Journal: Medical hypotheses
Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.
The preparation and consumption of bone broth is being increasingly recommended to patients, for example as part of the gut and psychology syndrome (GAPS) diet for autism, attention-deficit hyperactivity disorder, dyslexia, dyspraxia, depression and schizophrenia, and as part of the paleolithic diet. However, bones are known to sequester the heavy metal lead, contamination with which is widespread throughout the modern environment. Such sequestered lead can then be mobilised from the bones. We therefore hypothesised that bone broth might carry a risk of being contaminated with lead. A small, blinded, controlled study of lead concentrations in three different types of organic chicken broth showed that such broths do indeed contain several times the lead concentration of the water with which the broth is made. In particular, broth made from skin and cartilage taken off the bone once the chicken had been cooked with the bones in situ, and chicken-bone broth, were both found to have markedly high lead concentrations, of 9.5 and 7.01μgL(-1), respectively (compared with a control value for tap water treated in the same way of 0.89μgL(-1)). In view of the dangers of lead consumption to the human body, we recommend that doctors and nutritionists take the risk of lead contamination into consideration when advising patients about bone broth diets.
There are conflicting reports about the efficacy of electronic cigarettes (e-cigs) as nicotine delivery devices and smoking cessation products. In addition, smokers' responses to some nicotine dependence questions often change as they transition to exclusive e-cig use. Nicotyrine may explain these observations. Nicotyrine forms by the gradual oxidation of nicotine in e-liquids exposed to air. E-cigs aerosolize nicotyrine along with nicotine. Nicotyrine inhibits the cytochrome P450 2A family of enzymes (CYP2A) in airways and liver. These enzymes metabolize nicotine to cotinine, and then cotinine to trans 3-hydroxycotinine. In humans, nicotine is metabolized primarily by hepatic CYP2A6. We propose that e-cig users (vapers) achieve measurable serum nicotine levels when they inhale nicotine and nicotyrine together, because nicotyrine reversibly inhibits nicotine metabolism by CYP2A13 in airways. Consuming nicotyrine by any route should irreversibly inhibit hepatic CYP2A6. When CYP2A6 is substantially inhibited, nicotine clearance is delayed and nicotine withdrawal symptoms are attenuated. Small, relatively infrequent nicotine doses can then sustain satisfying nicotine levels. This theory has numerous implications for e-cig research and tobacco control. Behavioral and pharmacokinetic e-cig studies should be interpreted with attention to likely levels of nicotyrine delivery: e-cig studies may need to routinely measure nicotyrine exposure, assess CYP2A6 activity, confirm nicotine delivery, or deliberately compare unoxidized and oxidized e-liquids. The risks of nicotyrine exposure include impaired clearance of all CYP2A substrates and any effects of the metabolic products of nicotyrine. CYP2A inhibitors like nicotyrine may be useful for future smoking cessation therapy.
Drug poisoning deaths have more than doubled in the United States since 2000 with fentanyl and fentanyl analogues primarily responsible for the jump in opioid deaths. Robust data indicate a convincing correlation between the exposure of the fetus to other labor medications (morphine, pethidine hydrochloride, barbiturates, phenobarbitone, meperidine, and secobarbital) and the later addiction of young adults to the same category of drug. We present the hypothesis that this effect is also true of the opioid, fentanyl: there is a causal relationship between the increased popularity of fentanyl as a labor anesthetic in the United States since the 1980’s and the current epidemic of fentanyl abuse.
The hierarchical model of stem cell genesis is based on the idea that the number of cell divisions between the zygote and fully differentiated epithelial cells is kept close to the minimum, which is log to the base 2 of the total number of cells produced in a human lifetime. The model assumes the orderly progression of stem cell divisions requires precise control at every stage in development. If the orderly progression is maintained then cancer will be rare. A prediction of the model is that if the orderly progression of the stem cell hierarchy is disturbed by trauma, ulceration or inflammation then cancer will occur.
The hypothesis proposed is that functional disorders, such as irritable bowel syndrome, chronic fatigue syndrome and anorexia nervosa are caused by auto-antibodies to neuronal proteins induced by molecular mimicry with microbial antigens. The age incidence of these conditions, the marked female excess, increase with economic and technological advance, precipitation by infection, and the paucity of histological changes are all consistent with the hypothesis. It can be tested directly using human sera to search for cross reaction with brain proteins in model systems such as Drosophila melanogaster. The conditions might be amenable to treatment using pooled immunoglobulin. Identification and elimination from the microbial flora of the bacteria that express the cross reacting antigens should be possible.
Traumatic brain injury and chronic traumatic encephalopathy are both major health problems, well-publicized for the severe delayed effects attributed to them, including cognitive decline, psychiatric disorders, seizures, impaired motor function, and personality changes. For convenience, the two afflictions are considered together under the rubric traumatic brain injury. Despite the need for neuroprotective agents, no substances have shown efficacy in clinical studies. Thus, a deeper understanding of the neuropathological mechanism of such injury is still needed. Proposed here is a theory that microorganisms from within the brain and elsewhere in the body contribute to the long-term neurological deterioration characteristic of traumatic brain injury. The label, “The Beehive Theory”, is drawn from the well-known fact that disturbing a tranquil beehive with a blow can cause a swarm of angry bees to exit their dwelling place and attack nearby humans. Similarly, an impact to the head can initiate dislocations and disruptions in the microbiota present in the brain and body. First, since the normal human brain is not sterile, but is host to a variety of microorganisms, blows to the skull may dislodge them from their accustomed local environments, in which they have been living in quiet equilibrium with neighboring brain cells. Deleterious substances may be released by the displaced microbes, including metabolic products and antigens. Second, upon impact commensal microbes already resident on surfaces of the nose, mouth, and eyes, and potentially harmful organisms from the environment, may gain access to the brain through the distal ends of the olfactory and optic nerves or even a disrupted blood-brain barrier. Third, microbes dwelling in more distant parts of the body may be propelled through the walls of local blood vessels into the bloodstream, and then leak out into damaged areas of the brain that have increased blood-brain barrier permeability. Fourth, the impact may cause dysbiosis in the gastrointestinal microbiome, thereby disrupting signaling via the gut-brain axis. Possible preventatives or therapeutics that would address the adverse contributions of microbes to the late sequelae of traumatic brain injury include anti-inflammatories, antibacterials, antivirals, and probiotics.
The term ‘give-up-itis’ describes people who respond to traumatic stress by developing extreme apathy, give up hope, relinquish the will to live and die, despite no obvious organic cause. This paper discusses the nature of give-up-itis, with progressive demotivation and executive dysfunction that have clinical analogues suggesting frontal-subcortical circuit dysfunction particularly within the dorsolateral prefrontal and anterior cingulate circuits. It is hypothesised that progressive give-up-itis is consequent upon dopamine disequilibrium in these circuits, and a general theory for the cause and progression of give-up-itis is presented in which it is proposed that give-up-itis is the clinical expression of mental defeat; in particular, it is a pathology of a normal, passive coping response.
Medical students in the United States are taught little about nutrition and dietetics. Worse yet, their training biases them against the studies that show the power of dietary approaches to managing disease. The current approach to evidence-based medicine encourages physicians to ignore any information that does not come from a double-blind, randomized controlled trial. Yet human beings cannot be blinded to a dietary intervention. As a result, physicians are biased toward drug treatments and against dietary interventions for the management of chronic disease.
Individuals with autism who show high abilities are called savants. Whereas in their brains a disconnection in and between neural networks has been identified, savantism is yet poorly understood. Focusing on astrocyte domain organization, it is hypothesized that local astrocyte mega-organizations may be responsible for exerting high capabilities in brains of autistic savants. Astrocytes, the dominant glial cell type, modulate synaptic information transmission. Each astrocyte is organized in non-overlapping domains. Formally, each astrocyte contacting n-neurons with m-synapses via its processes generates dynamic domains of synaptic interactions based on qualitative computation criteria, and hereby it structures neuronal information processing. If the number of processes is genetically significantly increased, these astrocytes operate in a mega-domain with a higher complexitiy of computation. From this model savant abilities are deduced.