Medical Hypotheses - Articles in Press

Does diabetes hide osteoarthritis pain? - Corrected Proof

2012-02-03

Abstract: Clinical practice and research efforts related to the highly prevalent and disabling disease, osteoarthritis (OA), have long been hampered by an inadequate case definition. Much of the difficulty is due to a lack of agreement between X-rays evidence of OA and a patient’s report of pain at that site. Such discordance between reported pain and radiographic evidence of OA has been attributed to several factors. This paper proposes another possible explanation, for at least a portion of such patients. It is hypothesized that an insidiously increasing diabetic neuropathy, particularly in the lower extremity, while first causing some pain, may gradually inhibit the ability to feel pain which might have otherwise been reported by those patients without neuropathy. Many of these patients with early stage glucose dysmetabolism will proceed to develop overt type 2 diabetes; however, the pain-inhibiting neuropathy caused by glucose metabolism dysfunction may manifest long before such a diagnosis. The high prevalence of diabetes and pre-diabetic conditions, especially among the aged population, could mean that a substantial number of individuals with osteoarthritis will have both diseases to varying degrees over time. Validating and quantifying this hypothesized association would be useful to millions of persons and would significantly impact both research and clinical practice dealing with these major diseases of older persons.

Biodiversity as a barrier to glioma cell invasion - Corrected Proof

2012-02-02

Abstract: Gliomas are extremely aggressive and lethal forms of brain cancer. Unlike many other cancer types, glioma cells rarely metastasize. They spread throughout the brain and invasiveness of glioma cells is a major cause of therapeutic failure. In plant ecosystem, biodiversity acts locally as a barrier to ecological invasion. By analogy, we hypothesize that the low cell diversity of differentiated tissues, a counterpart of their functional specificity, opens the way to local cancer cell invasion. Seeding the brain tumor microenvironment with heterogeneous cell populations could be a mean to limit cancer cell invasion by enhancing cell biodiversity.

Can transcranial brain-targeted bright light treatment via ear canals be effective in relieving symptoms in seasonal affective disorder? – A pilot study - Corrected Proof

2012-02-02

Abstract: Bright light therapy (BLT) is widely accepted as first-line treatment of seasonal affective disorder (SAD). However, the mechanism of action of BLT is still widely unknown. On the other hand, in mammals, light penetrates the skull bone and reaches the brain, and extra ocular transcranial phototransduction has physiological influences such as changed reproductive cycles and increased brain serotonin levels. Therefore, we challenged the existing conceptual framework that light therapy would only be mediated through the eyes. Consequently, we run a pilot study on the putative effect of transcranial bright light in the treatment of SAD. The light was produced using light-emitting diodes (LEDs), which were attached to earplugs. The amount of photic energy was 6.0–8.5lumens in both ear canals, and the length of treatment was 8 or 12min five times a week during a four-week study period. Subjects were recruited through advertisements in the city of Oulu, Finland (latitude 65°01′N) during 14 January 2009–03 February 2009. The final patient series consisted of 13 (aged 37.1±7.2years) physically healthy indoor workers suffering from SAD according to DSM-IV-TR criteria. Severity of depressive symptoms was assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17) and Beck Depression Inventory (BDI)-21. Furthermore, severity of anxiety symptoms was measured by the 14-item Hamilton Anxiety Rating Scale (HAMA). The HAMD-17 mean sum score at screening was 23.1±1.6. Ten out of 13 SAD patients (76.9%) achieved full remission (i.e., HAMD-17 sum score ⩽7), and 92.3% (12/13) at least 50% reduction in HAMD-17 sum scores at “Week 4”. By using a mixed regression model of repeated measures (AR-1) controlling for age, gender, and HAMD-17 mean sum score at screening, significant differences were found comparing the HAMD-17 mean sum scores of “Week 0” with the corresponding scores at the “Week 3” (t=−2.05, p=0.045) and “Week 4” visit (t=−2.77, p=0.008). Correspondingly, significant differences were found comparing the BDI-21 mean sum scores (15.2±6.7) of “Week 0” with the corresponding scores at the “Week 3” (t=−2.37, p=0.021) and “Week 4” visit (t=−3.65, p<0.001). The HAMA mean sum score at screening was 20.5±5.4. During the study period, 12 out of 13 (92.3%) patients achieved at least 50% reduction in their HAMA sum scores, and in 10 out of 13 patients (76.9%), the HAMA sum score was <7. In conclusion, it is hard to believe that our findings could be explained solely by placebo effect. Consequently, the basic assumptions underlying extraocular photoreception in humans deserve to be reconsidered. Given that a proper placebo treatment can be implemented via ear canals, further investigations with randomized placebo-controlled and/or dose-finding study designs regarding the extraocular transcranial bright light in the treatment of SAD are called for.

RPE cell senescence: A key contributor to age-related macular degeneration - Corrected Proof

Michael R. Kozlowski — 2012-02-01

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in industrialized countries. Although much progress has been made recently in the management of later stages of the disease, no agents have yet been developed for the early stages or for prophylactic use. Furthermore, even the treatments for the later stages have limited effectiveness. The process of developing improved treatments for AMD is complicated by the existence of several theories concerning the cause of the disorder, each suggesting a different strategy for finding effective therapeutics. One of the potential contributors to AMD pathology is retinal pigment epithelial (RPE) cell senescence. The present paper hypothesizes that RPE senescence plays a central role in the etiology of AMD. This hypothesis is supported by the ability of RPE cell senescence to account for the signs, risk factors, and successful treatment modalities of the disorder. This hypothesis also points to several new prophylactic and treatment strategies for AMD.

Could nonunion tissue be transformed capable of bone formation by negative pressure: A new alternative to treat bone nonunion? - Corrected Proof

2012-01-30

Abstract: Despite substantial advances in orthopaedic surgery, bone nonunion is still a matter of debate for orthopaedic surgeon to provide optimal options on treatment of nonunion. Negative pressure therapy has already been successfully used in dealing with complex kinds of soft tissue healing. Some studies show that negative pressure can induce mesenchymal stem cells to differentiate into osteoblasts and others suggest that there are some mesenchymal-like cells existing in the nonunion tissue which can be re-activated and transformed into osteoblasts under some circumstance. We hypothesized that under negative pressure the mesenchymal-like cells can be transformed into osteoblasts in nonunion site. Under negative pressure, both “seeds” and “soils” can be made for new bone formation. If our hypothesis is proved to be corrected, it could be an innovative method to treat the bone nonunion.

A self-referential outlier detection method for quantitative motor unit action potential analysis - Corrected Proof

Geoffrey L. Sheean — 2012-01-30

Abstract: Quantitative MUAP analysis is often based on outlier detection, in the case of neurogenic conditions, the finding of MUAPs that are larger than the limit determined from a reference normal population. Such reference data is available from only a few sources and for only a few muscles. It would be desirable if muscles could serve as their own controls. The Henneman size principle determines the order of recruitment, following an exponential distribution of twitch force, motor neurone, motor unit, and MUAP size. Therefore, an outlier could be detected by being too large for the level of recruitment, as judged by its size relative to the other MUAPs. This would improve the sensitivity of detecting neurogenic muscles and obviate the need for external reference data.

Tumor malignancy is engaged to prokaryotic homolog toolbox - Corrected Proof

2012-01-30

Abstract: Cancer cells display high proliferation rates and survival provided by high glycolysis, chemoresistance and radioresistance, metabolic features that appear to be activated with malignancy, and seemed to have arisen as early in evolution as in unicellular/prokaryotic organisms. Based on these assumptions, we hypothesize that aggressive phenotypes found in malignant cells may be related to acquired unicellular behavior, launched within a tumor when viral and prokaryotic homologs are overexpressed performing likely robust functions. The ensemble of these expressed viral and prokaryotic close homologs in the proteome of a tumor tissue gives them advantage over normal cells. To assess the hypothesis validity, sequences of human proteins involved in apoptosis, energetic metabolism, cell mobility and adhesion, chemo- and radio-resistance were aligned to homologs present in other life forms, excluding all eukaryotes, using PSI-BLAST, with further corroboration from data available in the literature. The analysis revealed that selected sequences of proteins involved in apoptosis and tumor suppression (as p53 and pRB) scored non-significant (E-value>0.001) with prokaryotic homologs; on the other hand, human proteins involved in cellular chemo- and radio-resistance scored highly significant with prokaryotic and viral homologs (as catalase, E-value=zero). We inferred that such upregulated and/or functionally activated proteins in aggressive malignant cells represent a toolbox of modern human homologs evolved from a similar key set that have granted survival of ancient prokaryotes against extremely harsh environments. According to what has been discussed along this analysis, high mutation rates usually hit hotspots in important conserved protein domains, allowing uncontrolled expansion of more resistant, death-evading malignant clones. That is the case of point mutations in key viral proteins affording viruses escape to chemotherapy, and human homologs of such retroviral proteins (as Ras, Akt and EGFR) can elicit the same phenotype. Furthermore, a corollary to this hypothesis presumes that target-directed anti-cancer therapy should target human protein domains of low similarity to prokaryotic homologs for a well-succeeded anti-cancer therapy.

Does expression of the retrogene UTP14c in the ovary pre-dispose women to ovarian cancer? - Corrected Proof

Jan Rohozinski, Creighton L. Edwards, Matthew L. Anderson — 2012-01-30

Abstract: It has been previously shown that the spermatogenesis associated retrogene, UTP14c, is expressed in over 50% of normal human ovaries and 80% of ovarian cancers. UTP14c is located on chromosome 13 as an intronless copy of the X-linked housekeeping gene, UTP14a. Like all spermatogenesis associated retrogenes, UTP14c is expressed in the testis and is essential for sperm production. It has no known role in the female and is not normally expressed in any cells or organs outside of the gonads. By comparison the protein encoded by UTP14a is found in all cell types and has a dual function. It is primarily involved in the biosynthesis of 18S ribosomal RNA in the nucleolus where it is a component of the U3 small nucleolar RNA associated protein complex. In addition, it down regulates TP53 in both the nucleus and cytoplasm by targeting it for proteolytic degradation. By analogy, we propose that the UTP14c peptide also targets TP53 for degradation. This in turn may prevent cells expressing UTP14c from entering apoptosis. The loss of TP53 in ovarian cells can also result in the down regulation of microRNA-145 (miR-145) expression. The loss of miR-145 can result in the activation of factors that promote oncogenesis and cellular pluripotency which in turn could lead to the development of ovarian cancer. We hypothesize that women, whose ovaries express UTP14c, are predisposed to ovarian cancer due to the disruption of protective signals that normally trigger TP53-mediated apoptosis and the dysregulation of genes that promote oncogenesis, such as c-Myc, that occurs when miR-145 synthesis is disrupted.

Amino acids and our genetic code: A highly adaptive and interacting defense system - Corrected Proof

R.H. Verheesen, C.M. Schweitzer — 2012-01-30

Abstract: Since the discovery of the genetic code, Mendel’s heredity theory and Darwin’s evolution theory, science believes that adaptations to the environment are processes in which the adaptation of the genes is a matter of probability, in which finally the specie will survive which is evolved by chance.We hypothesize that evolution and the adaptation of the genes is a well-organized fully adaptive system in which there is no rigidity of the genes. The dividing of the genes will take place in line with the environment to be expected, sensed through the mother. The encoding triplets can encode for more than one amino acid depending on the availability of the amino acids and the needed micronutrients.Those nutrients can cause disease but also prevent diseases, even cancer and auto immunity. In fact we hypothesize that auto immunity is an effective process of the organism to clear suboptimal proteins, formed due to amino acid and micronutrient deficiencies. Only when deficiencies sustain, disease will develop, otherwise the autoantibodies will function as all antibodies function, in a protective way.Furthermore, we hypothesize that essential amino acids are less important than nonessential amino acid (NEA). Species developed the ability to produce the nonessential amino acids themselves because they were not provided by food sufficiently. In contrast essential amino acids are widely available, without any evolutionary pressure. Since we can only produce small amounts of NEA and the availability in food can be reasoned to be too low they are still our main concern in amino acid availability.In conclusion, we hypothesize that increasing health will only be possible by improving our natural environment and living circumstances, not by changing the genes, since they are our last line of defense in surviving our environmental changes.

Addendum: Gamma-tocopherol, cox-2, and cancer risk - Corrected Proof

Mark F. McCarty — 2012-01-30

A recent essay has proposed that a wide range of nutraceuticals and lifestyle measures capable of reducing the expression, activity, and/or downstream signaling of cyclooxygenase-2 (cox-2) have important practical potential for cancer prevention . An additional nutrient, not discussed in this essay, merits consideration in this regard.

An immunological basis of hyperphagia driven by GABAergic dysfunction in Prader–Willi Syndrome - Corrected Proof

Ujjwal Rout, Omar A. Abdul-Rahman, Dirk Marcel Dhossche — 2012-01-30

Abstract: Impaired immune function is increasingly seen as a core element of various neurological, psychiatric, and developmental disorders but has not yet been investigated in subjects with Prader–Willi Syndrome. We hypothesize that the emergence and the progression of PWS may be regulated by immune dysfunction involving auto-antibodies and miRNA driven by GABAergic dysfunction. Future research testing this hypothesis is discussed.

Finasteride as a potential tool to improve Mesenchymal stem cell transplantation for myocardial infarction - Corrected Proof

Ali M. Sharifi, Sayeh Mottaghi — 2012-01-30

Abstract: Mesenchymal stem cells (MSCs) therapy has emerged as a potent therapeutic strategy to improve myocardial infarction. However MSCs therapy encounters a few obstacles regarding the poor viability of the transplanted cells. Therefore, it is important to explore a strategy to enhance post-transplanted MSC viability. To overcome this problem, several protocols were suggested mainly by activating PI3K/Akt pathway. The PI3K/Akt cascade regulates several cellular processes such as proliferation and apoptosis. Finasteride is a specific inhibitor of type II 5α-reductase; the enzyme converts testosterone (T) to the more potent androgen receptor agonist dihydrotestosterone (DHT). Testosterone is found to stimulate rapid phosphorylation of Akt, and thereby activate the PI3K/Akt pathway. This pathway could lead to decreased apoptosis of the MSCs via increasing the expression of Bcl-2 and reducing Bax expression. It has been also reported that DHT would confine the differentiation capacity of MSCs so that a reduction in DHT levels caused by Finasteride would be accompanied by increased facilitation in differentiation of MSCs to cardiomyocyte by means of the signals originating from the injured cardiac tissue. These mechanisms could propose the potential role for Finasteride to improve the MSCs therapy for myocardial infarction.

Why do we not find polyps in the lungs? Bronchial mucosa as a model in the treatment of polyposis - Corrected Proof

Rogerio Pezato, Richard Louis Voegels — 2012-01-30

Abstract: The link between lower and upper airways has been reported since the beginning of 1800s. They share the same pseudostratified ciliated columnar epithelium lining and the concept of one airway, one disease is quite well widespread.Nasal polyposis and asthma share basically the same inflammatory process: predominant infiltration of eosinophils, mucus cell hyperplasia, edema, thickened basal membrane, polarization for Th2 cell immune response, similar pro-inflammatory mediators are increased, for example cysteinyl leukotrienes.If the lower and upper airways share a lot of common epithelial structural features so why is the edema in the nasal mucosa able to increase so much the size of the mucosa to the point of developing polyps?The article tries to underline some differences between the nasal and the bronchial mucosa that could be implicated in this aberrant change from normal mucosa to polyps.This paper creates the concept that there are no polyps with the features of nasal polyposis disease in the lower airway and through it is developed the hypothesis of the nasal polyps origin could partially lie on the difference between the upper and lower airway histology.

Hyperhomocysteinemia is an indicator of oxidant stress - Corrected Proof

2012-01-30

Sir, We found the recently published paper of Hoffman , to be alike to our work by focusing on the connection of elevated plasma homocysteine levels and the risk of developing diabetes or its complications. This correlation was first communicated by Looker et al. in 2003 and amended by Shukla et al. Later, in 2005, Cho et al. supported their findings. High homocysteine levels as a source of oxidant stress and the oxidative status were also targeted by our rutoside derivative.

Rheumatic autoimmune diseases: Proposed elimination of autoreactive B-cells with magnetic nanoparticle-linked antigens - Corrected Proof

F. Mathias Bollmann — 2012-01-30

Abstract: Although the pathogenesis of rheumatoid arthritis and other rheumatic diseases is still not fully understood, it has become clear that in many cases autoimmune responses with production of autoantibodies against physiological targets play a significant and causal role. Current immunosuppressive and immunomodulatory approaches such as bone marrow transplantation or the therapeutic antibody rituximab are effective, but unspecific and have serious side effects. Here, a method for targeted elimination of specific autoreactive B-cells which are essential for autoantibody production and maintenance of the autoimmune response is proposed. By binding to their receptive antigens linked to magnetic nanoparticles, the autoreactive B-cells can be separated from the rest of the blood in an extracorporeal filtration process, reducing the number of autoimmune cells and autoantibodies in the blood. The method can be adapted for use in different autoimmune diseases provided some key aspects of pathogenesis are known, and can be repeated if necessary. Evidence for feasibility and safety of this method is briefly reviewed, and potential limitations and hurdles to overcome are discussed.

Hypothesis: Catheter-based renal sympathetic denervation should be the initial therapy for essential hypertension - Corrected Proof

Jai R. Lakhanpal, Michael J. Domanski — 2012-01-30

Abstract: Hypertension affects 30–40% of the adult population in the developed world and is a major risk factor for stroke, myocardial infarction, heart failure, and kidney failure. Though the importance of controlling hypertension is well recognized, only about 50% of patients in the United States actually attain guideline recommended blood pressure goals. Limiting factors include patient noncompliance, suboptimal application of effective medication, and true medication resistance. Renal sympathetic denervation has been used to treat resistant hypertension and appears to be safe and effective and to produce durable results. We hypothesize that renal sympathetic denervation will produce similar results across the spectrum of hypertension severity for which pharmacologic therapy is currently indicated and propose that this is an important hypothesis to be tested in suitably powered randomized trials.

Self-reactivity against stress-induced cell molecules: The missing link between Takayasu’s arteritis and tuberculosis? - Corrected Proof

Diana Castillo-Martínez, Luis M. Amezcua-Guerra — 2012-01-30

Abstract: Takayasu’s arteritis (TA) is a chronic, occlusive, inflammatory disease of the aorta, its major branches and the pulmonary arteries. Its etiology remains unclear, although it has been suggested that a variety of antigens from Mycobacterium tuberculosis and probably other mycobacteria may trigger inflammatory pathology either directly in the arterial wall or remote from the actual location of mycobacterial infection, possibly through molecular mimicry mechanisms.However, recent evidence showing absence of both mycobacteria directly into arterial tissue as well as latent M. tuberculosis infection is challenging this notion. The hypothesis offered in this manuscript postulates that the lost of tolerance against self stress proteins is a primal pathogenic event in TA with the innate immune system as key culprit in the initiation and amplification of inflammatory response, while the extensive sequence homology between mycobacterial and human stress proteins leads to epiphenomenal cross-reactions mediated by adaptive immune system. If it is so, this postulate reconciles epidemiological, immunological and genetic linkage between TA and mycobacteria, while supporting the widespread Bacille Calmette-Guérin (BCG) vaccination worldwide and giving rationale to a safety use of anti-tumor necrosis factor (TNF) therapy in patients with TA.

Vitamin A, folate, and choline as a possible preventive intervention to fetal alcohol syndrome - Corrected Proof

Mark S. Ballard, Muxin Sun, Jenny Ko — 2012-01-30

Abstract: It is recognized that alcohol consumption during pregnancy is associated with fetal alcohol syndrome (FAS). Alcohol can trigger a pattern of neurodegeneration in rat brains similar to other known gamma-aminobutyric acid (GABA) specific agonists. However this does not seem to explain FAS entirely, as impoverished care-giving environments have been shown to increase the risk of FAS. Individuals living under the poverty level are at risk for micronutrient deficiencies due to insufficient intake. In particular, three nutrients commonly found to be deficient are folate, choline and vitamin A. There is evidence to suggest that ethanol alone may not explain the entire spectrum of anomalies seen in individuals with FAS. It is hypothesized that FAS may be caused more by the nutritional deficiencies that are exacerbated by alcohol than by direct alcoholic neurotoxicity.It is known that ethanol inhibits folate, choline, and vitamin A/retinoic acid metabolism at multiple steps. Additionally, mice exposed to ethanol demonstrated epigenetic changes, or variations in the methylation of DNA to control gene expression. Folate is important in the production of methyl groups, which are subsequently used to create and methylate DNA. Choline (which is metabolized to acetylcholine) is important in neurotransmission and neurodevelopment. It is also involved in an alternative pathway in the production of methyl groups. In fact a study by Thomas et al. in 2009 found that nutritional supplementation with choline in rats exposed to ethanol in utero almost completely mitigated the degenerative effects of ethanol on development and behaviour. Lastly, vitamin A and retinoic acid metabolism is associated with the regulation of one sixth of the entire proteome. Thus supplementation of folate, choline and vitamin A to mothers may mitigate the effects of the alcohol and reduce the severity or prevalence of FAS.

ApoE: The link between Alzheimer’s-related glucose hypometabolism and Aβ deposition? - Corrected Proof

Sachin P. Patil, Ryan Ballard, Sheena Sanchez, James Osborn, David Santangelo — 2012-01-30

Abstract: Alzheimer’s disease (AD) is a complex, multifactorial progressive neurodegenerative disease. Pathologically, AD is characterized by extracellular deposits of amyloid beta (Aβ) protein and intracellular accumulation of neurofibrillary tangles (NFTs) of tau. The central role of Aβ protein in the AD etiology is well-established, and its increased deposition in AD brain is attributed to its decreased clearance from the brain. It is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for late-onset AD, has been shown to play a vital role in brain Aβ clearance and the ability of ApoE to do this depends mainly upon its lipidation status. Thus, lower ApoE lipidation status leading to decreased Aβ clearance may underlie the increased Aβ deposition observed in AD brain. In addition to the pathophysiological Aβ deposits, AD is also characterized by certain metabolic changes. Among them, decreased cerebral glucose metabolism is one of the distinct characteristics of AD brain and is also observed in patients with Mild Cognitive Impairment (MCI) who subsequently develop AD. Thus, decreased cerebral glucose metabolism is an early event in AD pathology and may precede the neuropathological Aβ deposition associated with AD. In this context, we hypothesize here that the decreased glucose metabolism in pre-AD and early AD stages, may lead to lower ApoE lipidation status, which in turn may lead to decreased clearance and hence, increased deposition of Aβ protein in AD brain.

3D facial analysis can investigate vaccine responses - Corrected Proof

G. Baynam, M. Walters, P. Claes, P. Le Souef — 2012-01-30

Abstract: We propose that, given shared evolutionarily factors mediate vaccine response and facial development, objective, high-resolution 3D facial analysis can be employed to investigate phenomena underlying vaccine response/failure. To account for ontological processes, the optimal prospective cohort would be ascertained in early life and followed longitudinally. Additionally, the non-invasive and relatively inexpensive nature of these technologies is ideally suited for novel investigations of existing cohorts and for use in developing countries.

Why do we sneeze? - Corrected Proof

W. Burke — 2012-01-30

Abstract: According to textbooks, the function of a sneeze is to send a strong blast of air through the nose to remove foreign bodies. Three simple tests are described that show that the current views are wrong. The pressure developed in the mouth/pharynx of the author during a sneeze was recorded as about 135mmHg reached in about 0.1s. A forced maximal expiration but with the nose and mouth closed produced a nasal secretion although of smaller amount than in the sneez, in spite of a greater pressure; this is probably because the speed of tension development was much slower than in the sneeze. It is proposed that the high pressure stimulates secretory neurons via branches in the roof of the mouth. The nasal secretion dilutes irritant material in the nose and thus prevents it getting into the lungs.

Adding cetuximab to stereotactic radiotherapy for non-small cell lung cancer might reduce local failure rates - Corrected Proof

Carsten Nieder, Nicolaus Andratschke — 2012-01-27

Abstract: Encouraging results have been obtained with stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). However, local control rates decrease in larger volume disease. Several studies have found a correlation between T stage or tumor volume and local progression-free survival. In many cases with larger tumor volume, sufficiently high radiation doses can not be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents, which increase tumor cell kill, might improve the therapeutic ratio. Based on sound preclinical evidence and recent data from patients with stage III NSCLC and head and neck cancer, we hypothesize that cetuximab might be an investigational agent that merits further evaluation. The aim of prospective studies of SBRT and cetuximab would be to examine the toxicity profile of the drug in combination with high-dose hypofractionated thoracic radiotherapy and eventually to prove the superiority of combined treatment over SBRT alone. If improved local control rates could be observed, overall survival might improve accordingly.

Extra-mitochondrial aerobic metabolism in retinal rod outer segments: New perspectives in retinopathies - Corrected Proof

I. Panfoli, D. Calzia, S. Ravera, A.M. Morelli, C.E. Traverso — 2012-01-27

Abstract: Vertebrate retinal rods are photoreceptors for dim-light vision. They display extreme sensitivity to light thanks to a specialized subcellular organelle, the rod outer segment. This is filled with a stack of membranous disks, expressing the proteins involved in visual transduction, a very energy demanding process. Our previous proteomic and biochemical studies have shed new light on the chemical energy processes that supply ATP to the outer segment, suggesting the presence of an extra-mitochondrial aerobic metabolism in rod outer segment, devoid of mitochondria, which would account for a quantitatively adequate ATP supply for phototransduction.Here the functional presence of an oxidative phosphorylation in the rod outer limb is examined for its relationship to many physiological and pathological data on the rod outer segment. We hypothesize that the rod outer limb is at risk of oxidative stress, in any case of impairment in the respiratory chain functioning, or of blood supply. In fact, the electron transfer chain is a major source of reactive O2 species, known to produce severe alteration to the membrane lipids, especially those of the outer segment that are rich in polyunsaturated fatty acids. We propose that the disk membrane may become the target of reactive oxygen species that may be released by the electron transport chain under pathologic conditions. For example, during aging reactive oxygen species production increases, while cellular antioxidant capacity decreases. Also the apoptosis of the rod observed after exposure to bright or continuous illumination can be explained considering that an overfunctioning of phototransduction may damage the disk membrane to a point at which cytochrome c escapes from the intradiskal space, where it is presently supposed to be, activating a putative caspase 9 and the apoptosome. A pathogenic mechanism for many inherited and acquired retinal degenerations, representing a major problem in clinical ophthalmology, is proposed: a number of rod pathologies would be promoted by impairment of energy supply and/or oxidative stress in the rod outer segment. In conclusion we suppose that the damaging role of oxygen, be it hypoxia or hyperoxia invoked in most of the blinding diseases, acquired and even hereditary is to be seeked for inside the photoreceptor outer segment that would conceal a potential for cell death that is still to be recognized.

NYGGF4 as a new therapeutic target for obesity-associated insulin resistance - Corrected Proof

Zhangbin Yu, Xirong Guo — 2012-01-27

Abstract: Obesity-associated insulin resistance (IR) is manifested by increased hepatic glucose output and reduced glucose disposal in the peripheral tissues at a given level of insulin. Genetic factors play an important role in the development of obesity-associated IR. We identified a new cDNA by using suppression subtractive hybridization (SSH), which was expressed at a higher level in obese subjects and named NYGGF4. We found that the increased expression of NYGGF4 led to a reduction in insulin-stimulated glucose uptake and impaired insulin-stimulated glucose transport in mature adipocytes. We therefore propose the hypothesis that NYGGF4 may be a new therapeutic target for obesity-associated IR. NYGGF4 acts directly on the IRS1/PI3K/AKT insulin pathway to reduce glucose uptake and transport, impairs mitochondrial function and causes IR, which supports our hypothesis that NYGGF4 may be a useful therapeutic target for obesity-associated IR. However, its usefulness as a new therapeutic target need to be confirmed by further investigations, including NYGGF4 knockout mice models, which will be used to validate the role of NYGGF4 in vivo. Future studies are also required to determine whether downregulated expression of NYGGF4 contributes to these therapeutic actions.

Adjuvant therapy with GnRH agonists/tamoxifen in breast cancer should be a good council for patients with hormone receptor-positive tumours and wish to preserve fertility - Corrected Proof

2012-01-27

Abstract: Infertility represents one of the main long-term consequences of the chemotherapy used for the adjuvant treatment of breast cancer. Approximately 60–65% of breast cancers express the nuclear hormone receptor in premenopausal women. Adjuvant endocrine therapy is an integral component of care for patients with hormone receptor-positive (HR+) tumours. The GnRH agonist (GnRHa) alone or in combination with tamoxifen produces results at least similar to those obtained with the different chemotherapy protocols in patients with HR+ breast cancer with respect to recurrence-free survival and overall survival. It is time to indicate adjuvant therapy with GnRHa associated with tamoxifen for patients with breast cancer (HR+ tumours) if they want to preserve their reproductive function. The evaluation of ovarian reserve tests: follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume 6months, and 1year after the end of therapy with GnRHa/tamoxifen must be realised. The recurrence-free survival and overall survival should be analysed. The major implication of this hypothesis will be to avoid adjuvant chemotherapy for patients with breast cancer (HR+ tumours) that request fertility preservation. It is expected that ovarian function should not be altered in almost all cases and subsequent pregnancy a real possibility.

Essential hypertension – Is erroneous receptor output to blame? - Corrected Proof

Marcin Ufnal — 2012-01-27

Abstract: Hypertension is a chronic medical condition in which systemic arterial blood pressure is elevated. About 80–90% of diagnosed hypertension is considered essential (idiopathic), which means there is no obvious cause of the increase in blood pressure. My hypothesis states that part of idiopathic hypertension results from erroneous information that the brain receives from receptors involved in the regulation of arterial blood pressure, i.e. if, despite high systemic blood pressure, the brain receives false “low-arterial pressure input” from cardiovascular receptors. As a result the brain centres which control blood pressure reset and produce an inappropriate output to the effectors (heart, blood vessels, kidneys and glands). The information errors may result from: (i) structural and/or functional impairment of cardiovascular receptors, (ii) changes in cardiovascular receptors activity, which are caused by other factors than changes in blood pressure, and (iii) impaired transmission in afferent fibres. I assume that in contrast to the lack of input from damaged or denervated cardiovascular receptors, an erroneous input will impair the control of arterial blood pressure. This will apply especially to false input which imitates “low-arterial pressure input”. Higher priority of “low-arterial pressure input” over “high-arterial pressure input” or none input may be explained by the evolutionary adaptation, i.e. low blood pressure, mostly due to haemorrhage, used to be a more common condition than high blood pressure and constitute a major threat to humans.

Corrigendum to “Diabetes mellitus type 2 through oncology lens” [Med. Hypotheses 76 (2011) 761–762] - Corrected Proof

Khalid Omer Alfarouk, Adil H.H. Bashir — 2012-01-25

The authors regret that the e-mail address listed for Khalid Omer Alfarouk is incorrect. The correct email address is Alfarouk@Hala-Alfarouk.org. The authors would like to apologise for any inconvenience caused.

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.