Medical Hypotheses

Title page/Editorial Board

2010-03-01

Why are women so intelligent? The effect of maternal IQ on childhood mortality may be a relevant evolutionary factor

Bruce G. Charlton — 2009-09-22

Summary: Humans are an unusual species because they exhibit an economic division of labour. Most theories concerning the evolution of specifically human intelligence have focused either on economic problems or sexual selection mechanisms, both of which apply more to men than women. Yet while there is evidence for men having a slightly higher average IQ, the sexual dimorphism of intelligence is not obvious (except at unusually high and low levels). However, a more female-specific selection mechanism concerns the distinctive maternal role in child care during the offspring’s early years. It has been reported that increasing maternal intelligence is associated with reducing child mortality. This would lead to a greater level of reproductive success for intelligent women, and since intelligence is substantially heritable, this is a plausible mechanism by which natural selection might tend to increase female intelligence in humans. Any effect of maternal intelligence on improving child survival would likely be amplified by assortative mating for IQ by which people tend to marry others of similar intelligence – combining female maternal and male economic or sexual selection factors. Furthermore, since general intelligence seems to have the functional attribute of general purpose problem-solving and more rapid learning, the advantages of maternal IQ are likely to be greater as the environment for child-rearing is more different from the African hunter-gatherer society and savannah environment in which ancestral humans probably evolved. However, the effect of maternal IQ on child mortality would probably only be of major evolutionary significance in environments where childhood mortality rates were high. The modern situation is that population growth is determined mostly by birth rates; so in modern conditions, maternal intelligence may no longer have a significant effect on reproductive success; the effect of female IQ on reproductive success is often negative. Nonetheless, in the past it is plausible that the link between maternal IQ and child survival constituted a strong selection pressure acting specifically on women.

Do post-disaster public health interventions impede malaria eradication?

Philip Weinstein, James Goff, Chris Skelly — 2009-11-09

Summary: In this paper, we hypothesise that public health interventions aimed at controlling post-disaster malaria epidemics may in fact impede malaria eradication efforts in the longer term. A major factor hampering malaria eradication efforts is the development of resistance to antimalarial drugs in the Plasmodium parasite. Following natural disasters such as flooding, public health responses includes a massive influx of antimalarial drugs that may facilitate the development of resistance. Resistance is common in areas with frequent natural disasters, and if such an association could be shown to be generalisable and causative, there may be direct implications for the way that future disaster-related malaria risks are managed. Because the frequency and severity of climate-associated disasters is likely to increase with global warming, it is timely to study the possibility that well intentioned public health action may in fact exacerbate the disease burden from the very parasites that it sets out to control.

Science, dullness and truth: A rejoinder

Sérgio B. Volchan — 2009-11-30

Summary: In a recent series of polemical editorials in this journal, a scathing and much needed criticism is made of many aspects of current scientific mores, detecting some worrying dysfunctions which threaten the integrity of the whole scientific enterprise. Although the tone is a bit hyperbolic, many important issues are addressed, such as honesty in research, the centrality of truth in science, the role of creativity, just to cite a few. Though agreeing with the overall diagnosis, the discussion still suffers from a lack of a clear and systemic view of science, from which a more precise analysis could be carried out. The presentation is also predicated on a too strong adherence to some popular notions of scientific progress and a somewhat romantic notion of genius. In this paper we address these shortcomings with the aim of contributing to a better understanding of this timely discussion. Though conceding that major structural, historical and cultural shifts might have caused irreversible changes on the way science now evolves, we make some suggestions to counter this trend. These include, among others, the need for an honest and careful dealing with the media and public, to prize and abide by the ethos of science and its underlying values, to cultivate an exact philosophy and to insist that disinterested curiosity and the desire to understand the world are the vital motivations of science.

Apnea: A new training method in sport?

Frédéric Lemaître, Fabrice Joulia, Didier Chollet — 2009-10-22

Summary: The physiological responses to apnea training exhibited by elite breath-hold divers may contribute to improving sports performance. Breath-hold divers have shown reduced blood acidosis, oxidative stress and basal metabolic rate, and increased hematocrit, erythropoietin concentration, hemoglobin mass and lung volumes. We hypothesise that these adaptations contributed to long apnea durations and improve performance. These results suggest that apnea training may be an effective alternative to hypobaric or normobaric hypoxia to increase aerobic and/or anaerobic performance.

Breathing strategy to preserve exercising cardiac function in patients with heart failure

S. Lalande, B.D. Johnson — 2009-10-05

Summary: The heart and lungs are closely linked as they lie in series, share a common surface area and compete for space within the thoracic cavity. The heart and lungs are exposed to the similar changes in intrathoracic pressure, and reflexes within one organ can influence the other (i.e. vagal influence of lung inflation on heart rate). In patients with heart failure, these cardiopulmonary interactions may be altered due to decreased lung and left ventricular compliance, increased cardiac size, high cardiac filling pressure and altered receptor sensitivity to neural activation. Exercise further affects the cardiopulmonary interactions by stimulating an increase in the depth and frequency of breathing which accentuates the fluctuations in intrathoracic pressure, and by requiring large increases in stroke volume and heart rate in order to respond to the increased metabolic demand. Previous work from our laboratory suggested that patients with heart failure avoid high lung volumes during exercise, often at the expense of unnecessary large positive expiratory intrathoracic pressures resulting in significant wasted effort. Moreover, we also observed that voluntarily increases in lung volume in patients with heart failure induced a mild relative bradycardia, a response not observed in similar aged healthy individuals. Thus, we hypothesized that the rapid shallow low lung volume breathing, in combination with positive expiratory intrathoracic pressure, often adopted by patients with heart failure during exercise is an attempt to preserve, or even enhance, the cardiac response to exercise.

Oath-taking: A divine prescription for health-related behaviour change?

Stephen A. Buetow, Peter Adams — 2010-01-07

Summary: 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.

Exposure of the eyes to near-horizon sunshine may be a trigger for multiple sclerosis

William Bains — 2009-11-11

Abstract: Background: Multiple sclerosis (MS) incidence is higher among those who live at high latitudes before adulthood. This is usually attributed to lower levels of Vitamin D, caused by lower UV levels. However direct damage of the optic nerve by near-horizon sunshine is a possible alternative explanation.Method: Historical reports of MS from European populations in well characterised geographic locations where the numbers of cases and the target population were reported were collected, and the distribution of MS prevalence was calculated. Total UV, visible and infra-red exposure over a year as a function of latitude, and the fraction of time the Sun spends near the horizon as a function of latitude were calculated from geometric considerations, and were compared with the observed prevalence of MS.Results: The observed distribution of MS prevalence fits well with the relative time that the Sun spends within 3° and 8° of the horizon, as calculated geometrically and summed over a year. Correlation with total UV exposure (without consideration of weather or shielding by clothing or buildings) was less satisfactory.Conclusion: I suggest that direct solar damage to the optic nerve may be a trigger for MS.

Lipid autoreactivity in multiple sclerosis

M.M. Blewett — 2009-11-23

Summary: Lipids comprise over 70% of the myelin sheath but have been largely underinvestigated as autoantigens in multiple sclerosis (MS). This paper cites evidence for the involvement of lipid autoreactivity in MS and details how self lipid cross-reactivity may also contribute to the development of type 1 diabetes and autoimmune thyroid disorders (both of which have been associated with MS). A further analysis of myelin chemistry suggests several mechanisms by which infection may contribute to etiology and trigger lipid autoreactivity via molecular mimicry. This analysis may aid the development of new therapies for autoimmune diseases.

The innateness of coronary artery: Vasa vasorum

Dong-Gyun Han — 2009-11-09

Summary: Because heart originates from primitive endocardial tube (ventral aorta) embryologically, coronary arteries that supply this tube can be thought as “cardiac vasa vasorum” like arterial vasa vasorum that supply peripheral arteries. Coronary arteries have vasodilative reaction to noradrenaline, different from the most arteries that show vasoconstriction. This phenomenon is similar to vasa vasorum that are insensitive to noradrenaline and has its own vasoregulation. Coronary arteries can supply blood from epicardium, myocardium to endocardium under normal physiological conditions. But heart having a significant myocardial hypertrophy can be susceptible to subendocardial ischemia because the metabolic demands of hypertrophic myocardium cannot be met by a parallel increase of coronary myocardial capillaries. This peculiar characteristic of coronary arteries is similar to vasa vasorum that give rise to ischemic necrosis of media of the host vessel under chronic hypertension. Inherency of coronary arteries is the same endarteries as vasa vasorum. Coronary arteries have many smooth muscle fibers than elastic fibers in media, which protect them to collapse during systole to some extent. This feature also is similar to vasa vasorum. The above similarities support the hypothesis that coronary arteries are a kind of vasa vasorum.

Altered functional balance of Gfi-1 and Gfi-1b as an alternative cause of reticular dysgenesis?

2009-11-09

Summary: Reticular dysgenesis (RD) is a rare form of severe combined immunodeficiency (SCID). The underlying genetic defect for most cases of RD was recently identified in the gene encoding adenylate kinase 2 (AK2). However, rare patients with RD and no mutations in AK2 exist, suggesting that mutations in other genes may also cause RD. Although rare, RD has a devastating presentation involving severe neutropenia and T cell lymphopenia, in addition to life non-threatening, but still disabling sensori-neural deafness. An identical phenotype is observed in mice deficient for growth factor independence-1 (Gfi-1) or transgenic for Gfi-1b, related nucleoproteins with opposing, antagonizing roles in development. We hypothesize that a genetically based, altered functional balance between these two factors may be an alternative cause of RD.

Ultrasonic sonoporation can enhance the prostate permeability

Yongliang Liu, Zheng Liu, Tao Li, Gang Ye — 2009-11-09

Summary: As possible existence of the blood–prostate barrier and decreased prostate permeability due to inflammation, it is difficult to form an effective drug concentration in prostate tissues, which influences medication efficacy. This is one of principal reasons why it is difficult to treat prostate diseases including prostatitis etc. How to increase the permeability of drugs into prostate is inevitable to become an issue concerned by clinical research. Ultrasonic sonoporation may increase permeability of cells and tissues, so we propose a hypothesis that sonoporation induced by ultrasonic cavitation may increase the permeability of prostate tissues. This may be a non-invasive physical treatment method, and it has better safety and validity, and higher clinical value.

Possible involvement of ghrelin on pain threshold in obesity

Ensari Guneli, Mukaddes Gumustekin, Mehmet Ates — 2009-11-02

Summary: Pain threshold (or perception) can increase or decrease according to some factors like gender, depression or individual differences. Also, previous studies showed that pain threshold can change in obesity but, these studies on the effects of obesity on pain threshold have given controversial results. In the obese people who were exposed to pain stimulasyon to determined pain threshold, an increased pain threshold was observed. Contrarily, in the studies using electrophysiological test had lower pain threshold, which indicates a reverse correlation between degree of overweight and the threshold of the nociceptive reflex. These studies indicate possible interrelationships between the endogenous opioids, nociception and obesity or eating behavior. Nevertheless, its mechanism is still unclear. The endocrine changes that play an important role in obesity can lead an increase or decrease in pain threshold. There are a few researches about these hormonal factors which are related to pain pathways, that they are nociceptive (like leptin) or antinociceptive effect (like ghrelin, orexin A and B). Ghrelin is one of the hormones which is related to obesity. There are studies which prove the relationship between this hormone and the systems that play a role in pain modulation in the brain. However, there is no previous knowledge about the effects of ghrelin on pain threshold in obesity. But, many strong evidence are present to hypothesise that ghrelin may have effects on pain threshold. Obesity and fasting are the two main situations in which ghrelin secretion is mostly modified. Circulating ghrelin levels negatively correlate with BMI, meaning increased ghrelin secretion during fasting, malnutrition, cachexia, and in anorexia nervosa and reduced ghrelin secretion in obesity. Therefore, we have the opinion that ghrelin play an important role in obesity–pain relationship and/or regulate other systems that are related to pain pathway. Based on the above analyses, we propose a hypothesis that the diminution of the susceptibility to pain in lean subjects/animals may be induced by the increase in endogenous ghrelin activity, or increased of the susceptibility to pain in obese subject/animals may be induced by the decrease in endogenous ghrelin activity.

Does gastroesophageal reflux contribute to development of acquired nasolacrimal duct obstruction?

Naser Owji, Seyed Mohammad Bagher Abtahi — 2009-11-16

Summary: Primary acquired nasolacrimal duct obstruction results from inflammation of unknown cause that eventually leads to fibrosis and occlusion. The nasolacrimal duct is within the medial wall of maxillary sinus and open into the nasal cavity. It may be affected by gasteroesophageal reflux disease (GERD) by the possible direct noxious effect of the refluxate on the nasal mucosal cavity surrounding of the nasolacrimal duct opening at the inferior meatous and ascending of inflammation to the mucosa of the duct may leads to chronic inflammation and fibrosis. In addition to, the GERD may induce autonomic nervous system hyperactivity resulting in hyperemia of venous plexus surrounding nasolacrimal duct leading to secondary mucosal edema of nasolacrimal duct and dacryostenosis.

Water pipe smoking and human oral cancers

2009-11-05

Summary: While cigarette smoking is recognized as an important risk factor in human oral cancers, the effect of water pipe smoking (WPS) on these cancers is not known. WPS is very common in the young adult population, especially in the Middle East, and has been associated with several respiratory problems. However, to date, there have been no studies examining the association between WPS and the progression of human oral cancers. Currently, the role of WPS in human oral cancers remains uncertain because of the limited number of investigations. This raises the question of whether WPS plays a significant role in the development of human oral carcinomas. In this paper, we propose the hypothesis that human oral normal epithelial cells are vulnerable to persistent WPS; moreover, WPS could play an important role in the initiation of a neoplastic transformation of human normal oral epithelial cells. Therefore, we believe that an international collaboration of epidemiological and clinical studies as well as cellular and molecular biology investigations is necessary to answer this important question.

How to protect the heart in septic shock: A hypothesis on the pathophysiology and treatment of septic heart failure

2009-11-04

Summary: Heart failure is a well-recognized manifestation of organ failure in sepsis and septic shock. The pathophysiology of septic heart failure is complex and currently believed to involve several mechanisms. So far, the contributory role of high plasma catecholamine levels has not been investigated. In this manuscript, we present a hypothesis suggesting that excessive catecholamine production and exogenous administration of catecholamines may relevantly contribute to the development of heart failure and cardiovascular collapse in patients suffering from septic shock. Substantially elevated plasma catecholamine levels were measured during critical illness and sepsis or septic shock. There is a growing body of clinical and experimental evidence demonstrating that high catecholamine plasma levels exert direct toxic effects on the heart. The pathophysiologic mechanisms involved in catecholamine-induced cardiomyocyte toxicity may involve a combination of inflammation, oxidative stress, and abnormal calcium handling resulting in myocardial stunning, apoptosis and necrosis. Clinical signs of catecholamine-induced heart failure can present with a wide range of symptoms reaching from subtle histological changes with preserved myocardial pump function to severe heart failure exhibiting a distinctive echocardiographic pattern which became known as “Takotsubo”-like cardiomyopathy or the left ventricular apical ballooning syndrome. In a medical intensive care unit patient population, presence of sepsis was the only variable associated with the development of left ventricular apical ballooning. Since several therapeutic interventions influence catecholamine plasma levels in septic shock patients, treatment strategies aiming at the reduction of endogenous or exogenous catecholamine exposure may protect the heart during septic shock and could facilitate patient survival.

Environmental risk factors for temporal lobe epilepsy – Is prenatal exposure to the marine algal neurotoxin domoic acid a potentially preventable cause?

Ian Stewart — 2009-11-19

Summary: Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is one of the more common forms of chronic epilepsy. Its aetiology is unknown, though an early developmental insult is thought by some to be an important trigger. There is not a strong genetic predisposition; gene–environment interactions are more significant considerations. Environmental risk factors for TLE-HS are under-researched. Domoic acid (DA) is an environmental neurotoxin of algal origin that can contaminate marine food webs. DA can cross the placenta, is significantly more toxic to the developing brain compared to the adult brain, and has affected humans and marine wildlife through mass poisonings. DA coincidentally has a decades-long history of use as a chemical model of temporal lobe epilepsy, along with its close structural analogue kainic acid (also of algal origin). The principal hypothesis presented here is that dietary exposure to doses of DA that are sub-clinical in pregnant women may be sufficient to damage the foetal hippocampus and initiate epileptogenesis. The hypothesis could be tested both experimentally by in vivo proof-of-concept animal studies that expand on current knowledge of prenatal susceptibility to DA neurotoxicity, and by epidemiological investigations directed towards dietary exposure to marine food products. If only a small proportion of the attributable risk for TLE-HS is found to be due to gestational exposure to DA, the public health implications would still be of great significance, as this would represent a potentially preventable exposure.Other potent neurotoxins are produced by marine microalgae and freshwater cyanobacteria. These structurally and mechanistically diverse toxins can also contaminate water supplies, seafood and shellfish. Several operate by modulating ion channels, so may also be of interest to epilepsy researchers.DA is also the subject of preliminary scrutiny in strandings involving odontocete cetaceans. The implications of such work are discussed here.

Zinc lozenges as cure for the common cold – A review and hypothesis

George A. Eby — 2009-11-11

Summary: A 7-day reduction in duration of common colds was shown by Eby et al. in 1984 using 23mg zinc gluconate throat lozenges. Over the following 25years, 14 double-blind, placebo-controlled, randomized clinical trials produced widely differing results with about one-half showing success and the remainder showing failure. Positively charged, ionic zinc (iZn), but not bound zinc, is strongly astringent, antirhinoviral, increases interferon-gamma (IFN-γ) 10-fold, inhibits intercellular adhesion molecule-1 (ICAM-1) and inhibits the release of vasoactive ingredients from mast cell granules. Solution equilibrium chemistry analytical techniques showed lozenge iZn fraction varying from 0% to 100% of total lozenge zinc between trials, with zinc acetate (ZA) releasing 100% iZn, zinc gluconate (ZG) releasing 72% iZn and other zinc compounds releasing much less or none at physiologic pH 7.4. Since only iZn has in vitro benefits, iZn variations are hypothesized to have produced the widely varying clinical results. In support of the iZn hypothesis, lozenge iZn and total daily iZn in trials were found highly correlated with reductions in common cold durations with statistical significance for mean duration (P<0.001) and median duration (P<0.004), while total zinc (iZn plus bound) showed no correlation with changes in duration. Duration reductions (mean 0days, median 0.43days) for multi-ligand ZG and ZA lozenges differed significantly from duration reductions (mean 3.37days, median 2.9days) for single ligand ZA and ZG lozenges (P<0.001) showing that additive ligands as flavor-masks damaged or eliminated efficacy. Five of 6 trials with lozenges whose zinc compositions had a first stability constant of 1.7 or less succeeded, while only 2 of 9 trials of lozenges with higher stability succeeded (P<0.02). From the strong, multiple statistical relationships found, it is inferred that iZn is the active ingredient in zinc lozenges for colds, as it is in vitro against rhinoviruses, and that solution chemistry analytical techniques used at physiological pH are correct means for lozenge iZn analysis. Zinc lozenges slowly dissolving in the mouth over a 20–30min period releasing adequate iZn (⩾18mg) used each 2h are hypothesized to shorten common colds by 6–7days, which is a cure for the common cold. Due to inadequate lozenge iZn very few of more than 40 different brands of zinc lozenges on the US market are expected to have any effect on the duration or severity of common colds.

Methanol: A chemical Trojan horse as the root of the inscrutable U

Woodrow C. Monte — 2009-11-06

Summary: Until 200years ago, methanol was an extremely rare component of the human diet and is still rarely consumed in contemporary hunter and gatherer cultures. With the invention of canning in the 1800s, canned and bottled fruits and vegetables, whose methanol content greatly exceeds that of their fresh counterparts, became far more prevalent. The recent dietary introduction of aspartame, an artificial sweetener 11% methanol by weight, has also greatly increased methanol consumption. Moreover, methanol is a major component of cigarette smoke, known to be a causative agent of many diseases of civilization (DOC). Conversion to formaldehyde in organs other than the liver is the principal means by which methanol may cause disease. The known sites of class I alcohol dehydrogenase (ADH I), the only human enzyme capable of metabolizing methanol to formaldehyde, correspond to the sites of origin for many DOC. Variability in sensitivity to exogenous methanol consumption may be accounted for in part by the presence of aldehyde dehydrogenase sufficient to reduce the toxic effect of formaldehyde production in tissue through its conversion to the much less toxic formic acid. The consumption of small amounts of ethanol, which acts as a competitive inhibitor of methanol’s conversion to formaldehyde by ADH I, may afford some individuals protection from DOC.

The syncytiopathy hypothesis of depression: Downregulation of glial connexins may protract synaptic information processing and cause memory impairment

Bernhard J. Mitterauer — 2009-11-09

Summary: Astrocytes interconnected via gap junctions build an astrocytic syncytium. Gap junctions are composed of connexin proteins that are activated by substances of the neuronal system. It is hypothesized that disorders in the astrocytic syncytium may represent a main component of the pathophysiology of depression, called syncytiopathy. If the expression of connexin proteins is downregulated, a compensatory upregulation of astrocytic receptors may occur leading to an overproduction of these. Such an excess of astrocytic receptors exerts an imbalance of synaptic neurotransmission, because of a relative lack of neurotransmitters for the occupancy of astrocytic receptors so that neurotransmission is protracted. This delay of information processing may be responsible for the main symptoms of depression. In addition, the downregulation of connexin expression may also lead to an incomplete syncytium formation, responsible for memory impairment in severe depression. Finally, general approaches for testing the hypothesis are outlined.

An autologous falciparum vaccine using the erythrocyte’s band 3 molecule

James Randall Kennedy — 2009-11-19

Summary: Protection against the serious complications of falciparum malaria is provided to people with the minor forms of hematological conditions such as sickle cell disease and thalassemia and as a result natural selection has increased their incidence in malaria endemic areas. The explanation for this has thus far not been determined but experimental evidence that is now available suggest an explanation that also has therapeutic implications.The hypothesis presented suggests that the erythrocytes of these blood disorders experience premature senescence and are then eliminated by the same process that normally disposes of senescent erythrocytes. Erythrocytes express approximately one million widely dispersed band 3 molecules on their surface but when these erythrocytes age they form band 3 clusters that are recognized by the immune system which results in their elimination. In addition to senescent erythrocytes, both sickle and falciparum infected erythrocytes also display these clusters suggesting that band 3 antibodies contribute to their erythrocytes removal. Supporting band 3’s involvement in falciparum erythrocyte elimination are the facts that band 3 specific antibodies are elevated in falciparum endemic areas and the documentation that the falciparum erythrocytes displaying these clusters are rapidly phagocytized.Both sickle and falciparum infected erythrocytes adhere to endothelium and band 3 antibodies and adhesive band 3 peptides block this adhesion. This proves that the band 3 molecule is responsible for at least some of the endothelial adhesion and implies that band 3 antibodies are active in eliminating falciparum infected erythrocytes. It is proposed that the band 3 peptides could be used to develop a vaccine to reduce the lethality of falciparum infections. A conjugate vaccine using these peptides in early infancy may allow those infants to survive a falciparum infection and develop comprehensive natural immunity to the local endemic parasite.

Bioresonance hypothesis: A new mechanism on the pathogenesis of trigeminal neuralgia

De-ze Jia, Gang Li — 2009-11-09

Summary: Trigeminal neuralgia (TN) is an uncommon disorder characterized by recurrent attacks of lancinating pain in the trigeminal nerve distribution. To date, the precise mechanism for TN remains unclear. Among a variety of causes of TN, the microvascular compression (MVC) hypothesis is the most popular one, but controversies still focus on the origin and pathogenesis of the disorder. A number of clinical phenomena still cannot be well explained. We propose a new hypothesis on the pathogenesis of TN – bioresonance. The bioresonance hypothesis states that when the vibration frequency of a structure surrounding the trigeminal nerve becomes close to its natural frequency, the resonance of the trigeminal nerve occurs. The bioresonance can damage trigeminal nerve fibers and lead to the abnormal transmission of the impulse, which may finally result in facial pain. Under the guidance of the bioresonance hypothesis, we hope to explore more non-invasive methods to treat or even cure TN.

Facial paralysis: A critical review of accepted explanation

Karthik Mahadevappa, Ariana Vora, Andrew Graham, Shanker Nesathurai — 2009-11-12

Summary: Historically, paralysis of facial muscles has been divided into “upper motor neuron injury” and “lower motor neuron injury”. Patients who experience a stroke in the cortex or internal capsule have UMN injury and cannot purse their lips or smile on command. They are, however, able to wrinkle their forehead, raise their eyebrows, and completely close their eyes. Patients with LMN injury, in addition to the aforementioned impairments cannot raise their eyebrows. The classical explanations for these clinical findings are that the upper facial muscles receive bilateral innervation from the cerebral cortex and the lower facial muscles receive only unilateral innervation from the contralateral cerebral cortex. However, a review of the basic science literature indicates that commonly accepted explanations and the pattern of cortical projections are not consistent with anatomical studies. Studies in monkeys demonstrate that both the upper facial nucleus and the lower facial nucleus receive bilateral cortical projections. As well, there is no direct anatomical evidence in human beings that the facial nucleus (upper or lower) receives any innervation from the cortex.

The potential roles of cell migration and extra-cellular matrix interactions in Dupuytren’s disease progression and recurrence

Linda Vi, Bing Siang Gan, David B. O’Gorman — 2009-11-06

Summary: Dupuytren’s disease is a pathological condition of the palmar fascia characterized by the formation of contractile disease cords that result in permanent finger contracture. This condition is believed to progress from a myofibroblast-rich nodule in the early clinical stages of the disease to a contractile disease cord spanning a portion of the fascia, leading to contracture of one or more digits. The mechanism(s) by which this disease progresses from a nodule to a collagenous disease cord are poorly understood. Here, we discuss two possible models of disease progression. Firstly, disease progression might be mediated by the proliferation and outward migration of disease cells from within the nodule to populate the adjacent palmar fascia, resulting in a disease cord containing contractile cells derived from the nodule itself. Alternatively, nodular cells may secrete disease-associated factors into the surrounding extra-cellular matrix, thereby altering its composition and triggering quiescent, phenotypically normal cells in the adjacent palmar fascia to take on a proliferative and contractile phenotype. Based on the available evidence and the current state of knowledge of myofibroblast biology, we hypothesize that extra-cellular matrix interactions resulting in conversion of adjacent palmar fascia cells to a disease phenotype is more likely than cell migration from the nodule. Understanding the mechanisms of Dupuytren’s disease progression will assist in the development of effective therapeutic interventions to address the high clinical recurrence rate of this condition.

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS)

2009-11-16

Summary: Using fMRI, Menon and Levitin clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author’s suggested that they found the first “reward gene” located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein ). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual’s D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction.

Increased vagal airway tone in fatal asthma

Nestor A. Molfino — 2009-11-11

Summary: Slow-onset asthma deaths are characterized by eosinophilic airway infiltrates and thickening of the basal membrane, while rapid-onset asthma deaths are associated with fewer airway inflammatory changes, suggesting that bronchospasm may be responsible for the latter events.Airway tone is primarily controlled by the autonomous nervous system and can be pharmacologically modified. Therapies that stimulate the sympathetic β2 adrenoreceptor or inhibit the muscarinic receptor signal transduction induce bronchodilation. Parasympathetic (vagal) airway tone is enhanced in some asthmatics due to a number of stimuli, while in others it is constitutively heightened. Mainstream asthma therapy, however, only consists of corticosteroids and β2 agonists, not addressing this aspect.In this publication, I propose that increased vagal airway tone resulting in overwhelming bronchoconstriction and mucus plugging could be responsible for the near-fatal or fatal events observed in a number of asthmatics, in spite of their adequate treatment with standard therapies. On the basis of this hypothesis, I recommend that vagal airway tone be assessed in all patients with asthma, particularly in those with a history of near-fatal events. If the airway tone is increased, individuals should be treated with a triple combination of long-acting β2 agonists, inhaled steroids, and inhaled anticholinergics to prevent vagally mediated fatal events.

Modic type III lesions and Schmorl’s nodes are the same pathological changes?

2009-10-30

Summary: Introduction: Degenerative disc disease (DDD) is a major health problem worldwide. Both Modic lesions and Schmorl’s nodes are considered to correlate with DDD such as low back pain. Modic lesions are the changes of degenerative vertebral endplate and adjacent bone marrow observed on magnetic resonance imaging and are divided into three types. Modic type III lesions are thought to represent extensive subchondral bone sclerosis within the bone marrow of adjacent endplate. The pathological performance of Schmorl’s nodes is cystic lesions around indistinct sclerotic margins and beneath the cartilaginous endplate. Coincidently, there are many similarities between Modic type III lesions and Schmorl’s nodes including pathological appearances, pathogenetic location and related diseases.Hypothesis: We hypothesize that Modic type III lesions and Schmorl’s nodes are the same pathological changes, and Modic type III lesions may be the quiescent or incipient pathology phrase of Schmorl’s nodes. The clinical symptoms of DDD are also accompanied by emergence of these pathological changes.Testing: A longitudinal study could be used to test this hypothesis. We could measure and analyze whether Modic type III lesions have increased in size or evolved into Schmorl’s nodes as time goes on.Significance: This hypothesis explains the possible pathologic process of Modic type III lesions and Schmorl’s nodes. If the hypothesis were conformed, Modic type III lesions and Schmorl’s nodes will be rediscovered, which provides the new basis for the clinical treatment of DDD. In additions, this hypothesis also has crucial significances for the classification of Modic lesions.

Mechanism of postsystolic contraction and of multiple myocardial contractions during each single cardiac cycle

Goran Milicevic, Zeljka Gavranovic — 2009-10-19

Summary: Postsystolic contraction and other forms of phenomenon of multiple myocardial contractions are characterised by secondary or even tertiary contraction that follow regular one during each single cardiac cycle, triggered by a single sinus node impulse. These additional contractions occur at circumscribed areas of different myocardial regions, in many cardiac patients and healthy subjects. The mechanism of onset and perpetuation of the phenomenon is unknown.Our hypothesis is based on idea of existence of accessory, dead-end, slow-conducting, low-voltage pathways, derived from atrioventricular node or the bundle of His. Secondary contraction could occur in the following way: sinus node impulse divides into two pathways, the main atrioventricular conduction axis that depolarises the entire myocardium and the accessory pathway that depolarises again target region of myocardium where it ends blindly. Slow conduction through such accessory pathway enables a delay of secondary depolarisation needed to overcome the absolute refractory period of the myocardium following the ‘regular’ contraction. Electrocardiographic signal of a postsystolic potential is not visible at body surface because the pathway is low-voltage.The purpose of multiple myocardial contractions could be, although rarely, completing of current ejection, but more often, in the case of postsystolic contraction it could be a postsystolic tightening of the myocardium which would influence the regular contraction of the next cardiac cycle with the aim to reverse or prevent ventricular remodelling. In those circumstances, regional pathological function of ventricles (deformation of remodelled ventricle during the contraction, maybe during the relaxation as well, and furthermore asynchronous, but otherwise suboptimal contraction as well) would be detected by hypothetical myocardial receptors for strain and stretch, which would activate and sustain the function of accessory dead-end pathways by a neuroendocrine feed-back mechanism.The hypothesis is supported by anatomical findings of dead-end tracts originating from atrioventricular node and disappearing in the muscular part of interventricular septum. Extensive differences in the velocity of impulse propagation, which exist along the conduction system, allow the possibility that the accessory pathways are of slow-conducting properties. Low-amplitude signal of such pathways was confirmed by our intracardiac electrophysiological recording. Feed-back mechanism based on myocardial receptors for strain and stretch is a relevant option, keeping in mind well-known receptor based regulatory mechanisms across the cardiovascular system.The phenomenon is easily detectible, but hard to explain, so even considering herein presented hypothesis implies a need for change of settled perception of myocardial kinetics, and of physiological and pathological function of conducting system.

Gold, coal and oil

Sergio U. Dani — 2009-10-21

Summary: Jared Diamond has hypothesized that guns, germs and steel account for the fate of human societies. Here I propose an extension of Diamond’s hypothesis and put it in other terms and dimensions: gold, coal and oil account not only for the fate of human societies but also for the fate of mankind through the bodily accumulation of anthropogenic arsenic, an invisible weapon of mass extinction and evolutionary change. The background is clear; arsenic species fulfill seven criteria for a weapon of mass extinction and evolutionary change: (i) bioavailability to all living organisms; (ii) imperceptibility; (iii) acute toxicity; (iv) bioaccumulation and chronic toxicity; (v) adverse impact on reproductive fitness and reproductive outcomes and early-age development and growth in a wide range of microbial, plant and animal species including man; (vi) widespread geographical distribution, mobility and ecological persistence on a centennial to millennial basis and (vii) availability in necessary and sufficient amounts to exert evolutionarily meaningful effects. The proof is becoming increasingly feasible as human exploitation of gold, coal and oil deposits cause sustainable rises of arsenic concentrations in the biosphere. Paradoxically, humans are among the least arsenic-resistant organisms because humans are long-lived, encephalized and complex social metazoans. An arsenic accumulation model is presented here to describe how arsenic accumulates in the human body with increasing age and at different provisionally safe exposure levels. Arsenic accumulates in the human body even at daily exposure levels which are within the lowest possible WHO provisional tolerance limits, yielding bodily arsenic concentrations which are above WHO provisional limits. Ongoing consequences of global scale arsenic poisoning of mankind include age-specific rises in morbidity and mortality followed by adaptive changes. The potential rise of successful forms of inborn resistance to arsenic in humans will make it certain that a number of other hardly won, nicely balanced human-specific adaptednesses will decline. These include a decline of encephalization and life-span, and consequentially intelligence and longevity. These changes are likely to have far-reaching impacts on biological and cultural evolution of mankind. The only efficient way of reducing chronic global exposure to arsenic and avoiding further human losses is the inactivation of important sources of anthropogenic arsenic such as hard rock mining and burning of fossil fuels.

Immunization via the anal mucosa and adjacent skin to protect against respiratory virus infections and allergic rhinitis: A hypothesis

J. Lloyd Spencer — 2009-10-23

Summary: Exposure of the immune system to environmental antigens and infectious agents by way of the anal mucosa and perianal skin could play an important role in protecting the respiratory tract against allergic conditions and virus infections. Hygienic practices that have reduced exposure of the immune system to such agents include the use of modern toiletry, disposable diapers and clothes dryers. Historically, the anal region was cleansed following defecation with natural materials that would have brought antigens and infectious agents from the environment into frequent contact with the perianal skin and anal mucosa. This practice was a crude form of transcutaneous and mucosal vaccination, whereby antigenic agents that are topically applied to skin or mucosal surfaces, penetrate into the tissues and stimulate immune responses that can extend to the respiratory tract. Furthermore, until the 1960s, diapers and other cloth items were often dried outdoors where they would have collected environmental antigens that, when applied to the body, could have made contact with the immune system in the skin. Herein, it is hypothesized that prevention of allergic rhinitis and possibly other disorders involving the immune system could be achieved by the daily application of preparations composed of environmental antigens and infectious agents to the anal mucosa and adjacent skin. In support of the proposal, immunotherapy for allergic rhinitis currently involves administration of specific allergens to subcutaneous tissue or to the sublingual mucosa. It is considered that superior protection could be achieved by applying the allergens to the anal region where they would target the immune system in both mucosal tissue and adjacent skin. It is also hypothesized that respiratory viruses applied to the anal region would infect tissues at that site and induce immune responses that would protect the respiratory tract against the common cold and influenza. This approach is supported by evidence that orally administered adenovirus vaccine can induce an infection in the intestinal mucosa that stimulates immunity to protect the respiratory tract. Although other respiratory viruses are unlikely to survive passage through the intestinal tract, rhinovirus has on rare occasion been detected in stool specimens, suggesting the possibility of an infection at the terminal end of the digestive tract. Respiratory syncytial viruses and influenza viruses are amenable to modification by reverse genetics and other techniques and it is expected that natural or modified viruses applied to the anal region could serve to immunize the respiratory tract.

Do monoamine-synthesizing cells constitute a complex network of oxygen sensors?

K. Ondicova, B. Mravec — 2009-10-21

Summary: Oxygen represents an essential molecule for organisms. Because of this, sophisticated systems of sensors have evolved to monitor oxygenation of tissues. We propose that monoamine-synthesizing cells represent an important part of this system. It is well known that the carotid body, which contains chromaffin cells, serves as a chemical sensor of blood oxygenation. Similarly, the activity of adrenal medullary chromaffin cells is increased during hypoxia. Moreover, neurons located in the central nervous system containing catecholamines, serotonin, and histamine are also sensitive to hypoxia. On the basis of this common sensitivity of monoamine-synthesizing cells to changes in oxygenation we propose the hypothesis that these cells constitute a widely distributed network of sensors that monitor oxygen levels. The role of monoamine-synthesizing cells in monitoring tissue oxygen supply during both physiological and pathological conditions is also discussed.

Possible key role of immune system in Schmorl’s nodes

Ning Zhang, Fang-Cai Li, Yi-Jiang Huang, Chong Teng, Wei-Shan Chen — 2009-10-26

Summary: Schmorl’s nodes (SNs) are common abnormalities in the human spine, which represent herniation of the nucleus pulposus of the intervertebral disc into the adjacent cartilaginous endplate of the vertebra. However, the principle mechanism of SNs is still not fully understood. And the relationship of SNs in the spine and their clinical significance as a source of low back pain in the general population remains unknown. It is therefore important to get better understanding of this. Here, we review the clinical and experiment evidence on inducing of the SNs and correlative back pain, and propose a possible mechanism. Studies showed that once the nucleus pulposus enters into vascular tissue, the immune system could recognize it as a foreign body, and induces the immunological reaction. Then, there would be osteoimmunology action, a crosstalk between the immune system and bone, leading to bone loss by dysregulating T-lymphocyte function, and resulting to the bone absorption. Furthermore, the cytokines are involved in the development of immunological reactions and could be responsible for the significant pathology of symptomatic SNs. Given the above background, we hypothesize that immune system could be a key role in SNs and result in the pain.

A unifying hypothesis of schizophrenia: Abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction

2009-10-19

Summary: We propose a unifying hypothesis of schizophrenia to help reconcile findings from many different disciplines. This hypothesis proposes that schizophrenia often involves pre- or perinatal exposure to adverse factors that produce a latent immune vulnerability. When this vulnerability is manifested, beginning around puberty with changes in immune function and involution of the thymus, individuals become more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Our hypothesis suggests theoretical bridges between different lines of evidence on schizophrenia and offers explanations for many puzzling findings about schizophrenia. For example, the hypothesis helps account for why schizophrenia patients tend to have had increased exposure to neurotropic infections, but most individuals with such exposure do not develop schizophrenia, and why prenatal hardships increase risk for schizophrenia, but the onset of symptoms typically does not occur until after puberty. The hypothesis also explains another paradox: lower socioeconomic status and poor prenatal care increase risk for schizophrenia at the same geographic site, but international comparisons indicate that countries with higher per capita incomes and better prenatal care actually tend to have higher schizophrenia prevalences. As the hypothesis predicts, (1) prenatal adversity, which increases risk for schizophrenia, also impairs post-pubertal immune competence, (2) schizophrenia patients experience elevated morbidity from infectious and auto-immune diseases, (3) genetic and environmental risk factors for schizophrenia increase vulnerability to these diseases, (4) factors that exacerbate schizophrenic symptoms also tend to impair immune function, (5) many anti-psychotic medications combat infection, (6) effects of early infections may not appear until after puberty, when they can produce neurologic and psychiatric symptoms, and (7) immune dysfunctions, such as imbalances of pro- and anti-inflammatory cytokines, may contribute to the onset of psychotic symptoms and the progressive loss of brain tissue in schizophrenia. The disruptive effects of prenatal adversity on the development of the immune system may often combine with adverse effects on prenatal brain development to produce schizophrenia. This paper focuses on the adverse immune system effects, because effects on the brain have been extensively discussed in neurodevelopmental theories of schizophrenia. We propose new tests of scientific predictions. We also point out potential clinical implications of the hypothesis; for example, individuals with schizophrenia may often have underlying infections or immune dysfunctions, such as imbalances in inflammatory cytokines, that contribute to the illness. This possibility could be tested experimentally – e.g., by clinical trials in which patients’ exposure to infection is reduced or immune function is normalized.

Developmental diseases and the hypothetical Master Development Program

George E. Parris — 2009-10-15

Summary: Small deletions and duplications frequently occur in the pericentromeric region of chromosomes and many of these are associated with developmental abnormalities. These developmental syndromes are conventionally attributed to abnormal expression of protein-coding genes in the affected region. A hypothesis has recently been published concerning a Master Development Program based on noncoding transcripts from these regions (Parris GE. A hypothetical Master Development Program for multi-cellular organisms: Ontogeny and phylogeny. Biosci Hypotheses 2009;2:3–12.). This paper summarizes and expands the recently published hypothesis to include it application to developmental diseases. The author proposes that development of multi-cellular organisms is guided by a Master Development Program (MDP) located primarily in the pericentromeric heterochromatin. The MDP is believed to consist of a series of Generation-Specific Control Keys (GSCK) transcribed in sequence by Ikaros family transcription factors unless the GSCKs are suppressed by Sall1-family or Dnmt3b-family proteins. The MDP is proposed to increment with each cell cycle to the next GSCK resulting in development of the clone. A clone may be programmed to split into two clones as necessary through a two-cycle mitosis processes. The transcripts of the GSCKs presumably yield noncoding nuclear messenger RNAs (nmRNAs, 8–30 nt units) that act directly (e.g., as primers for RNA polymerase II) and indirectly to regulate HOX and other high-level transcription factor and developmental genes. As envisioned, the MDP would evolve by terminal addition of new GSCKs. The new GSCKs are produced by evolutionary consolidation of retro-transcripts into pyknons that collect and evolve at the end of the pericentromeric heterochromatin and are eventually incorporated into the MDP. The retro-transcripts are though to be produced during episodic retrovirus epidemics and account for punctuated equilibrium in species evolution.

Is pituitary failure the real therapeutic target in septic shock?

Yasser Kouatli — 2009-10-23

Summary: Severe sepsis and septic shock have been part of intensivists’ major challenges since the birth of the specialty. This clinical picture is followed by the development of a multiple organ failure syndrome. Our working hypothesis today is that multiple organ failures develop due to a systemic intravascular malignant inflammatory response. This article proposes an alternative understanding of the problem based on some of the recent data and understandings of non glycemic, non insulinemic endocrine dysfunction in severe sepsis and septic shock. Our presentation of selected literature supports the presence of a decreased production and activity in steroids, thyroid hormones, growth hormone, vasopressin and prolactin in septic shock. These hormones have important and synergistic functions. The disruption of which can lead to multiple organ failure in septic shock. Developing research focusing on the broad hypothalamic and pituitary functions could improve our understanding of metabolic derangements in severe sepsis and septic shock and thus provide new therapeutic options. These new therapies based on hormonal replacement are currently available at low cost and could improve outcomes.

Metabolic syndrome: Aggression control mechanisms gone out of control

2009-10-05

Summary: An upcoming hypothesis about the evolutionary origins of metabolic syndrome is that of a ‘soldier’ to ‘diplomat’ transition in behaviour and the accompanying metabolic adaptations. Theoretical as well as empirical studies have shown that similar to the soldier and diplomat dichotomy, physically aggressive and non-aggressive strategists coexist in animal societies with negative frequency dependent selection. Although dominant individuals have a higher reproductive success obtained through means such as greater access to females, subordinate individuals have alternative means such as sneak-mating for gaining a substantial reproductive success. The alternative behavioural strategies are associated with different neurophysiologic and metabolic states. Subordinate individuals typically have low testosterone, high plasma cholesterol and glucocorticoids and elevated serotonin signalling whereas dominant ones are characterized by high testosterone, low brain serotonin and lower plasma cholesterol. Food and sex are the main natural causes of aggression. However, since aggression increases the risk of injury, aggression control is equally crucial. Therefore chronic satiety in the form of fat should induce aggression control. It is not surprising that the satiety hormone serotonin has a major role in aggression control. Further chronically elevated serotonin signalling in the hypothalamus induces peripheral insulin resistance. Meta-analysis shows that most of the anti-aggression signal molecules are pro-obesity and pro-insulin-resistance. Physical aggression is known to increase secretion of epidermal growth factor (EGF) in anticipation of injuries and EGF is important in pancreatic beta cell regeneration too. In anticipation of injuries aggression related hormones also facilitate angiogenesis and angiogenesis dysfunction is the root cause of a number of co-morbidities of insulin resistance syndrome. Reduced injury proneness typical of ‘diplomat’ life style would also reorient the immune system resulting into delayed wound healing on the one hand and increased systemic inflammation on the other. Diabetes is negatively associated with physically aggressive behaviour. We hypothesize that suppression of physical aggression is the major behavioural cue for the development of metabolic syndrome. Preliminary trials of behavioural intervention indicate that games and exercises involving physical aggression reduce systemic inflammation and improve glycemic control.

Is the pharynx a muscular hydrostat?

Kristina Kairaitis — 2010-01-07

Summary: 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.

NAPDH oxidase mediates glucolipotoxicity-induced beta cell dysfunction – Clinical implications

Mark F. McCarty, Jorge Barroso-Aranda, Francisco Contreras — 2009-07-03

Summary: An impairment of glucose-stimulated insulin secretion – reflecting decreased glucokinase expression – and a moderate decrease in beta cell mass attributable to increased apoptosis, constitute the key features of beta cell failure in type 2 diabetes. Oxidative stress, provoked by prolonged exposure to excessive levels of glucose and/or fatty acids (glucolipotoxicity), appears to be a key mediator of these defects. Oxidant-provoked JNK activation induces nuclear export of the PDX-1 transcription factor, required for expression of glucokinase and other beta cell proteins. Conversely, increases in cAMP induced by incretin hormones promote the nuclear importation of PDX-1, counteracting the diabetogenic impact of oxidant stress; this may explain the utility of measures that slow dietary carbohydrate absorption for diabetes prevention. The ability of oxidative stress to boost apoptosis in beta cells is poorly understood, but may also entail JNK activation. Recent work establishes a phagocyte-type NADPH oxidase as the chief source of glucotoxicity-mediated oxidative stress in beta cells. Since bilirubin is now known to function physiologically as an inhibitor of NADPH oxidase, and phycocyanobilin (PCB) derived from spirulina likewise can inhibit this enzyme complex, supplemental PCB may have utility in the prevention and control of diabetes, and Gilbert syndrome, associated with chronically elevated free bilirubin, may be associated with decreased diabetes risk.

Oral phycocyanobilin may diminish the pathogenicity of activated brain microglia in neurodegenerative disorders

Mark F. McCarty, Jorge Barroso-Aranda, Francisco Contreras — 2009-07-03

Summary: There is considerable evidence that activated microglia play a central role in the pathogenesis of many prominent neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. The elevated NADPH oxidase activity of these microglia contributes importantly to their pathogenic impact, collaborating with increased iNOS activity to generate the cytotoxic oxidant peroxynitrite. Phycocyanobilin (PCB), a chromophore derived from biliverdin that constitutes up to 1% of the dry weight of spirulina, has recently been shown to be a potent inhibitor of NADPH oxidase. The possibility that orally administered PCB could reach the brain parenchyma in sufficient concentrations to influence microglial function is consistent with the findings of two rodent studies: orally administered C-phycocyanin (the spirulina holoprotein that includes PCB) suppresses the neurotoxic impact of the excitotoxin kainite in rats, and a diet high in spirulina ameliorates the loss of dopaminergic neurons in the MPTP-induced Parkinsonian syndrome in mice. Hence, supplemental PCB may have considerable potential for preventing or slowing the progression of a range of neurodegenerative disorders. Some of the central physiological effects of PCB may also reflect inhibition of neuronal NADPH oxidase, which is now known to have a modulatory impact on neuron function, and can mediate neurotoxicity in certain circumstances. Neuronal NADPH oxidase activation is an obligate mediator of the central pressor effect of angiotensin II, and there is suggestive evidence that it may also play a role in inflammatory hyperalgesia; these findings point to possible antihypertensive and analgesic applications for PCB. The likely favorable effects of PCB on vascular health may also protect the brain by decreasing stroke risk, and inhibition of NADPH oxidase in rodents has been shown to lessen the neurotoxic impact of temporary cerebral ischemia. PCB may thus have versatile potential for preserving the healthful function of the central nervous system into advanced old age – albeit optimal neuroprotection may require more complex regimens that incorporate PCB along with other well tolerated nutraceuticals and drugs, in conjunction with prudent lifestyle modifications.

The creative brain – Revisiting concepts

Ambar Chakravarty — 2009-11-09

Summary: Creativity is a complex neuro-psycho-philosophical phenomenon which is difficult to define literally. Fundamentally it involves the ability to understand and express novel orderly relationships. The creative process involves four stages – preparation, incubation, illumination and verification. A high level of general intelligence, domain specific knowledge and special skills are necessary pre-requisites. It is possible that in addition, some creative people might have architectural alternations of specific portions of the posterior neocortex. Associated with such pre-requisites, the process of creative innovation (incubation and illumination stages) necessitates the need for an ability of divergent thinking, a novelty seeking behavior, some degree of suppression of latent inhibition and a subtle degree of frontal dysfunction. The author hypothesizes that these features are often inter-linked and subtle frontally disinhibited behavior is conducive towards creativity by allowing uninterrupted flow of creative thought possessing and opening up new avenues towards problem solving. Perhaps the most essential feature of the creative brain is its degree of connectivity – both inter-hemispheric and intra-hemispheric. Connectivity correlates or binds together functions of apparently structurally isolated domains on brain modules sub-serving different functions. It is felt that creative cognition is a self rewarding process where divergent thinking would promote connectivity through development of new synapses. In addition, the phenomenon of synaesthesia has often been observed in creative visual artists. Creative innovation often occurs during low arousal states and creative people often manifests features of affective disorders. This suggests a role of neurotransmitters in creative innovation. Dopaminergic pathways are involved in the novelty seeking attitude of creative people while norepinephrine levels are depressed during discovery of novel orderly relationships. The relationship between mood and catecholamines and that of creative cognition is often in an inverted U-shaped form. It is hypothesized that that subtle frontal dysfunction is a pre-requisite for creative cognition but here again the relationship is also in an inverted U-form.

Dental caries: Cola, calor or calories?

Arunachalam Kumar, C. Jairaj Kumar — 2009-10-05

Man alone among every known living creature on earth, by choice or preference voluntarily imbibes food or drink, either heated or cooled. Heating food as prelude to ingestion, is a widely prevalent socio-cultural anthropological attribute of evolution seen the world over. In evolutionary scale of time, eating or dinking heated solids or liquids is a fairly recent taste acquisition of the mammal, man: a culinary development probably even less than two million years.

Might the widespread use of statin drugs explain the increase in prevalence of breast carcinoma in situ?

Mark R. Goldstein, Luca Mascitelli, Francesca Pezzetta — 2009-11-06

It has been recently reported a 7× increase in the prevalence of breast carcinoma in situ (BCIS) over the 1985–2005 time period in the United States . Moreover, the prevalence of BCIS was nearly double in white compared to black and other minority subjects. We suggest that statin use might partially explain these disturbing findings.

Treatment of croup with topical ionic zinc

George A. Eby — 2009-11-05

While writing my article for this journal titled “Zinc lozenges as cure for the common cold – a review and hypothesis” , I reflected upon the long 25-year history of zinc in treating colds, and also remembered that the history of use of zinc to treat croup in infants and young children was much longer. The first published use that I found for treating croup with zinc was in 1899; yes, eighteen ninety-nine . Apparently, topical zinc sulfate was routinely used to treat croup effectively during the 19th century. In 1984, Linus Pauling mentioned to me that he remembered physicians in the 1930s treating croup by painting the throats of infants and young children with mild zinc sulfate solutions. I used zinc gluconate tablets (50mg zinc) as throat lozenges to treat croup in my young children during the late 1970s and early 1980s. Croup disappeared in about 15–30min from a zinc gluconate lozenge treatment in my children. Without ionic zinc, their croup lasted about 5days and required medical intervention. Even so, if one conducts a PubMed search, there are no entries for “croup” and “zinc”. I think it is important to revive old, effective treatments and try to explain their actions.

Nebivolol in the treatment of metabolic syndrome: Making the fat more brownish

Yalcin Solak, Huseyin Atalay — 2009-11-05

Metabolic syndrome represents a combination of cardiovascular risk determinants such as central obesity, insulin resistance, hypertension and lipid abnormalities . The etiology or initiating events have not been clearly established. However, insulin resistance and/or visceral obesity seem to be responsible for the development of full-blown syndrome. Obesity has reached epidemic proportions thus the prevalence of metabolic syndrome has increased substantially .

Electrification may have induced civilization diseases through changes of lifestyle

M.C. Gracia — 2009-11-11

Recently, this journal has published an article suggesting that the main cause of most civilization diseases, including cancer, cardiovascular diseases, diabetes, a variety of degenerative troubles, and even suicide, is the electrification of residential areas, by direct electromagnetic action on the organism. Although this may well be true for some cancers, for which the damage of DNA by electromagnetic fields is a plausible mechanism, the rest of the argumentation of this article is entirely compatible with the idea that the main cause of civilization diseases is lifestyle and electrification caused these diseases by inducing changes like the following:

All first trimester uterine ruptures caused by scar implantation?

Samir Hidar, lassad BenRegaya, Meriem ElAbed, Mohamed Bibi, Hédi Khairi — 2009-11-16

We read with great interest the recently published paper by Sliutz et al. After a comprehensive search in medical literature for which they have to be congratulated, the authors postulated that all first trimester uterine rupture are caused by scar implantation of the trophoblast.

Post-operative meningitis: Patients with glioblastoma multiforme might profit from it?

Bin Wang, Qichao Xie, Qilin Huang, Haipeng Liu, Hui Yang — 2009-11-11

Glioblastoma multiforme (GBM) is the highest grade primary brain tumor with the most heterogeneous, invasive properties and can cause high rate of mortality. Despite tumor resection, post-operative radiotherapy and adjuvant chemotherapy were recommended, the prognosis of patients with GBM still remains poor. The median survival after combined therapy is only 14.6months .

Infecting dose can explain different severity of cases in new influenza A (H1N1)

Juan Martínez Hernández — 2009-09-30

As in the case of chickenpox, new influenza A (H1N1) can be more severe if viral infective inoculum dose is greater than if it is little. In chickenpox, first case in a family outbreak usually is a middle case of disease. Second case shows a greater count of pustules and finally, a third case is more serious, not only by count of lesions, but in terms of general symptoms as fever . The explanation of this fact is inoculum dose of second and third cases, which is greater than in the first case.

Honey bee sting and venom offering active as well as passive immunization could reduce swine flu pandemic A (H1N1)

Rajeev K. Singla, Varadaraj G. Bhat — 2009-12-16

About half of the hospitalized patients affected by swine-origin influenza virus (S-OIV) have had underlying conditions such as asthma and other lung diseases, diabetes, morbid obesity, auto-immune disorders, immunosuppressive therapies, neurological or cardiovascular disorders or pregnancy (febrile respiratory infection) . It is fairly clear that the invasion of influenza virus into the respiratory system might give rise to pneumonia. The occurrence of pneumonia invariably incurs with inflammation, leading to pulmonary oedema and, in some cases, to respiratory exhaustion . In Mexico, where the largest numbers of fatalities have been seen, severe pneumonia with multifocal infiltrates and rapid progression to acute respiratory distress syndrome (ARDS) and multi-organ failure has been reported. And since S-OIV is so far antigenically homogeneous, so therapy which could sufficiently shows immunogenic properties, are likely to afford protection for the foreseeable future .

Altitude suicide death rate hypothesis since 2002

David Cheng, Barry Brenner — 2009-11-30

In response to a recent Medical Hypothesis journal article, “The possible effect of altitude on regional variation in suicide rates” by Dr. Haws, we would like to alert the readers that the hypothesis linking altitude and suicide death rate was first reported in abstract form in 2002 with national exposure via Reuter Health on October 8, 2002 .

GYKI-52466: A potential therapeutic agent for glutamate-mediated excitotoxic injury in Cerebral Palsy

M.S. Nandhu, Jes Paul, Jobin Mathew, T. Peeyush Kumar, C.S. Paulose — 2009-11-16

Cerebral Palsy (CP) has been defined as a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetus or infant . Acquired lesions such as hypoxia–ischemia, infection, endocrine/metabolic disorders, or trauma are the most important causes of CP, but genetic disorders and malformations of the brain make an important contribution . Injury to the deep white matter of the premature brain, referred to as periventricular leukomalacia (PVL), has been recognized more commonly in premature infants and it remains the most common brain abnormality responsible for CP . The developing periventricular white matter is most vulnerable to injury before 32weeks of gestation .

Ultrasound of 10MHz frequency as a novel strategy for skin anti-aging therapy

Ilja L. Kruglikov, Werner Sontag — 2009-11-27

Aging is believed to be connected with accumulated damaging of cellular macromolecules in non-dividing cells as well as with reduction of the cells capability to repair this damage. Damage of the macromolecules occurs through different physical and chemical factors (e.g. different types of irradiation, heat, toxins, etc.). The fate of the damaged macromolecules is dependent on such processes as degradation of unstable proteins, refolding of misfolded proteins, controlling of regulatory proteins and prevention of protein folding. These processes are essentially regulated through activation of heat shock proteins (HSPs) . HSP family includes different proteins classified according to their molecular weights. Among them the HSP70 and HSP90 seems to be responsible for the recognition and refolding of proteins. HSPs are present in all cell types and were found not only inside of the cells where they believed to act cytoprotectively (to prevent the cells against the second stress that would otherwise cause lethal molecular damage) but also in the cell membrane and in the extracellular space where they can show the cytotoxic effect increasing the cell death . It is well known that HSPs are over-expressed in cancer cells as well as on outer cellular membranes of damaged cells after some aggressive treatments (e.g. ). There is also increasing evidence of HSPs expression in different neurodegenerative disorders, during inflammation, by trauma as well as by cerebral and cardiac ischemia. It is believed that in the most of these diseases induction of a heat shock response might be an effective prophylactic treatment to minimize the severe injuries, making HSPs activation a potential therapeutic modality.