labelling; (c) with some, a delay in myelination from autoimmune effects disrupts labelling; (d) the likelihood of this ‘delay autism’ is reduced by long chain omega oils; (e) self-pressuring, which underlies taking on challenges and play like Hide and Seek, brings relief from the competition by raising the influence of one side; (f) the same left–right competition occurs in confused episodes and schizophrenia in vulnerable people who encounter pressures to use both hemispheres at the same time; (g) some symptoms raise the influence on one side ideationally. This leads to coherent theories of autism and schizophrenia. In both competition between the hemispheres is relieved primarily by self-pressuring, which raises influence on one side.

WITHDRAWN: HIV-AIDS hypothesis out of touch with South African AIDS - A new perspective - Corrected Proof

2009-07-21

This Article-in-Press has been permanently withdrawn.The editorial policy of Medical Hypotheses makes it clear that the journal considers “radical, speculative, and non-mainstream scientific ideas”, and articles will only be acceptable if they are “coherent and clearly expressed.” However, we received serious expressions of concern about the quality of this article, which contains highly controversial opinions about the causes of AIDS, opinions that could potentially be damaging to global public health.Given these important signals of concern, we commissioned an external expert panel to investigate the circumstances in which this article came to be published online. The panel recommended that the article should be externally peer-reviewed. Following a peer-review process managed by The Lancet editorial team, all five external reviewers recommended rejection, as a result of which the expert panel recommended permanent withdrawal.The Publisher apologizes for any inconvenience this may cause.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: Aids denialism at the ministry of health - Corrected Proof

M. Ruggiero, M. Prayer Galletti, S. Pacini, T. Punzi, G. Morucci, M. Gulisano — 2009-07-08

This Article-in-Press has been permanently withdrawn.The editorial policy of Medical Hypotheses makes it clear that the journal considers “radical, speculative, and non-mainstream scientific ideas”, and articles will only be acceptable if they are “coherent and clearly expressed.” However, we received serious expressions of concern about the quality of this article.Given these important signals of concern, we commissioned an external expert panel to investigate the circumstances in which this article came to be published online. The panel recommended that the article should be externally peer-reviewed. Following a peer-review process managed by The Lancet editorial team, all five external reviewers recommended rejection, as a result of which the expert panel recommended permanent withdrawal.The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: Erratum to “Which are the best nations and institutions for revolutionary science 1987–2006? Analysis using a combined metric of Nobel prizes, Fields medals, Lasker awards and Turing awards (NFLT metric)” [Medical Hypotheses 68 (2007) 1191–1194] - Corrected Proof

Bruce G. Charlton — 2007-09-28

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Medical Hypotheses, doi:10.1016/j.mehy.2007.08.005. The duplicate article has therefore been withdrawn.