Medical Hypotheses RSS feed: Articles in Press. Medical Hypotheses takes a deliberately different approach to review: the editor sees his role as a 'chooser', not a 'changer', choosing to publish what are judged to be the best papers from those submitted. The Editor sometimes uses external referees to inform his opinion on a paper, but their role is as an information source and the Editor's choice is final. The papers chosen may contain radical ideas, but may be judged acceptable so long as they are coherent and clearly expressed. The authors' responsibility for the integrity, precision and accuracy of their work is paramount. From Charlton BG. Peer usage versus peer review BMJ 2007; 335: 451 :- "Traditionally, editorial review is the main alternative to peer review. A scientist editor or editorial team applies a sieve, with varying degrees of selectivity, to research submissions. Strictly, this process should not attempt to predict whether ideas and facts are "true," because truth can be established only in retrospect. Instead, editorial selection works within constraints of subject matter on the basis of factors such as potential importance and interest, clarity and appropriateness of expression, and broad criteria of scientific plausibility. Even probably untrue papers may be judged worth publishing if they contain aspects (ideas, perspectives, data) that are potentially stimulating to the development of future science." Papers in Medical Hypotheses take a standard scientific form in terms of style, structure and referencing. The journal therefore constitutes a bridge between cutting-edge theory and the mainstream of medical and scientific communication, which ideas must eventually enter if they are to be critiqued and tested against observations. Abstracting/indexing Medical Hypotheses is indexed and abstracted in: Science Citation Index, Index Medicus/Medline, Adonis, BIOSIS, Chemical Abstracts, Elsevier BIOBASE/Current Awareness in Biological Sciences, Current Contents/Clinical Medicine, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Medical Documentation Service, Reference Update, Research Alert, SciSearch, UMI (Microfilm), Russian Academy of Sciencehttp://www.medical-hypotheses.com//inpress?rss=yesElsevier Inc.en © 2009 Published by Elsevier Inc. Medical Hypotheses0306-98772010-02-08 © 2009 Published by Elsevier Inc. healthpermissions@elsevier.comhttp://www.medical-hypotheses.com/article/PIIS0306987709003016/abstract?rss=yesPeriodically the pathophysiology and mechanisms of disease processes needs updating and revision. The basis for this reconsideration is a consequence of significant new findings that compels an overall re-evaluation of a concept.From benign prostatic hyperplasia to benign chronic prostatopathy - Corrected ProofPaul Cohen10.1016/j.mehy.2009.04.033Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987709003934/abstract?rss=yesSummary: Previous reports of specific patterns of increased fragility at common chromosomal fragile sites (CFS) found in association with certain neurobehavioural disorders did not attract attention at the time due to a shift towards molecular approaches to delineate neuropsychiatric disorder candidate genes. Links with miRNA, altered methylation and the origin of copy number variation indicate that CFS region characteristics may be part of chromatinomic mechanisms that are increasingly linked with neuroplasticity and memory. Current reports of large-scale double-stranded DNA breaks in differentiating neurons and evidence of ongoing DNA demethylation of specific gene promoters in adult hippocampus may shed new light on the dynamic epigenetic changes that are increasingly appreciated as contributing to long-term memory consolidation. The expression of immune recombination activating genes in key stress-induced memory regions suggests the adoption by the brain of this ancient pattern recognition and memory system to establish a structural basis for long-term memory through controlled chromosomal breakage at highly specific genomic regions. It is furthermore considered that these mechanisms for management of epigenetic information related to stress memory could be linked, in some instances, with the transfer of the somatically acquired information to the germline. Here, rearranged sequences can be subjected to further selection and possible eventual retrotranscription to become part of the more stable coding machinery if proven to be crucial for survival and reproduction. While linkage of cognitive memory with stress and fear circuitry and memory establishment through structural DNA modification is proposed as a normal process, inappropriate activation of immune-like genomic rearrangement processes through traumatic stress memory may have the potential to lead to undesirable activation of neuro-inflammatory processes. These theories could have a significant impact on the interpretation of risks posed by heredity and the environment and the search for neuropsychiatric candidate genes.Common chromosomal fragile sites (CFS) may be involved in normal and traumatic cognitive stress memory consolidation and altered nervous system immunity - Corrected ProofG.S. Gericke10.1016/j.mehy.2009.05.039Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08http://www.medical-hypotheses.com/article/PIIS0306987709006252/abstract?rss=yesI welcome Lobo et al.’s interest in my article and would be happy to debate the issue – but I respectfully disagree with several of their comments. In the paper cited by Lobo et al. and my other companion papers published elsewhere ; I went to some lengths to uncover the secrets of the human testes, understanding the reasons behind their descent into the scrotum and their different levels of swinging. My interest however, is in understanding why the natural processes of evolution, so meticulous and observant when it came to depicting the human body, got it wrong when it came to the male organ. From observations of our body, it was intriguing to me that the nature which has nurtured vital organs like the brain, heart, and the lungs by encasing them in different bony and soft tissue cages has left another important organ, the male gonads hanging down in a thin-walled soft sac exposing it to increased risk of injuries. Why?Asymmetric testicular levels in the crotch: Authors’ reply - Corrected ProofHari Prasad10.1016/j.mehy.2009.09.020Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987710000113/abstract?rss=yesVitamin A deficiency is highly prevalent among pregnant women of the developing world. The gestational age, nutritional status, per-capita expenditure on food, antenatal care and maternal hemoglobin levels are the important factors influencing the vitamin A status of these women . Vitamin A deficiency in pregnant and lactating women render their babies susceptible to develop vitamin A deficiency. Vitamin A plays a key role in fetal lung development by up regulating genes responsible for fetal lung growth leading to alveologenesis and increased surfactant production . Vitamin A also plays a major role in repair and healing following lung injury . Vitamin A deficiency is associated with depressed maternal immune function and can cause intrauterine growth retardation, anemia and low birth weight in newborns . Bronchopulmonary dysplasia and pneumonia are important causes of respiratory morbidity in infancy. Bronchopulmonary dysplasia is a chronic lung disease seen in preterm babies requiring prolonged oxygenation and ventilation. Vitamin A supplementation decreases the incidence of bronchopulmonary dysplasia in at risk preterm infants and hastens recovery in pneumonia . Vitamin A deficiency may be the underlying factor responsible for increased incidence of respiratory morbidity in infants of developing countries. Treating vitamin A deficiency can decrease the respiratory morbidity in these infants.Vitamin A deficiency in pregnant women and respiratory morbidity in their infants – Is there a link? - Corrected ProofT. Arun Babu, V. Sharmila10.1016/j.mehy.2010.01.007Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987710000125/abstract?rss=yesSummary: This hypothesis named Salerian Addictive Potential (SAP) suggests that the addictive potency of any substance may be calculated with an algebraic equation of A=E/Tmax×t1/2, where A is the addictive potency, E represents the euphoric potency, Tmax is the time to reach peak plasma concentration, and t1/2 is the plasma elimination half-life.This review offers medical evidence to suggest there is a negative association between the addictive potency of a substance and Tmax and t1/2, whereas the euphoric potency of a substance increases its addictive potency.SAP seems incompatible with the current FDA and government sponsored schedule for classification of addictive substances.Addictive potential: A=E/Tmax×t1/2 - Corrected ProofAlen J. Salerian10.1016/j.mehy.2010.01.008Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08http://www.medical-hypotheses.com/article/PIIS0306987710000137/abstract?rss=yesSummary: Human papillomavirus (HPV) infection is the second leading cause of cancer-associated morbidity and mortality among sexually active women worldwide due to its prerequisite role in cervical carcinogenesis. However, HPV infection alone is not sufficient to bring about cervical cancer. Sexual behaviour is consistently the most important co-factor for HPV infection and cervical cancer, but what is the underlying biological basis? In this paper, we postulate that human semen is the biological basis of sexual behaviour to promote HPV infection and cervical cancer. Based on international collaboration of epidemiological investigations and various HPV-infected in vivo models, it is likely for us to explore the exact role and pathogenesis of human semen in HPV infection and cervical carcinogenesis. If our hypothesis is true, regular use of condoms in the sexual intercourse should be recommended as a way of preventing genital transmission of HPV and reducing the incidence of cervical cancer, no matter women are infected by HPV or not.Human semen: The biological basis of sexual behaviour to promote human papillomavirus infection and cervical cancer - Corrected ProofXianding Wang, Jing Zhuang, Ke Wu, Ruiling Xu, Mingyuan Li, Yiping Lu10.1016/j.mehy.2010.01.009Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08http://www.medical-hypotheses.com/article/PIIS0306987710000150/abstract?rss=yesSummary: For many years medical admissions to acute hospitals have been increasing at a rate far higher than expected from demographic change. Factors such as emergency re-admission, GP thresholds, breakdown of the family unit and deficiencies in community and social care have been suggested to explain this widening gap. Solutions to the problem have revolved around demand management strategies. While such strategies do result in a relative reduction in demand they are unable to prevent the underlying long-term behaviour. Analysis of daily admissions in Scotland, England and at individual hospitals over the past 25years shows that the admissions tend to increase in a step-like manner at an interval of three to six years. This causes a typical 10% step-increase in physician work-load and inpatient medical costs and across England adds over 1,200,000 occupied bed days of additional bed demand into the health service within the space of around three months. There are knock-on effects to demand for ambulance services, accident and emergency attendance and GP referral. The step-increase is characterised by a cluster of diagnoses, increases with age and effects women more than men. Such behaviour has similarities to an infectious outbreak and the evidence for this and alternative hypotheses are discussed.Unexpected, periodic and permanent increase in medical inpatient care: Man-made or new disease? - Corrected ProofRodney P. Jones10.1016/j.mehy.2010.01.011Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08http://www.medical-hypotheses.com/article/PIIS0306987710000241/abstract?rss=yesSummary: Despite successful intensive care a substantial portion of critically ill patients dies after discharge from the intensive care unit or hospital. Observational studies investigating long-term survival of critically ill patients reported that most deaths occur during the first months or year after discharge. Only limited data on the causes of impaired quality of life and post-intensive care unit deaths exist in the current literature. In this manuscript we hypothesize that the acute inflammatory response which characteristically accompanies critical illness is ensued by a prolonged imbalance or activation of the immune system. Such a chronic low-grade inflammatory response to critical illness may be sub-clinical and persist for a variable period of time after discharge from the intensive care unit and hospital. Chronic inflammation is a well-recognized risk factor for long-term morbidity and mortality, particularly from cardiovascular causes, and may thus partly contribute to the impaired quality of life as well as increased morbidity and mortality following intensive care unit and hospital discharge of critically ill patients. Assuming that critical illness is indeed followed by a prolonged inflammatory response, important implications for treatment would arise. An interesting and potentially beneficial therapy could be the administration of immune-modulating drugs during the time after intensive care unit or hospital discharge until chronic inflammation has subsided. Statins are well-investigated and effective drugs to attenuate chronic inflammation and could potentially also improve long-term outcome of critically ill patients after intensive care unit or hospital discharge. Future studies evaluating the course of inflammation during and after critical illness as well as its response to statin therapy are required.Prolonged inflammation following critical illness may impair long-term survival: A hypothesis with potential therapeutic implications - Corrected ProofWilhelm Grander, Martin W. Dünser10.1016/j.mehy.2010.01.020Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08http://www.medical-hypotheses.com/article/PIIS0306987710000253/abstract?rss=yesSummary: Arsenic poisoning has become a worldwide public health concern since arsenic is recognized as a human carcinogen although the detailed mechanisms of carcinogenesis related to arsenic exposure are not completely understood at present. In particular, the skin and the kidneys are prone to neoplastic transformation upon occupational exposure of the human body to inorganic arsenic compounds. The cell-surface endopeptidase CD10 is variably expressed in cutaneous and renal malignancies, and due to this expression profile, might theoretically be implicated in arsenic-induced skin and renal neoplasias. From the functional point of view, CD10 conveys important anti-tumorigenic effects brought about by the inactivation of neuropeptide growth factors implicated in cancer progression. Placing the focus on the structural composition of arsenic hydrate microcrystals encountered in the cellular microenvironment, the present hypothesis suggests so far neglected molecular interactions between arsenic microcrystals and membrane-bound CD10 to be implicated in arsenic-induced carcinogenesis.Molecular interaction between arsenic hydrate microcrystals and the cell-surface endopeptidase CD10 (neprilysin) – A possible link to the development of renal and cutaneous malignancies upon occupational exposure to arsenic compounds? - Corrected ProofSven Gunia10.1016/j.mehy.2010.01.021Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08http://www.medical-hypotheses.com/article/PIIS0306987710000265/abstract?rss=yesAcupuncture is a traditional Chinese medical method that could basically be defined as the practice of inserting one or more needles into specific sites on the body surface for therapeutic treatment. Although several hypotheses have been put forward to explain the mechanism of action of acupuncture, an interesting article just published in this journal proposes a mechanism involving purinergic signalling, suggesting that ATP also acts as an extracellular signalling molecule . This innovative idea is interesting because it might throw light on controversies of the mechanism of action of acupuncture at the cellular level, which has been a mystery for centuries. However, in my opinion, it lacks in addressing some major points that are crucial for the implementation of acupuncture. First of all, this hypothesis fails to explain why only specific points (acupoints) on the body give particular access to the body’s energy system. Secondly, the above-mentioned hypothesis also fails to explain why these acupoints perform different functions depending on their location and the patterns of disease disharmony involved.Sticking the pieces together: A unifying hypothesis for the acupuncture meridian pathways and extracellular signalling - Corrected ProofYavuz Beyazit, Murat Kekilli, Fatma Beyazit10.1016/j.mehy.2010.01.022Medical Hypotheses (2010)2010-02-08Medical Hypotheses2010-02-08CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS030698771000006X/abstract?rss=yesSummary: Post concussion symptoms following mild traumatic brain injury are a difficult clinical state to conceptualise. The constellation of symptoms include those with an organic signature (and presumed organic aetiology), and those with overt psychological features. A seemingly trivial head injury may result in enduring symptoms. The validity of post concussion syndrome (PCS) has been the focus of much medico-legal debate, as has its cause. Whether PCS is ‘neurogenic’ or ‘psychogenic’ in aetiology remains contestable. Babinski, in 1918, hypothesised that an organic factor initiated the symptoms of the disorder now known as PCS, and that this acted as a ‘bait’, or attractor, for pre-existing and post-injury psychological influences. This hypothesis, which has been neither proven nor disproven over the subsequent nearly one hundred years, deserves reconsideration for it is an appealing model of PCS.Post concussion syndrome: The attraction of the psychological by the organic - Corrected ProofA.D. (Sandy) Macleod10.1016/j.mehy.2010.01.002Medical Hypotheses (2010)2010-02-03Medical Hypotheses2010-02-03http://www.medical-hypotheses.com/article/PIIS0306987710000071/abstract?rss=yesSummary: Although preeclampsia represents a major threat for many pregnant women, the pathogenesis of this complication is far from being clear. Recent studies suggest that preeclampsia is an autoimmune disorder. Auto-antibodies against angiotensin receptor might explain some of the pathologic findings associated with preeclampsia. However, the origin of the autoimmune reaction is unknown. Here we hypothesize that circulating fetal RNA in maternal plasma might transfect maternal cells. Expression of fetal specific sequences could lead to an immune reaction breaking the immune tolerance against some antigens. Male fetus bearing pregnancies could be at higher risk of preeclampsia due to expression of Y-specific transcripts. This hypothesis is testable by analyzing antibodies and T-lymphocytes of pregnant women with male and female fetuses.Circulating free fetal nucleic acids in maternal plasma and preeclampsia - Corrected ProofBarbora Vlková, Tomáš Szemes, Gabriel Minárik, Ján Turňa, Peter Celec10.1016/j.mehy.2010.01.003Medical Hypotheses (2010)2010-02-03Medical Hypotheses2010-02-03http://www.medical-hypotheses.com/article/PIIS0306987710000216/abstract?rss=yesSummary: The prognosis of esophageal cancer (EC) remains poor, lymph node metastasis is one of the most important factors for determining the prognosis of patients with EC. Extensive lymph node dissection has long been considered as the favorable procedure to achieve an accurate pathologic staging and a better prognosis. However, the effect of extensive lymphadenectomy during esophagectomy on survival of EC patients has been doubted. Herein we present the hypotheses that the selective lymphadenectomy might be a potential strategy for EC by creating the traps of cancer cells. Once metastatic cancer cells immersed in, patients will acquire remarkable survival profit by surgical removal these traps.Controllable metastasis: The trap for the esophageal cancer cells? - Corrected ProofWei Guo, Zheng Ma, Yun-Ping Zhao, Yao-Guang Jiang10.1016/j.mehy.2010.01.017Medical Hypotheses (2010)2010-02-03Medical Hypotheses2010-02-03http://www.medical-hypotheses.com/article/PIIS0306987709005039/abstract?rss=yesCleft lip occurs in 1/500–1/1000 births worldwide . Cleft lip is among the most common types of major birth defects that impair the development of speech, teeth, and feeding capabilities . For many years, plastic surgeons have been working hard on how to improve the surgical techniques about cleft lip repair and reduce the suffering of patients. Advances in modern surgical techniques have led to improved clinical management of cleft lip, with many patients achieving excellent functional and cosmetic outcomes . However, cleft lip usually requires multiple surgeries, and often results in emotional stress for affected children and their families . Because it is difficult to obtain stable cosmetic outcomes in a single operation, many plastic surgeons have recently become increasingly focused on how to improve the surgical techniques about cleft lip repair.A possible method on how to improve the surgical techniques about cleft lip repair - Corrected ProofCheng-hao Li, Bing Shi, Ren-kai Liu10.1016/j.mehy.2009.07.012Medical Hypotheses (2010)2010-02-01Medical Hypotheses2010-02-01CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987709007968/abstract?rss=yesChung et al. found that mature human monocyte-derived dendritic cells that express indoleamine 2,3-dioxygenase (IDO), can expand regulatory T lymphocytes, Tregs, which then significantly downregulate cytotoxic effector T cells. This is in accord with a large body of work (reviewed in Ref. ) documenting Treg upregulation following increases in IDO. Tregs can suppress the self-antigen directed B cells in autoimmune diseases such as systemic lupus erythematosus . We conclude that increases in IDO has potential to enhance Treg function and suppress manifestations of lupus and related diseases.Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells: Consideration of triamterene to treat lupus - Corrected ProofRichard E. Kast, Eric L. Altschuler10.1016/j.mehy.2009.11.039Medical Hypotheses (2010)2010-02-01Medical Hypotheses2010-02-01CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987710000058/abstract?rss=yesSummary: Hypoxia may result from hypoperfusion, as seen in the cardio-respiratory arrest. Subsequent to the acute neuronal damage, the delayed neuronal death ensues, and further neurons die within hours or days thereafter. An effective neuroprotective therapeutic agent should counteract one or, ideally, all well-established neuronal death pathways, i.e., excitotoxicity, oxidative stress and apoptosis. All these three mechanisms propagate through distinctive and mutual exclusive signal transduction pathway and contribute to the neuronal loss following the initial hypoxic–ischemic brain injury. Thus, the ideal therapeutic intervention against the hypoxic–ischemic neuronal injury should aim to prevent all three mechanisms of the neuronal death in a concerted effort. Recent studies demonstrated that intranasally administered leptin results in supra-physiological leptin levels at various regions of the brain (including hippocampus) within 30min of administration. We consider leptin to be an ideal neuroprotective agent, having targeted excitotoxicity (directly, by inhibiting AMDA and NMDA) oxidative stress (indirectly, by HIF1 mediation) and apoptosis (directly, by activating ERK 1/2 pathway) and hypothesize that intranasally administered leptin has neuroprotective effect against the neuronal hypoxic injury. If our hypothesis is confirmed, leptin administered before and/or soon after hypoxic injury, may be effective in minimizing the devastating sequelae of such event.The neuroprotective effect of intranasally applied leptin against hypoxic neuronal injury - Corrected ProofMadalina Minciu Macrea, Hara Misra, Leon Zagrean10.1016/j.mehy.2009.12.033Medical Hypotheses (2010)2010-02-01Medical Hypotheses2010-02-01http://www.medical-hypotheses.com/article/PIIS0306987710000095/abstract?rss=yesAbstract: Mitochondrial DNA (mtDNA) directs key metabolic functions in eukaryotic cells. While a number of mtDNA mutations are known causes of human diseases and age-related dysfunctions, some mtDNA haplotypes are associated with extreme longevity. Despite the mutagenic mitochondrial environment naturally enhancing somatic mtDNA mutation rates, mtDNA remains grossly stable along generations of plant and animal species including man. This relative stability can be accounted for by the purging of deleterious mutations by natural selection operating on growing cells, tissues, organisms and populations, as observed in gametogenesis, embryogenesis, oncogenesis and cladogenesis. In the adult multicellular organism, however, mtDNA mutations accumulate in slowly dividing cells, and, to a much higher degree, in postmitotic cells and tissues. Dynamic mitochondrial fusion and fission, by redistributing polymorphic mtDNA molecules; mitophagy, by clearing defective mitochondria and mutated mtDNA; compensatory mutations and mtDNA repair can compensate for the accumulation of mtDNA mutations only to a certain extent, thereby creating a dysfunctional threshold. Here we hypothesize that this threshold is naturally up-regulated by both vertical and horizontal transfers of mtDNA from stem cells or cell types which retain the capacity of purging deleterious mtDNA through cell division and natural selection in the adult organism. When these natural cell and tissue mtDNA reserves are exhausted, artificial mtDNA therapy may provide for additional threshold up-regulation. Replacement of mtDNA has been already successfully accomplished in early stage embryos and stem cells in a number of species including primates. It is thus simply a matter of refinement of technique that somatic mtDNA therapy, i.e., therapy of pathological conditions based on the transfer of mtDNA to somatic eukaryotic cells and tissues, becomes a medical reality.Improving upon nature’s somatic mitochondrial DNA therapies - Corrected ProofM.A. Dani, S.U. Dani10.1016/j.mehy.2010.01.005Medical Hypotheses (2010)2010-02-01Medical Hypotheses2010-02-01http://www.medical-hypotheses.com/article/PIIS0306987710000101/abstract?rss=yesSummary: Psammoma bodies are structures classified in the group of dystrophic calcifications, which occur in some kind of tumors and in choroid plexus during the aging process. Despite early discovery of their presence in choroid plexus stroma, mechanisms responsible for their formation remained unclear. Their presence in some kind of tumors was even more extensively studied, but significant breakthrough in the field of their etiology was not attained, too. However, till today correlation between their presence in tumors and aging is not established. Also, there are not any data about structural differences between ones found in tumors and ones found in choroid plexus. This might points to the assumption that besides the aging, some other causes might be involved in their formation in choroid plexus. Furthermore, it is contradictory that forms, like psammoma bodies, present in such malignant formations as tumors, represent quite benign phenomenon in choroid plexus. Literature data and the results of our previous researches revealed that there might be connections between, these, on the first sight quite different processes. Firstly, psammoma bodies are present in stroma of tumors with predominantly papillomatous morphology, which is present in choroid plexus, too. Initial forms of psammoma bodies might be formed in fibrovascular core of choroid plexus villi, similarly like in tumors papillae of papillary thyroid cancer. Their further growth leads to the progressive destruction of both tumors papillae and choroidal villi. Choroid plexus stroma is characterized by the fenestrated blood vessels presence, which are similar to newly formed vessels in tumors. This makes it vulnerable to the noxious agents from circulation. It can contain lymphocytes, macrophages, dendritic cells and myofibroblasts in cases with psammoma bodies, similarly to tumors stroma which is in activated, proinflammatory state. So, all these facts can suggest that similar processes can lead to psammoma bodies formation in both tumors and choroid plexus and, that they might have harmful effect on choroid plexus structure and function during the aging process. Significantly higher degree of choroidal epithelial cells atrophy, in cases with present psammoma bodies proves that partially. Further researches should be focused on detection of osteopontin and nanobacteria, already detected in tumors psammoma bodies, in choroid plexus ones. Discovery of choroidal psammoma bodies mechanisms formation can be important for elucidation of some aspects in pathogenesis of some tumors, too. Application of choroid plexus epithelial cells functional markers in cases with psammoma bodies should show their functional status.Psammoma bodies – Friends or foes of the aging choroid plexus - Corrected ProofIvan Jovanović, Sladjana Ugrenović, Ljiljana Vasović, Dragan Petrović, Sonja Cekić10.1016/j.mehy.2010.01.006Medical Hypotheses (2010)2010-02-01Medical Hypotheses2010-02-01http://www.medical-hypotheses.com/article/PIIS0306987709008305/abstract?rss=yesSummary: The diffusion of the cattle pastoralism across Europe during the Neolithic period was probably accompanied by the emergence and spread of diverse contagious diseases that were unknown in the Paleolithic and that would have affected the frequency of genes directly or indirectly associated with differential susceptibility and/or resistance to infectious pathogens. We therefore propose that the high frequency of the CFTR gene, and in particular, the common Delta F508 allele mutation in current European and European-derived populations might be a consequence of the impact of selective pressures generated by the transmission of pathogenic agents from domesticated animals, mainly bovine cattle, to the man. Intestinal infectious diseases were probably a major health problem for Neolithic peoples. In such a context, a gene mutation that conferred an increased resistance to the diseases caused by pathogens transmitted by dairy cattle would have constituted a definite selective advantage, particularly in those human groups where cow’s milk became an essential component of the diet. This selective advantage would be determined by an increased resistance to Cl−-secreting diarrheas of those individuals carrying a single copy of the Delta F508 CFTR mutation (heterozygote resistance). This hypothesis is supported by the strong association between the geography of the diffusion of cattle pastoralism (assessed indirectly by the lactase persistence distribution), the geographic distribution of a sizeable number of HLA alleles (as indicative of potential selective pressures generated by epidemic mortality) and the geographic distribution of the most common mutation causing cystic fibrosis (Delta F508). The systematic interaction of humans with infectious pathogens would have begun in northern Europe, among the carriers of the Funnel Beaker Culture, the first farmers of the North European plain, moving progressively to the south with the dissemination of the cattle pastoralism. This gradual exposure to epidemic mortality among populations located further and further south in Europe as cattle pastoralism expanded could have generated differences in CFTR gene frequencies, thereby shaping the latitudinal frequency gradients observed in present-day European populations.An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations - Corrected ProofMiguel A. Alfonso-Sánchez, Ana M. Pérez-Miranda, Susana García-Obregón, José A. Peña10.1016/j.mehy.2009.12.018Medical Hypotheses (2010)2010-01-28Medical Hypotheses2010-01-28http://www.medical-hypotheses.com/article/PIIS0306987710000022/abstract?rss=yesSummary: Although all multicellular organisms undergo structural and functional deterioration with age, senescence is not a uniform process. Rather, each organism experiences a constellation of changes that reflect the heterogeneous effects of age on molecules, cells, organs and systems, an idiosyncratic pattern that we refer to as mosaic aging. Varying genetic, epigenetic and environmental factors (local and extrinsic) contribute to the aging phenotype in a given individual, and these agents influence the type and rate of functional decline, as well as the likelihood of developing age-associated afflictions such as cardiovascular disease, arthritis, cancer, and neurodegenerative disorders. Identifying key factors that drive aging, clarifying their activities in different systems, and in particular understanding how they interact will enhance our comprehension of the aging process, and could yield insights into the permissive role that senescence plays in the emergence of acute and chronic diseases of the elderly.Mosaic aging - Corrected ProofLary C. Walker, James G. Herndon10.1016/j.mehy.2009.12.031Medical Hypotheses (2010)2010-01-28Medical Hypotheses2010-01-28http://www.medical-hypotheses.com/article/PIIS0306987709008226/abstract?rss=yesSummary: Malaria affects thousands of people around the world representing a critical issue regarding health policies in tropical countries. Similarly, also haemolytic diseases such as sickle cell disease and thalassemias are a concern in different parts of the globe. It is well established that haemolytic diseases, such as sickle cell disease (SCD) and thalassemias, represent a resistance factor to malaria, which explains the high frequencies of such genetic variants in malaria endemic areas. In this context, it has been shown that the rate limiting enzyme heme oxygenase I (HO-1), responsible for the catabolism of the free heme in the body, is an important resistance factor in malaria and is also important in the physiopathology of haemolytic diseases. Here, we suggest that allelic variants of HO-1, which display significant differences in terms of protein expression, have been selected in endemic malaria areas since the HO-1 enzyme can enhance the protection against malaria conferred by haemolytic diseases This protection apply mainly in what concerns protection against severe malaria forms. Therefore, HO-1 genotyping would be fundamental to determine resistance of a given individual to lethal forms of malaria as well as to common clinical complications typical to haemolytic diseases and would be helpful in the establishment of public health politics.HO-1 polymorphism as a genetic determinant behind the malaria resistance afforded by haemolytic disorders - Corrected ProofD. Garcia-Santos, J.A.B. Chies10.1016/j.mehy.2009.12.010Medical Hypotheses (2010)2010-01-27Medical Hypotheses2010-01-27http://www.medical-hypotheses.com/article/PIIS0306987709008366/abstract?rss=yesSummary: Osteoporosis is a serious health problem worldwide and leads to a significant burden on society. Unfortunately, efforts to control osteoporosis are largely unsuccessful. Lowering an individual’s risk for osteoporosis must focus not only on treatment but also on modification of risk factors. One of the common risk factors is smoking tobacco. Here, we review the clinical evidence on nicotine consumption and osteoporosis, and propose a possible protective mechanism. It should be note that there is no strong clinical evidence that proves nicotine is detrimental. Studies also indicated that the prime criminal for osteoporosis is smoking not nicotine. Moreover, low level nicotine has preventive efforts on osteoporosis by stimulating osteoblasts proliferation and differentiation. We present a hypothesis that low level nicotine may be a novel approach to reduce osteoporosis incidence.Low level nicotine: A novel approach to reduce osteoporosis incidence - Corrected ProofJun Zhang, Feng Chen, Feng Yun, Jinping Chen10.1016/j.mehy.2009.12.024Medical Hypotheses (2010)2010-01-27Medical Hypotheses2010-01-27http://www.medical-hypotheses.com/article/PIIS0306987710000046/abstract?rss=yesSummary: Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. Genotoxic and oncogenic stresses-induced DNA damage activate the tumor suppressor pathways initiate DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence and adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disorder the existing cellular homeostasis. This is a disease state similar to metabolic syndrome occurred by the systemic DDR to inhibit ongoing malignant transformation. Significant metabolic changes occurred by the influence of the major tumor suppressor proteins p53 and FOXO discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that “metabolic syndrome” is a real disease.Metabolic syndrome is a real disease and premalignant state induced by oncogenic stresses to block malignant transformation - Corrected ProofAdnan Erol10.1016/j.mehy.2010.01.001Medical Hypotheses (2010)2010-01-25Medical Hypotheses2010-01-25http://www.medical-hypotheses.com/article/PIIS0306987710000034/abstract?rss=yesSummary: Transcranial direct current stimulation (tDCS) is a non-invasive technique for brain stimulation and it increasingly being used in the treatments of some neurological/psychiatric conditions (e.g. chronic pain, epilepsy, depression, motor rehabilitation after stroke and Parkinson’s disease). With tDCS, cortical neurons excitability increases in the vicinity of the anodal electrode and suppressed near the cathodal electrode. There is evidence that anorexia is associated with hyperactivity in right-hemisphere frontal regions. tDCS, therefore has a promising potential in facilitating inter-hemispheric balance. A tDCS protocol is proposed: the anode electrode placed over the left prefrontal cortex and the cathode electrode located, either on the right homotopic region for non-SSRI-medicated anorexics, or on a non-cephalic site for SSRI-medicated anorexics. Together with nutritional supplements, psychotherapy and other treatments, tDCS have a good potential, as a complementary tool, in the treatment of anorexia.Transcranial direct current stimulation in the treatment of anorexia - Corrected ProofDavid Hecht10.1016/j.mehy.2009.12.032Medical Hypotheses (2010)2010-01-22Medical Hypotheses2010-01-22http://www.medical-hypotheses.com/article/PIIS0306987709008329/abstract?rss=yesSummary: There is considerable evidence that oxidative stress and a loss of nitric oxide bioactivity are key mediators of the vasculopathies associated with sickle cell disease. A comprehensive nutraceutical strategy for mitigating the contribution of oxidative stress to pathogenesis – dubbed “full-spectrum antioxidant therapy” – may have utility in this syndrome. This strategy entails concurrent administration of phycocyanobilin – a phytochemical richly supplied by spirulina, shown to inhibit NADPH oxidase in a manner analogous to its chemical relatives biliverdin and bilirubin; high-dose folate – recently shown to quench peroxynitrite-derived radicals and restore coupling of NO synthase; N-acetylcysteine – for boosting intracellular glutathione levels; and a phase 2 inducer such as lipoic acid – to further promote glutathione synthesis while increasing expression of antioxidant enzymes. Suboptimal endothelial arginine levels, reflecting increased plasma arginase activity and elevated ADMA, contribute to the loss of NO bioactivity in sickle cell disease; supplementation with the arginine precursor citrulline may ameliorate this defect. Increased intakes of plant-derived nitrate have the potential to diminish the quenching of NO by plasma hemoglobin in sickle cell patients, while boosting systemic NO production independent of NO synthase activity. In addition to the well-documented utility of hydroxyurea – possibly a suboptimal strategy for life-long therapy owing to its mutagenic activity – rational pharmaceutical options for managing sickle cell disease include pentoxifylline and phosphodiesterase 5 inhibitors such as sildenafil.Potential utility of full-spectrum antioxidant therapy, citrulline, and dietary nitrate in the management of sickle cell disease - Corrected ProofMark F. McCarty10.1016/j.mehy.2009.12.020Medical Hypotheses (2010)2010-01-20Medical Hypotheses2010-01-20http://www.medical-hypotheses.com/article/PIIS0306987709008330/abstract?rss=yesSummary: The characteristic leanness of vegans and adherents to “Mediterranean” diet patterns may reflect the fact that the high saturate-to-unsaturate ratio of Western omnivore diets tends to impair muscle insulin sensitivity, leading to a compensatory up-regulation of insulin secretion. Since insulin signals adipocytes to take up and retain fatty acids, a high dietary saturate-to-unsaturate ratio would be expected to promote obesity. It is proposed that, at any given level of total fat intake, the dietary saturate/unsaturate ratio will correlate positively with BMI and propensity for weight gain – a readily testable prediction. The relatively low ratios of saturates to unsaturates and of essential to non-essential amino acids in plant-based diets may be primarily responsible for the low rates of obesity, diabetes, coronary disease, and “Western” cancers observed in quasi-vegan societies.Dietary saturate/unsaturate ratio as a determinant of adiposity - Corrected ProofMark F. McCarty10.1016/j.mehy.2009.12.021Medical Hypotheses (2010)2010-01-20Medical Hypotheses2010-01-20http://www.medical-hypotheses.com/article/PIIS0306987709008342/abstract?rss=yesSummary: The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal–mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases – which promote proteasomal degradation of HIF-1alpha under aerobic conditions – with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O2-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens.Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy - Corrected ProofMark F. McCarty, Jorge Barroso-Aranda, Francisco Contreras10.1016/j.mehy.2009.12.022Medical Hypotheses (2010)2010-01-20Medical Hypotheses2010-01-20http://www.medical-hypotheses.com/article/PIIS030698770900841X/abstract?rss=yesSummary: Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation – as with 2-deoxyglucose administration or a hypoglycemic insulin clamp – and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials.Oxidative stress therapy for solid tumors – A proposal - Corrected ProofMark F. McCarty, Jorge Barroso-Aranda, Francisco Contreras10.1016/j.mehy.2009.12.029Medical Hypotheses (2010)2010-01-20Medical Hypotheses2010-01-20http://www.medical-hypotheses.com/article/PIIS0306987709008378/abstract?rss=yesSummary: A wealth of research data points to increased oxidative stress as a key driver of the cardiac remodeling triggered by chronic pressure overload, loss of functional myocardial tissue, or atrial fibrillation. Oxidative stress is a mediator of the cardiomyocyte hypertrophy and apoptosis, the cardiac fibrosis, and the deficits in cardiac function which typify this syndrome, and may play a role in initiating and sustaining atrial fibrillation. Nox2- and Nox4-dependent NADPH oxidase activity appears to be a major source of this oxidative stress, and oxidants can induce conformational changes in xanthine dehydrogenase, nitric oxide synthase, and the mitochondrial respiratory chain which increase their capacity to generate superoxide as well. Consistent with these insights, various synthetic antioxidants have been shown to suppress cardiac remodeling in rodents subjected to myocardial infarction, aortic constriction, or rapid atrial pacing. It may prove feasible to achieve comparable benefits in humans through use of a “full-spectrum antioxidant therapy” (FSAT) that features a complementary array of natural antioxidants. Spirulina is a rich source of phycocyanobilin, a derivative and homolog of biliverdin that appears to mimic the potent inhibitory impact of biliverdin and free bilirubin on NADPH oxidase activity. Mega-doses of folate can markedly increase intracellular levels of tetrahydrofolates which have potent and versatile radical-scavenging activities – including efficient quenching of peroxynitrite-derived radicals Supplemental coenzyme Q10, already shown to improve heart function in clinical congestive failure, can provide important antioxidant protection to mitochondria. Phase 2 inducer nutraceuticals such as lipoic acid, administered in conjunction with N-acetylcysteine, have the potential to blunt the impact of oxidative stress by boosting myocardial levels of glutathione. While taurine can function as an antioxidant for myeloperoxidase-derived radicals, its positive inotropic effect on the failing heart seems more likely to reflect an effect on intracellular calcium dynamics. These measures could aid control of cardiac modeling less directly by lowering elevated blood pressure, or by aiding the perfusion of ischemic cardiac regions through an improvement in coronary endothelial function. Since nitric oxide functions physiologically to oppose cardiomyocyte hypertrophy and cardiac fibrosis, and is also a key regulator of blood pressure and endothelial function, cocoa flavanols – which provoke endothelial release of nitric oxide – might usefully complement the antioxidant measures recommended here.Practical prevention of cardiac remodeling and atrial fibrillation with full-spectrum antioxidant therapy and ancillary strategies - Corrected ProofMark F. McCarty10.1016/j.mehy.2009.12.025Medical Hypotheses (2010)2010-01-18Medical Hypotheses2010-01-18http://www.medical-hypotheses.com/article/PIIS0306987709008391/abstract?rss=yesSummary: In the high proportion of vascular disorders associated with excessive oxidative stress and production of pro-inflammatory cytokines, activation of NF-kappaB plays a key pathogenic role. Thus, there is considerable evidence that NF-kappaB is a mediator of atherogenesis, plaque destabilization, ischemia–reperfusion damage, cardiac remodeling, atrial fibrillation, and aneurysm formation and rupture; some studies suggest that it may also play a role in the microvascular complications of diabetes. IkappaB kinase-beta (IKKbeta) is the upstream kinase that appears to be primarily responsible for NF-kappaB activation in these disorders; moreover, chronic IKKbeta activation plays a prominent role in induction of insulin resistance in the metabolic syndrome. Salicylate inhibits IKKbeta in concentrations that are achievable with dose schedules traditionally used in treating rheumatoid arthritis (3–4.5g daily); indeed, this is likely to be the mechanism responsible for salicylate’s utility in this disorder. Salicylate, unlike aspirin, is only a very weak, reversible inhibitor of cyclooxygenase in clinical doses, and thus is not associated with the potentially dangerous side effects seen with NSAIDs; fully reversible ototoxicity, the dose-limiting side effect in salicylate therapy, can be avoided in most patients by dosage adjustment. Hence, it is proposed that salicylate may have practical utility in the prevention or management of a wide range of vascular disorders as well as of metabolic syndrome and diabetes; its efficacy in these regards would likely be complemented by effective antioxidant measures, which would lessen the stimulus to NF-kappaB activation while providing benefits independent of NF-kappaB activity. Salsalate, consisting of two salicylate molecules united by an ester bond, is a venerable drug that may be the best tolerated delivery vehicle for salicylate. Appropriate rodent studies should pave the way for clinical trials with salsalate in patients at vascular risk.Salsalate may have broad utility in the prevention and treatment of vascular disorders and the metabolic syndrome - Corrected ProofMark F. McCarty10.1016/j.mehy.2009.12.027Medical Hypotheses (2010)2010-01-18Medical Hypotheses2010-01-18http://www.medical-hypotheses.com/article/PIIS0306987709008408/abstract?rss=yesWe have read with interest the article by Zhuang et al. considering adipocytokines as a connecting bridge between obesity and insulin resistance (IR). Adipocytokines seem to link obesity with most IR states, including type 2 diabetes mellitus, hypertension, polycystic ovary syndrome, cardiovascular disease and particularly non-alcoholic fatty liver disease (NAFLD) . However, the role of most adipocytokines seems to be bidirectional in IR and NAFLD. Their grouping into beneficial (i.e., adiponectin, visfatin, leptin) or detrimental [i.e., resistin, tumor necrosis factor (TNF)-α] is simplified and highlights only their main effects on IR.Adipocytokines in insulin resistance and non-alcoholic fatty liver disease: The two sides of the same coin - Corrected ProofStergios A. Polyzos, Jannis Kountouras, Christos Zavos, Christos Stergiopoulos, Stergios A. Polyzos10.1016/j.mehy.2009.12.028Medical Hypotheses (2010)2010-01-18Medical Hypotheses2010-01-18CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987709008421/abstract?rss=yesAbstract: Gastroesophageal reflux (GER) and asthma have been linked, but the true nature of this relationship is incompletely understood. Most of the literature examining this association has implicated GER as the factor contributing to asthma. GER has also been linked to conditions of the upper airway like sinusitis and obstructive sleep apnea (OSA), and once again, usually presumed to be the causative factor. While GER seems to be capable of exacerbating airway disease, mounting evidence suggests that airway obstruction is a risk factor for developing GER. This article examines the principles of physics that predict what should occur given the anatomy of the airway and the esophagus, and provides multiple examples of disease associations that appear to support the hypothesis that airway obstruction is a significant risk factor for development of gastroesophageal reflux.Applying principles of physics to the airway to help explain the relationship between asthma and gastroesophageal reflux - Corrected ProofJoseph C. Turbyville10.1016/j.mehy.2009.12.030Medical Hypotheses (2010)2010-01-18Medical Hypotheses2010-01-18http://www.medical-hypotheses.com/article/PIIS030698770900838X/abstract?rss=yesSummary: Presently, the textbook description of cerebrospinal fluid absorption is through the arachnoid granules into the superior sagittal sinus. The theory is based on non-physiologic experiments and fails to explain multiple observations. Photographs and microphotographs of choroid plexus portals are included. Evidence is presented that cerebrospinal fluid is moved from the choroid fissure into the ventricular system. The deposition pattern of corpora amylacea demonstrates the bulk flow of cerebrospinal fluid. Melatonin is found in higher concentration in the cerebrospinal fluid than in simultaneously sampled blood. Melatonin is a potent antioxidant and the loss of its protection in the cerebrospinal fluid in Alzheimer’s disease can explain the pattern of cell destruction. Challenges of the embedded dogma of the arachnoid granule absorption of cerebrospinal fluid have been ignored; however this old faulty theory must be abandoned in order to understand the pathophysiology of Alzheimer’s disease.Choroid plexus portals and a deficiency of melatonin can explain the neuropathology of Alzheimer’s disease - Corrected ProofCharles P. Maurizi10.1016/j.mehy.2009.12.026Medical Hypotheses (2010)2010-01-14Medical Hypotheses2010-01-14http://www.medical-hypotheses.com/article/PIIS0306987709007956/abstract?rss=yesSummary: Everyone living in modernizing ‘Western’ societies will have noticed the long-term, progressive growth and spread of bureaucracy infiltrating all forms of social organization: nobody loves it, many loathe it, yet it keeps expanding. Such unrelenting growth implies that bureaucracy is parasitic and its growth uncontrollable – in other words it is a cancer that eludes the host immune system. Old-fashioned functional, ‘rational’ bureaucracy that incorporated individual decision-making is now all-but extinct, rendered obsolete by computerization. But modern bureaucracy evolved from it, the key ‘parasitic’ mutation being the introduction of committees for major decision-making or decision-ratification. Committees are a fundamentally irrational, incoherent, unpredictable decision-making procedure; which has the twin advantages that it cannot be formalized and replaced by computerization, and that it generates random variation or ‘noise’ which provides the basis for natural selection processes. Modern bureaucracies have simultaneously grown and spread in a positive feedback cycle; such that interlinking bureaucracies now constitute the major environmental feature of human society which affects organizational survival and reproduction. Individual bureaucracies must become useless parasites which ignore the ‘real-world’ in order to adapt to rapidly-changing ‘bureaucratic reality’. Within science, the major manifestation of bureaucracy is peer review, which – cancer-like – has expanded to obliterate individual authority and autonomy. There has been local elaboration of peer review and metastatic spread of peer review to include all major functions such as admissions, appointments, promotions, grant review, project management, research evaluation, journal and book refereeing and the award of prizes. Peer review eludes the immune system of science since it has now been accepted by other bureaucracies as intrinsically valid, such that any residual individual decision-making (no matter how effective in real-world terms) is regarded as intrinsically unreliable (self-interested and corrupt). Thus the endemic failures of peer review merely trigger demands for ever-more elaborate and widespread peer review. Just as peer review is killing science with its inefficiency and ineffectiveness, so parasitic bureaucracy is an un-containable phenomenon; dangerous to the extent that it cannot be allowed to exist unmolested, but must be utterly extirpated. Or else modernizing societies will themselves be destroyed by sclerosis, resource misallocation, incorrigibly-wrong decisions and the distortions of ‘bureaucratic reality’. However, unfortunately, social collapse is the more probable outcome, since parasites can evolve more rapidly than host immune systems.The cancer of bureaucracy: How it will destroy science, medicine, education; and eventually everything else - Corrected ProofBruce G. Charlton10.1016/j.mehy.2009.11.038Medical Hypotheses (2010)2010-01-13Medical Hypotheses2010-01-13EDITORIALhttp://www.medical-hypotheses.com/article/PIIS0306987709008214/abstract?rss=yesSummary: Chronic pain conditions often “mimic” the symptoms of restless legs syndrome (RLS) with worse pain in the evening and upon rest, associated with an urge to move and relief upon movement. We propose that too little has been made of these parallels, with pain conditions resembling RLS being dismissed as mimics. We found, in a large questionnaire study (n=283) on phantom limb perception, a pattern of phantom pain that resembled RLS: amputees with nocturnal phantom pain were more likely to report worse pain upon rest and/or lying down, with an urge to move the phantom and/or walk to relieve their pain, and to experience spontaneous limb movements akin to periodic leg movements of RLS. We present the hypothesis that a model of restless legs syndrome may provide new insights into the mechanisms underlying phantom pain, and lead to new mechanism-based phantom pain treatment. In particular, central changes associated with sensory and motor symptoms of RLS, neuropathy, and dopamine may also be involved in those predisposed to experience phantom pain that mimics the symptoms of RLS. Ultimately, restless legs syndrome may indeed be a pain syndrome, and warrants further investigation in chronic pain populations.The phantom of the night: Restless legs syndrome in amputees - Corrected ProofMelita J. Giummarra, John L. Bradshaw10.1016/j.mehy.2009.12.009Medical Hypotheses (2010)2010-01-13Medical Hypotheses2010-01-13http://www.medical-hypotheses.com/article/PIIS0306987709008238/abstract?rss=yesSummary: Many women who suffer from the symptoms of urinary tract infection have a negative urine culture when conventional methods are used. Their condition is described as ‘urethral’ (or ‘dysuria/frequency’) syndrome’ (US). As they may be indistinguishable clinically from those with positive cultures antibiotics are often prescribed. Their symptoms are usually recurrent and they may receive many courses of treatment. Some women are said to have ‘interstitial cystitis’ (IC); they have a long history of symptoms and antibacterial treatment. The urine contains white blood cells (pyuria) and biopsy of the bladder wall shows the histological changes of chronic inflammation. Additional culture techniques applied to urine from these two groups of patients consistently yield bacteria, most commonly lactobacilli in those with US. From the urine of women with IC, lactobacilli and some other ‘fastidious’ bacteria are isolated from catheter specimens and also from bladder wall biopsies. These bacteria are known to be constituents of the mixed commensal flora of the distal one-third of the urethra. It is proposed that these two syndromes are different stages in the natural history of UTI, and that antibacterial agents, by selection of resistant bacteria in the urethral commensal flora, are an important aetiological factor. It is possible that these bacteria may invade the paraurethral glands via their ducts – a situation analogous to invasion of the prostate in men.There is a considerable body of evidence supporting this hypothesis, but as it all emanates from one centre it needs to be confirmed elsewhere. Acceptance would bring great clinical benefit and considerable financial savings. A laboratory protocol which requires only small additional expenditure, and a clinical management regimen are proposed. At present, much antibacterial treatment is prescribed and many patients undergo radiological and invasive investigations such as cystoscopy and urethral dilatation, the latter incurring the risk of post-instrumentation UTI. There is evidence that ‘US’ responds gradually if antibiotics are withheld. ‘IC’ is a more difficult problem because bacteria may have invaded the bladder wall. Carefully targeted antibacterial treatment given for at least 10–14days might be effective, but there are no data on this. Rational management of ‘US’ might prevent the development of ‘IC’. A recent thorough review of published work on this condition states that the aetiology is still unknown. It appears, however, that no attempt has been made in any recent studies to use urine culture techniques capable of detecting bacteria other than the recognised aerobic pathogens.The natural history of urinary tract infection in women - Corrected ProofR.M. Maskell10.1016/j.mehy.2009.12.011Medical Hypotheses (2010)2010-01-11Medical Hypotheses2010-01-11http://www.medical-hypotheses.com/article/PIIS0306987709008275/abstract?rss=yesAbstract: The etiology of non-occupational carpal tunnel syndrome is not well understood. It is proposed that carpal tunnel syndrome can develop during sexual intercourse when the hands become repeatedly extended while under pressure from the weight of the upper body. Of the eight risk factors associated with non-occupational carpal tunnel syndrome, age, marital status, pregnancy and use of hormonal agents can be explained by changes in the frequency of sexual intercourse. On the other hand, obesity, macromastia and large chest circumference can be explained by the increased pressure imposed on the wrists by the heavier upper body associated with such conditions. The bilaterality of carpal tunnel syndrome can be explained by the fact that both hands are needed to support the upper body during sexual intercourse. A parallel decrease in the frequency of sexual intercourse and the incidence of carpal tunnel syndrome between the sixth and the seventh decades of life suggests a possible cause and effect relationship between sexual intercourse and carpal tunnel syndrome.The role of sexual intercourse in the etiology of carpal tunnel syndrome - Corrected ProofJohn Zenian10.1016/j.mehy.2009.12.015Medical Hypotheses (2010)2010-01-11Medical Hypotheses2010-01-11http://www.medical-hypotheses.com/article/PIIS0306987709008287/abstract?rss=yesSummary: The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Any therapeutic or prophylactic measure which holds promise or provides clues of eliminating or inhibiting the infection is worthy of investigation. As our body’s own saliva is suspiciously escaping from the infection and providing clues regarding the resistance/inhibition of HIV; in this paper, a treatment approach is suggested with the rationale of in vitro effective antiviral action of autogenous saliva may also have a better therapeutic potential by its intravenous administration along with dextran.Autologous saliva transfusion: Treatment for HIV? - Corrected ProofGururaj Arakeri10.1016/j.mehy.2009.12.016Medical Hypotheses (2010)2010-01-11Medical Hypotheses2010-01-11http://www.medical-hypotheses.com/article/PIIS0306987709008299/abstract?rss=yesSummary: Diabetes has become a global epidemic. The increased incidence of NIDDM is seen all over the world but there is geographical variation. Certain population groups show increased susceptibility to develop diabetes. The prevalence is lowest in Caucasian whites and highest in Pima Indians and Naurans. Iceland has a particularly low incidence whereas Bahrain is among the countries with highest prevalence. The highest prevalence of diabetes in 2000 was found in Papua New Guiana (15.5%), Mauritius (15%), Bahrain (14.8%), Mexico (14.2%), Trinidad and Tobago (14.1%). Most of the hypotheses developed to explain this trend concerned mainly on dietary and nutritional factors. Man had to struggle against harsh climatic conditions for survival. It has been observed that people who have been adapted to cold environment for generations demonstrate some resistance to develop diabetes. It is hypothesized that presence of thick subcutaneous fat, reactivation of brown adipose tissue in cold environment and effective mitochondrial enzyme systems for heat generation act as adaptive mechanisms for survival in cold environment and retard the development of visceral obesity. Mitochondrial defects have been found in patients with NIDDM and NAFLD. Changes of nuclear genes which encode mitochondrial enzyme systems involved in thermo genesis could be the cause for development of visceral obesity and NIDDM.Impact of ecology on development of NIDDM - Corrected ProofD.A.R.K. Dayaratne10.1016/j.mehy.2009.12.017Medical Hypotheses (2010)2010-01-11Medical Hypotheses2010-01-11http://www.medical-hypotheses.com/article/PIIS0306987709008354/abstract?rss=yesSummary: A high serum uric acid is common in subjects with pulmonary hypertension. The increase in serum uric acid may be a consequence of the local tissue ischemia and/or hypoxia, and it may also result from other factors independent of ischemia or hypoxia that occur in various forms of pulmonary hypertension. While classically viewed as a secondary phenomenon, recent studies suggest that hyperuricemia may also have a role in mediating the local vasoconstriction and vascular remodeling in the pulmonary vasculature. If uric acid does have a contributory role in pulmonary hypertension, we may see an increasing prevalence of pulmonary hypertension as hyperuricemia is common in subjects with obesity and metabolic syndrome. We propose studies to investigate the role of uric acid in pulmonary hypertension and to determine if lowering serum uric acid may have clinical benefit in this condition.Could uric acid be a modifiable risk factor in subjects with pulmonary hypertension? - Corrected ProofSergey I. Zharikov, Erik R. Swenson, Miguel Lanaspa, Edward R. Block, Jawaharlal M. Patel, Richard J. Johnson10.1016/j.mehy.2009.12.023Medical Hypotheses (2010)2010-01-11Medical Hypotheses2010-01-11http://www.medical-hypotheses.com/article/PIIS030698770900824X/abstract?rss=yesSummary: Twenty years ago, circumstantial evidence was compiled to link the 1918 pandemic influenza virus to a CNS disorder called epidemic encephalitis or encephalitis lethargica. A challenge was issued to naysayers. During the past two decades, the knowledge about the influenza virus and the 1918 pandemic virus in particular has had dramatic advancement. The 1918 virus has been resurrected and reconstructed. Experimental studies of mice inoculated with a neurovirulent avian virus have delineated the neuropathology of influenza encephalitis. Review of autopsy cases of encephalitis lethargica revealed that the neuropathology during and shortly after the pandemic was unique.Surprisingly two different viruses were involved with the great pandemic. A single amino acid difference in the hemagglutinin of the two viruses changed the preferred receptor of the virus in the host cell. One virus has qualities that suggest that it is neurovirulent. Circumstantial evidence suggests that the cause of death in some influenza patients was neurogenic congestive heart failure with pulmonary edema. Theories about the pathophysiology of encephalitis lethargica and postencephalitic Parkinson’s disease are offered.Influenza caused epidemic encephalitis (encephalitis lethargica): The circumstantial evidence and a challenge to the nonbelievers - Corrected ProofC.P. Maurizi10.1016/j.mehy.2009.12.012Medical Hypotheses (2010)2010-01-08Medical Hypotheses2010-01-08http://www.medical-hypotheses.com/article/PIIS0306987709004666/abstract?rss=yesSummary: Approaches to personal behaviour change include contractual and negotiation models. This paper elaborates these partnership models by linking a religious act to desired behaviour change beyond narrow and specific domains, such as promotion of sexual abstinence. It discusses the hypothesis that oath-taking can facilitate positive, health-related behaviour change in human individuals. The change must be desired by these individuals when they nevertheless feel conflicted in their motives, and believe in a divine presence to which they can oath-take. In support of this meta-hypothesis of the effectiveness of oath-taking to a hypothetical divinity, we first describe the nature of oaths and oath-taking, including legitimacy and satisfaction conditions, and then postulate how ten interrelated sets of mechanisms can be expected to facilitate oath-keeping. We playfully and heuristically express these mechanisms as ‘ten commandments’. Constituting a divine prescription for health-related change, the mechanisms require oath-takers to: believe in the oath, recognise oath-taking as an established and legitimate social behaviour, crystallise the content of the oath, declare the oath aloud, oath-take privately if they prefer, commit to relationships that support oath-taking, replace their relationship with the unwanted behaviour, sanctify the divine presence, honour obligations produced by the oath-taking, and fear oath-breaking. Limitations of oath-taking are then considered as are some of the implications of our arguments.Oath-taking: A divine prescription for health-related behaviour change? - Corrected ProofStephen A. Buetow, Peter Adams10.1016/j.mehy.2009.06.035Medical Hypotheses (2010)2010-01-07Medical Hypotheses2010-01-07http://www.medical-hypotheses.com/article/PIIS0306987709004721/abstract?rss=yesSummary: Failure to maintain the patency of the pharyngeal airway during sleep is central to the pathogenesis of obstructive sleep apnoea (OSA). This failure is hypothesised to be due to the combination of a small pharyngeal airway and inadequate state-dependent neuro-mechanical control. Little is known of how the pharyngeal muscles function in an integrated function to alter the size and shape of the pharyngeal airway. We hypothesise that the muscles of the pharynx function as a muscular hydrostat. Muscular hydrostats are organs that are composed almost entirely of muscle, with a complex muscular arrangement within the organ. Examples of muscular hydrostats include the mammalian tongue, octopus tentacles, elephant trunks and the medicinal leech. During muscle contraction the organ will maintain a constant volume as muscle tissue is mostly water and hence incompressible. The mechanical effect of contraction of individual muscles within the muscular hydrostat is dependent on the integrated activity of all other muscles, as muscle orientation is dependent on the organ shape. Functionally the significance of the muscular hydrostat model lies in the concept that alterations in organ shape are achieved via muscle contraction driven redistribution of hydrostatic tissue pressure. The tissues which comprise the pharynx are predominantly muscle, and thus incompressible. The pharynx is composed of 20 muscles that are arranged in a complex fashion. Within the peri-pharyngeal tissues the only bony structure is the hyoid bone and in adult humans this is a free-floating bone. Evidence already exists that the functional outcome of contraction of some of the pharyngeal muscles is dependent on stage of respiration, the intra-luminal pressure, or the position of the hyoid bone when the muscle is activated. There is also evidence that muscle contraction can alter the pressure in the tissues surrounding the pharynx in a non-uniform fashion. However, it has not been demonstrated for the pharynx that pharyngeal luminal shape is determined by muscle contraction determined transmural pressure distribution. The consequences of this hypothesis are that reported pharyngeal anatomical abnormalities in subjects with OSA, such as increased peri-pharyngeal fat deposition or thickening of the lateral pharyngeal walls, could result in alteration in integrated muscular function and thus a failure to maintain upper airway patency. In addition, nocturnal pharyngeal airway obstruction may result from a failure of cross muscle activation. This novel paradigm may lead to greater insights into the pathogenesis of OSA as well as opening new avenues for exploration of novel therapeutic strategies.Is the pharynx a muscular hydrostat? - Corrected ProofKristina Kairaitis10.1016/j.mehy.2009.06.040Medical Hypotheses (2010)2010-01-07Medical Hypotheses2010-01-07http://www.medical-hypotheses.com/article/PIIS0306987709008056/abstract?rss=yesSummary: Benign joint hypermobility syndrome (BJHS) is a hereditable disorder of connective tissue, which is characterized by the occurrence of multiple musculoskeletal problems in hypermobile individuals who do not have a systemic rheumatological disease. Rectal, uterine and mitral prolapses, varicose veins, myopia and recurrent urinary tract infections are more common in patients with BJHS, which indicates a diffuse anomaly in the structure of connective tissue rather than a limited involvement of the musculoskeletal system. Asthma, as a complex trait disease, develops after environmental exposure to innocuous allergens, infectious agents and air pollutants in susceptible individuals on the basis of their genetics. However, genetic factors cannot explain the recent rise in the prevalence, morbidity, or mortality of asthma. Asthma may also be caused by a connective tissue defect. Changes in the mechanical properties of the bronchial airways and lung parenchyma may underlie the increased tendency of the airways to collapse in asthmatic children. In this paper, we postulate that BJHS may lead to persistent childhood wheezing by causing airway collapse through a connective tissue defect that affects the structure of the airways.Benign joint hypermobility syndrome: A cause of childhood asthma? - Corrected ProofErdogan Soyucen, Fehim Esen10.1016/j.mehy.2009.12.004Medical Hypotheses (2010)2010-01-07Medical Hypotheses2010-01-07http://www.medical-hypotheses.com/article/PIIS0306987709008317/abstract?rss=yesSummary: In a 1994 Medical Hypotheses paper, it was speculated that high intracranial pressure (ICP) might increase the probability of developing Alzheimer’s disease (AD). A study of cerebrospinal fluid pressure (CSFP) in normal volunteers showed interindividual variations in CSFP. Some normals had what would normally be considered elevated CSFP. The hypothesis postulated that this subgroup with a high characteristic individual ICP level might be more susceptible to developing AD. The Medical Hypotheses paper further speculated that in more advanced stages of AD, such pressure factor could already be missing due to the disease process. The present article discusses recent research findings regarding CSFP distribution in AD patients that could be interpreted as support for this hypothesis. Exposure of central nervous system tissue to high pressure stress is not unique to the ICP space. Indeed, a similar situation occurs in the intraocular pressure (IOP) space in eyes with glaucoma. Interestingly, recent research has revealed similarities in the process leading to retinal ganglion cell death in glaucoma and neuronal cell death in AD. In the present paper, we raise the question of whether AD could be a cerebral form of glaucoma. Indeed, the linking of glaucoma to mechanisms of AD could reflect the anatomical and functional similarities between the IOP space and the ICP space. Further studies are warranted, however, especially to determine the possible role of high ICP in at least some cases of AD.Alzheimer’s disease: Cerebral glaucoma? - Corrected ProofPeter Wostyn, Kurt Audenaert, Peter Paul De Deyn10.1016/j.mehy.2009.12.019Medical Hypotheses (2010)2010-01-07Medical Hypotheses2010-01-07http://www.medical-hypotheses.com/article/PIIS0306987709008081/abstract?rss=yesSummary: Trigeminal neuralgia is a painful unilateral neuralgia of the trigeminal nerve characterized by agonizing, paroxysmal, and lancinating facial pain with unidentified causes. Usually it is triggered by stimuli at specific area in head or neck which is called trigger zone clinically. The pathophysiology of trigeminal neuralgia is thought to be focal mechanical compression of the trigeminal nerve at a point close to the brain stem, but also not quite clear. Unclear causes lead to unidentified treatments. Most therapeutic methods are simply symptomatic treatment. Many medicine and treatment methods have been proved effective, such as carbamazepine, gabapetin, phenytoin, microvascular decompression, percutaneous techniques and radiosurgery methods, but their long term efficiency remains a matter of dispute. Therefore, novel etiological and therapeutic concepts are urgently needed. According to our clinical observation and some facts that do not favor the mechanical compression theory, such as epidemiological analysis, clinical manifestation and pathoanatomical characters of trigeminal neuralgia, we can conclude that not all trigeminal neuralgia is related to mechanical compression, some may be caused by abnormality of receptors or nerve endings in the trigger zone. Based on this hypothesis, we make the hypotheses that subcutaneous or submucous injection of carbamazepine at the position of trigger zone might be more effective than taking carbamazepine orally as we usually do. We also make further hypotheses that destruction of trigger zone such as by laser, freezing or surgery may be a novel and effective treatment methods for trigeminal neuralgia.Trigeminal neuralgia may be caused by abnormality of the trigger zone - Corrected ProofJiaqiang Liu, Juan Dai, Lingling E, Dongsheng Wang, Hongchen Liu10.1016/j.mehy.2009.12.007Medical Hypotheses (2010)2010-01-06Medical Hypotheses2010-01-06http://www.medical-hypotheses.com/article/PIIS0306987709007993/abstract?rss=yesMandibular retrognathia is the major aetiology of class II malocclusion . The treatment effects of mandibular retrognathia with traditional functional appliances remain unsatisfactory.Earphone: A new approach to enhance mandibular growth in class II malocclusion - Corrected ProofXiaohuan Zhong, Huixin Wang, Xinchun Jian10.1016/j.mehy.2009.11.042Medical Hypotheses (2010)2010-01-04Medical Hypotheses2010-01-04CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987709008019/abstract?rss=yesSummary: Vital bleaching procedures are a popular means of improving the appearance of discolored teeth. There is a wide array of whitening products for home and dental office use; all involves placing peroxide containing gels or solutions in contact with the teeth. In order to whiten teeth peroxide has to be able to penetrate tooth structure and oxidize colored compounds in the dentin. Unfortunately beauty comes with a price; many patients undergoing peroxide based whitening procedures complain of bleaching sensitivity (BS) arising in the treated teeth. In BS, pain can occur in healthy intact teeth without any provoking stimulus. Currently the mechanism of nociceptors activation in BS is unknown. A more common form of dental pain-dentin sensitivity (DS) occurs when stimuli such as cold or tactile stimulation contact areas of exposed dentin in otherwise healthy teeth. In DS, stimulation of the dentin results in fluid shifts in the dentinal tubules, these fluid shifts activate mechanosensitive nerve endings in the deep dentin and pulp. Since many aspects of BS and DS symptoms differ, it is hypothesized that that the mechanism of pain generation differs for these two conditions. Recently the functional properties of a chemosensitive ion channel-TRPA1 have been described. This channel is activated by a variety of oxidizer compounds including hydrogen peroxide. Pulpal sensory afferents express TRPA1. It is hypothesized that direct activation of intradental nerve activity via TRPA1 is the mechanism of BS pain. If this theory were correct, tooth sensitivity treatments that reduce the excitability of the intradental nerves such as potassium salts, would be the treatment of choice for BS.Pretty painful: Why does tooth bleaching hurt? - Corrected ProofKenneth Markowitz10.1016/j.mehy.2009.11.044Medical Hypotheses (2010)2010-01-04Medical Hypotheses2010-01-04http://www.medical-hypotheses.com/article/PIIS030698770900807X/abstract?rss=yesIt is well known that intraventricular cerebrospinal fluid (CSF) adhesions in the subarachnoid space and arachnoid villi can lead to obstruction after intracranial bleeding, trauma, surgery, and infections, and may be the main cause for acute hydrocephalus. Patients with acute hydrocephalus often require surgical intervention, such as external ventricular drainage or ventriculoperitoneal shunts to prevent a progressive increase in intracranial pressure and enlargement of the cerebral ventricles; the most common and severe complications for surgical intervention include intracranial infections and re-haemorrhage .Intrathecal injection of urokinase: A promising therapeutic method for acute hydrocephalus? - Corrected ProofBin Wang, Qilin Huang, Haipeng Liu, Hui Yang10.1016/j.mehy.2009.12.006Medical Hypotheses (2010)2010-01-04Medical Hypotheses2010-01-04CORRESPONDENCEhttp://www.medical-hypotheses.com/article/PIIS0306987709008093/abstract?rss=yesSummary: In the kidney there is a co-transport relationship in the nephron between the reabsorption of positive Na+ ions and the reabsorption of negative ions such as uric acid anions. Uric acid acts as an anti-oxidant and it has been shown to have a sealing effect on the blood–brain barrier.The theory developed here is that chronic neurological vasoconstriction in cool environmental conditions injects an offset into the rennin–angiotensin–aldosterone system (RAAS) blood pressure control loop and reduces demand for angiotensin and aldosterone. (Aldosterone is produced in the adrenal gland and has a direct effect on renal reabsorption of Na+ ions.) Via co-transport these conditions will reduce the body’s ability to reabsorb uric acid and this in turn will weaken the integrity of the blood–brain barrier. Also, in cool environments, where levels of vasopressin (ADH) and aldosterone are lower, the gain of the hypothalamus–pituitary–adrenal gland (HPA) axis is reduced so that the production average levels of ACTH, cortisone and aldosterone will be biased at a lower level and the kidney-local levels of aldosterone in particular will remain lower.This paper develops these ideas and suggests that they can help explain the traditionally-recognized latitudinal gradient in MS epidemiology. Also, acclimatization to heat encourages sweating, which should create a greater demand for the renal reabsorption of Na+ ions which enables greater reabsorption of uric acid. Therefore people living at low latitudes should have a lower chance of hypouricemia and a lower chance of developing MS. In fact people who spend their first fifteen years in the tropics almost never go onto develop MS. And MS patients in relapse are consistently hypouricemic. This hypothesis can explain both of these facts.The paper goes onto show how the MS condition will tend to progress because of a number of self-sustaining effects: over time the immune system becomes more targeted to myelin, MS patients are unlikely to become acclimatized to heat because they tend to avoid heat since demyelinated nerve function is worsened by elevated temperature, and the normal circadian excitation of the HPA axis gets weaker under the benign environmental conditions typically adopted by MS patients as the disease develops.Endocrine system dynamics and MS epidemiology - Corrected ProofJames Moynihan, Helena Moore10.1016/j.mehy.2009.12.008Medical Hypotheses (2010)2010-01-04Medical Hypotheses2010-01-04