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Journal: Medical hypotheses


The acquisition of cognitive, sensory-motor and social emotional functions depend on a proper development of the Central Nervous System (CNS). This set of functions, known as intelligence, allows a better adaptation to the environment. In the last decades, an increase in the average of intelligence has been reported. However, such an increase cannot be observed in an equivalent way in economically and social underprivileged regions. Children from those regions are in great risk of being affected by mental retardation or impaired cognitive development. In later life they will, probably, be unable to transform and improve themselves and their communities, perpetuating the poverty of the region. Therefore, knowledge of factors involved in CNS development is a matter of health closely related to social improvement. Malnutrition throughout pregnancy and breastfeeding is clearly identifiable as a cause of damage in CNS development. Vitamin B1 (Thiamine) is a micronutrient important to the growth and maturity of the CNS. Thiamine shortcoming may affect 50% of pregnant women. Thiamine function in cerebral development is still not well known. There is a gap in the literature regarding systematical research about the blood thiamine concentration throughout the periods of gestation and breastfeeding. These studies are relevant in populations with a high level of nutritional vulnerability, because in a follow up offspring cognitive exam they could reveal if the maternal thiamine deficiency is related to child CNS impairment. This paper introduce the hypothesis that thiamine shortcoming during pregnancy and breastfeeding is directly related to cognitive impairment of child. Data about the neurophysiological role of thiamine, consequences of its shortcoming in experimental models, populations under the risk of thiamine shortcoming are presented. The hypothesis that maternal thiamine shortcoming causes damage related to child cognitive development needs to be considered. Thus, thiamine shortcoming during gestation and breastfeeding and its effects on children must be studied in many populations in order to know the magnitude of the problem and to indicate actions to overcome it.

Concepts: Breastfeeding, Embryo, Beriberi, Nervous system, Pregnancy, Vitamin, Central nervous system, Thiamine


Sporadic amyotrophic lateral sclerosis (sALS) is a fatal neurodegenerative disease with no known cause. There are many clues to suggest an environmental trigger for the disease, including reports of conjugal couples and co-localized employees that developed sALS. On the island of Guam,a very high incidence of sALS occurred among the Chamorro natives back in the 1940s and 1950s and has been linked to the neurotoxin beta-N-methylamino-l-alanine (BMAA) that is produced by cyanobacteria that live symbiotically in the roots of the cycad plant, the seeds from which were a staple of the Chamorro diet. It has been shown that BMAA was biomagnified up the food chain from the cycad seeds to the now largely extinct, indigenous flying foxes, a former delicacy of the Chamorro natives. Recent evidence suggests that long term, chronic exposure to low levels of BMAA might cause ALS in genetically predisposed individuals. Many exposure routes to BMAA have been implicated thus far, including consumption of contaminated food and exposure to water harboring cyanobacterial blooms which have the capability of producing BMAA. Aerosolization is a well documented means for bacterial or toxin exposure causing subsequent illness, as in the case of brevetoxins and pulmonary disease and Legionnaire’s disease. We hypothesize that some cases of ALS may be related to chronic exposure to the aerosolization of cyanobacteria derived BMAA from cooling towers and might explain the observation of conjugal ALS couples.

Concepts: Lou Gehrig, Medicine, Neurodegenerative disorders, Cycad, Lytico-Bodig disease, Bacteria, Plant, Amyotrophic lateral sclerosis


Oculocutaneous albinism type 2 (OCA2) is present at significantly higher frequencies in sub-Saharan African populations compared to populations in other regions of the world. In Tanzania and other sub-Saharan countries, most OCA2 is associated with a common 2.7kb deletion allele. Leprosy is also in high prevalence in sub-Saharan African populations. The infectious agent of leprosy, Mycobacterium leprae, contains a gene, 38L, that is similar to OCA2. Hypopigmented patches of skin are early symptoms that present with infection of leprosy. In consideration of both the genetic similarity of OCA2 and the 38L gene of M. leprae and the involvement of pigmentation in both disorders, we hypothesized that the high rates of OCA2 may be due to heterozygote advantage. Hence, we hypothesized that carriers of the 2.7kb deletion allele of OCA2 may provide a protective advantage from infection with leprosy. We tested this hypothesis by determining the carrier frequency of the 2.7kb deletion allele from a sample of 240 individuals with leprosy from Tanzania. The results were inconclusive due to the small sample size; however, they enabled us to rule out a large protective effect, but perhaps not a small advantage. Mycobacterium tuberculosis is another infectious organism prevalent in sub-Saharan Africa that contains a gene, arsenic-transport integral membrane protein that is also similar to OCA2. Interestingly, chromosomal region 15q11-13, which also contains OCA2, was reported to be linked to tuberculosis susceptibility. Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility. Confirmation of our hypothesis would enable development of novel pharmocogenetic therapies for the treatment of tuberculosis, which in turn, may enable development of drugs that target other pathogens that utilize a similar infection mechanism as M. tuberculosis. From an evolutionary perspective, confirmation of our hypothesis may provide another example of heterozygote advantage.

Concepts: Sub-Saharan Africa, Tuberculosis, Allele, Mycobacterium leprae, Bacteria, Leprosy, Mycobacterium tuberculosis, Mycobacterium


Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance.

Concepts: Toll-like receptors, Receptor, Pain, TLR 4, Opioid, Immune system, Toll-like receptor, Innate immune system


As a general observation, wet hair in cold weather seems to be a predisposing factor for sinus headache and posterior eye pain. We offer a mechanism through selective brain cooling system for this observation. Selective brain cooling (SBC) is a mechanism to protect brain from hyperthermia. Components of SBC are head skin and upper respiratory tract (nose and paranasal sinuses). Cool venous blood from head skin and mucous membranes of nose and paranasal sinuses drains to intracranial dural sinuses and provide brain cooling. Brain will be cooled very much when head skin exposes to hypothermia such a condition like wet hair in cold weather. We suggest that, in order to reduce brain cooling activity, some alterations are being occurred within paranasal sinuses. For this purpose, sinus ostiums may close and mucus may accumulate to reduce air within sinuses. Also there may be some vasomotor changes to prevent heat loss. We hypothesize that this possible alterations may occur within paranasal sinuses as a control mechanism for brain temperature control during exposure of head skin to hypothermia. Paranasal sinuses may also cool brain directly by a very thin layer of bone separates the posterior ethmoid air sinus from the subarachnoid space and only thin plates of bone separate the sphenoidal sinuses from internal carotid artery and cavernous sinuses. Because of their critical role in the SBC, posterior ethmoid air sinus and sphenoidal sinuses may be affected from this alterations more than other paranasal sinuses. This situation may cause posterior eye pain. This mechanism can explain why a person who expose to hypothermia with wet hair or a person who don’t use a beret or a hat during cold weather gets sinus headache and posterior eye pain. These symptoms could lead to an incorrect diagnosis of sinusitis.

Concepts: Cerebrospinal fluid, Mucus, Sinusitis, Headache, Internal carotid artery, Common carotid artery, Upper respiratory tract infection, Respiratory system


Complex Regional Pain Syndrome (CRPS) has defied a clear unified pathological explanation to date. Not surprisingly, treatments for the condition are limited in number, efficacy and their ability to enact a cure. Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn’t develop CRPS remains unclear. We propose a new overarching hypothesis to explain the condition that invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. We outline pathophysiological changes that may initiate a cascade of events involving dendritic cells and the cholinergic anti-inflammatory pathway resulting in the condition, and the changes that maintain the condition into its chronic phase. This hypothesis should provide fertile ground for further investigations and development of new treatments that holistically address the nature of the disorder along its developmental continuum.


Schizophrenia is a complex psychiatric syndrome whose exact causes remain unclear. However, current scientific consensus has highlighted the importance of neurodevelopmental and neurocognitive processes in the development of schizophrenic symptoms. Research over the past three decades, motivated by the findings of the World Health Organization’s large-scale studies, has highlighted the importance of psychosocial adversities - including childhood abuse and neglect - in this disorder. In this paper, I propose a hypothesis based on John Bowlby’s framework of attachment theory, which I have termed the attachment-developmental-cognitive (ADC) hypothesis. The ADC hypothesis integrates recent developments related to (1) existing models of schizophrenia, (2) studies examining the effect of attachment on brain biology and cognitive development, and (3) various known facts about the course and outcome of this disorder. In doing so, it explains how disturbed childhood attachment leads to core psychological and neurochemical abnormalities which are implicated in the genesis of schizophrenia and also affect its outcome. The ADC hypothesis compasses and expands on earlier formulations, such as the “social defeat” and “traumagenic” models, and has important implications regarding the prevention and treatment of schizophrenia. Ways of testing and refining this hypothesis are outlined as avenues for future research. Though provisional, the ADC hypothesis is entirely consistent with both biological and psychosocial research into the origins of schizophrenia.

Concepts: Maternal deprivation, Attachment therapy, Scientific method, Mary Ainsworth, Attachment theory, Family therapy, Psychology, John Bowlby


Various positively selected adaptations to new nutrients have been identified. Lactase persistence is among the best known, conferring the ability for drinking milk at post weaning age. An augmented number of amylase gene (AMY1) copies, giving rise to higher salivary amylase activity, has been implicated in the consumption of starch-rich foods. Higher AMY1 copy numbers have been demonstrated in populations with recent histories of starchy-rich diets. It is however questionable whether the resulting polymorphisms have exerted positive selection only by providing easily available sources of macro and micronutrients. Humans have explored new environments more than any other animal. Novel environments challenge the host, but especially its immune system with new climatic conditions, food and especially pathogens. With the advent of the agricultural revolution and the concurrent domestication of cattle came new pathogens. We contend that specific new food ingredients (e.g., gluten) and novel pathogens drove selection for lactase persistence and higher AMY gene copy numbers. Both adaptations provide ample glucose for activating the sodium glucose-dependent co-transporter 1 (SGLT1), which is the principal glucose, sodium and water transporter in the gastro-intestinal tract. Their rapid uptake confers protection against potentially lethal dehydration, hyponatremia and ultimately multiple organ failure. Oral rehydration therapy aims at SGLT1 activity and is the current treatment of choice for chronic diarrhoea and vomiting. We hypothesize that lifelong lactase activity and rapid starch digestion should be looked at as the evolutionary covalent of oral rehydration therapy.

Concepts: Natural selection, Enzyme, Dehydration, Oral rehydration therapy, Starch, Digestion, Nutrition, Alpha-Amylase


The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients' genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients' immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients' blood and tissue. No known pathogen has been shown to cause ME/CFS. Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.

Concepts: Bacteria, Vaccination, Disease, Medicine, Infection, Epidemiology, Infectious disease, Immune system


Biofilm formation by nonpathogenic bacteria is responsible for their stable maintenance in vivo ecosystems as it promotes long-term permanence on the host’s vaginal mucosa. Biofilm formation by Lactobacilli has been reported in vitro but not in vivo. We hypothesize the presence of biofilm formation in vivo could be also documented by microscope photographs (MP) of wet mounts obtained from uninfected vaginal samples satisfying rigorous scientific identification criteria. We analyzed 400 MP from our database, and we were able to determine that 12 MP from 6 different patients contained clues of the formation of biofilm by Lactobacilli. The most probable lactobacillus involved is presumed to be Lactobacillus jensenii. The documentation of biofilm formation by vaginal Lactobacilli at fresh wet mount preparation is significant and has several important clinical preventive and therapeutic implications.

Concepts: Microbiology, Biofilm, Microscope slide, Lactobacillus acidophilus, In vivo, In vitro, Bacteria, Lactobacillus