How easy is it for viruses to mutate?

It is a pleasure to be back, and believe me it hasn't been easy being away for so long. However, in all honesty, my absence wasn't result of my immediate choice. I have been flooded with work and the current world crisis didn't really help anyone. From having my children under my responsibility 24/7, plus all the extra work that results immediately from living, or better put, adapting to survive in a quarantined existence/lockdown-style, meets new thresholds that none of us had been exposed to before.

I have struggled to write a single line but I have struggled a lot more with reading the enormous idiotic and, sometimes, overtly ignorant information spread out in different platforms, covid-wise! I realised that for some questions the official sources out there are quite good, even though, and I remain with my personal view on it, numbers do no immediately add-up.

Information and counter-information got to such ludicrous levels of ignorant presumptuousness that I decided to educate myself directly form few selected sources and experts. But during my self informing I wasn't able to find an adequate simplified explanation that would respond to different aspects of all this covid-19 pandemics. One of such aspects emerged exactly whilst trying to understand how Italy, UK, Portugal and Spain met such different levels of infectiousness and lethality when presented to basically similar approaches and external/internal pressures/strategies. I just couldn't make sense of certain aspects but the one that caught me empty handed was hearing from a specialist in virology that the virus had just mutated from country to country. I can't easily recall who this person was or what organisation was he speaking from, but to be fair it is not my role to criticise these people, let alone try to play a role of key opinion leader on a matter I am not specialised at all. But because I am a curious person with a thirst for knowledge I researched further in order to try and understand how can that be feasible. How mutable is a viral strain? In even more simplified words....

How easy is it for viruses to mutate?

To be able to address this complex question with a simplified answer it is imperative to accurately estimate virus mutation rates, so then one can infer on the individual and particular evolution of the different object viruses. Only then applicable strategies can be designed to control spread, infectivity and foresee a plausible safe future ahead of any epidemic. That was the work of Sanjuan et al (2010) where different methods of estimation (that in their own nature are quite varied and usually fairly complex) were applied [1]. But how can one define mutation rate? Well, the authors defined it as substitutions per nucleotide per cell infection (s/n/c) (so to account for viability rather than just mutations with no biological meaning at all) and corrected for selection bias where applicable and deemed necessary. 

Their observations were quite impressive as the obtained rates stretched from from 10−8 to10−6 (in DNA viruses) and from 10−6 to 10−4 (in RNA viruses) supporting the classic idea of a negative correlation (meaning one decreases when the other increases, and vice-versa) between mutation rate and genome size among RNA viruses and also DNA viruses. In addition, [1] shows that nucleotide substitutions are on average 4 times more frequent than insertions of nucleotides and deletions of nucletotides in the 'viral genome', the usually called 'indels'. But another very useful public tool they came up with is the regularly updated (so they say) virus mutation rate data that one can find at the url: www.uv.es/rsanjuan/virmut [2] with the main objective of providing an easily available, organised and professional data set on viral mutation rates. Just for the sake of curiosity and example, I can tell you that corona virus, as expected, is not part of the studied viruses, and that HIV-1 has a mutation rate of 4.9E-5 (s/n/c) whereas Influenza A virus sits at 4.5E-5 (s/n/c) - both these values are mutation rates per cell infection.

It is easy to understand that not all mutations are biologically effective and significant and that lethality power can actually undermine the relevance of the virus because a virus with a deadly mutation to humans, basically kills rapidly the host on which the virus itself depends on (for viruses are not living beings, they are merely simple algorithms of genetic code that operate not knowing very well in what overall program do they actually integrate - that is how funny and scary viruses are!!!).  If they kill the host quickly, let's say even faster than Ebola kills, the virus would require an immediate host to progress with spreading infection... and in that sense its associated lethality can undermine it's biological success. To avoid disappearing, a virus should be very infectious and lesser lethal! That is my understanding.

But what about their mutation 'strategy'? Apparently there are several types of consequential mutation 'strategies' if we can exaggerate and affirm these things even have a subliminal plan. Basically pure evolutionary and external pressures and forces shape their 'swarming' but apparently, at least in what relates to HIV and Influenza, their mutation is linked to antigenic drift and antigenic shift. The former occurs with a change in aspect of the outer surface protein where the host won't be able to identify the virus, hence an insufficient defensive response takes place; and the latter is defined by 'fusion' of different types of the same virus merging and becoming a new very different type from its root strains - that will catch the host by surprise and their limited antibodies will not be able to cope with the new profile of viral infection [3] - the 2003 zoonotic H5N1 influenza A virus epidemic that infected humans is a good example, but luckily one with limited infectivity/lethality correlation!

The mutational capability and profiling of viruses is a world of knowledge. And not only time is limited but also your patience. So allow me to save these last two short paragraphs to discur on two straight points:

What other factors participate on the mutational rate of viruses? Population density where the highest density (overcrowding) will find successful jumps of viruses from one host to another, more rapidly and more effectively. Also, a virus with longer incubation times associated to what I had explained in the previous paragraphs, lesser pronounced lethality. This will even allow a zoonotic virus to live freely in migratory animals and spread happily to distant geographical points. Biologically clever, isn't it?! But in a nutshell, the best answer to how easy it is for viruses to mutate, can be found in the work of Sanjuan and Domingo-Calap (2016) [4] where the authors state that impressive capacity of some viral strains to adapt to new hosts and environments is strongly determined by their capacity to produce newer viral proteins in a short period of time. As the authors state, the present knowledge of viral mutation rates shows that "viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures", as discussed above. Viral mutation rates are programmed and performed by means of polymerase fidelity inclusion, at sequence context, at template secondary structure, at cellular microenvironment, through replication mechanisms, during proofreading and/or during access to post-replicative repairing,  by means of virus-encoded diversity-generating elements or even by host-encoded cytidine/adenine deaminases [4]. 

What is the mutational rate of SARS-CoV-2? The jury is unfortunately still out there and so will be for a long time, but I suspect that a recent article by Tang et al (2020) [5] offers the best most up-to-date original information we have accomplished so far (though naturally limited, as you may well understand). They propose that SARS-CoV-2 can be classified in two major lineages (L and S) defined by just two tightly linked SNPs (single nucleotide polymorphisms) at positions 8,782 (orf1ab: T8517C, synonymous) and 28,144 (ORF8: C251T, S84L). Their mutational load analysis reports that "the L lineage had accumulated a significantly higher number of derived mutations than S lineage". Moreover, they also found merely 4% variability in genomic nucleotides between SARS-CoV-2 and a used-for-reference "bat SARS-related coronavirus (SARSr-CoV; RaTG13)", and the identified "difference at neutral sites was 17%", pointing towards the idea that, as the result of different selective pressures, "the divergence between the two viruses is way larger than initially thought. 

[1] Sanjuan, R., Nebot. M. R., Chirico, N., Mansky, L. M., Belshaw, R. (2010). "Viral Mutation Rates". Journal of Virology, 84(19), pp. 9733-9748.

[2] Viral Mutation Rates, Institute for Integrative Systems Biology (I2SysBio), [https://www.uv.es/rsanjuan/virmut], last access on 29th of June 2020, last updated on 2010.

[3] Viruses and Evolution, The History of Vaccines - An Educational Resource by the Colleage of Physicians of Philadelphia, [https://www.historyofvaccines.org/content/articles/viruses-and-evolution], last accessed on 29th of June 2020, last updated on the 10th of January 2018.

[4] Sanjuan, R., Domingo-Calap, P. (2016). "Mechanisms of viral mutation". Cell Mol Life Sci, 73(23), , pp. 4433-4448.

[5] Tang, X., Wu, C., Li, X. et al (2020). "On the origin and continuing evolution of SARS-CoV-2". Natural Science Review, 7(6), pp. 1012-1023.

Post photo by CDC on Unsplash.

On the actual scientifically proven health benefits of Kombucha

I have been given Kombucha by a recent acquaintance and this mate of mine spared no time in positive adjectives about this Thing! This is the most accurate name I can attribute it since my wife tells me that it resembles her the Alien, by H. R. Giger. I had no idea what Kombucha was but at the same time I was no ignorant as to the potentials of many different probiotic elements out there in the food markets of our cities. Nevertheless, I must assume my ignorance, from Kefyr to a few other names I can't really recall having heard of Kombucha before in my life. 

I had to ask him for a few pointers and then browse the web to get to know what exactly was all this Kombucha thing about. As it is usually my approach, when the information available for free on the web is of good quality (with proper scientific backing in terms of research papers and identifiable sources), I waste no time in producing posts about it. I realised that most of the information out there concerning Kombucha, especially that relating or scrutinising the health benefits for humans, is abundant in quantity but not so much in identifiable scientific references.

My idea was immediately to produce a series of easy responded-to questions with adequate sources that could complement the necessary information to one of the most ambiguous present ideas concerning Kombucha. It seems that there is immense unclear information based on broad assumptions as to the actual health benefits of Kombucha for us.

What is Kombucha?

Kombucha* is a traditional fermented tea drink (of pH ~2.5) supposedly originating from ancient East Asia (northeast China - Manchuria), and more recently Germany and Russia [1], that is obtained from the fermentation process of a SCOBY (Symbiotic Culture Of Bacteria and Yeast) in sweetened tea, and that after undergoing a flavoring process for a user-determined period of time (that typically goes by adding sliced fruits to the liquid and permitting a certain marination period), is served cold as a nutritious beverage believed to hold important health benefits for its consumers. Due to its content in different organic acids and the fermentation process that uses sucrose, the drink gains a bittersweet taste that ranges in acidity and fizziness according to the time the acetic acid bacteria and yeasts are allowed to metabolise and grow. 

If you are willing to access comprehensive information on the microbiology, composition, fermentation process, toxicity and beneficial effects of this symbiotic partnership, please read the article by Jayabalan et al., 2014 [2].

What are the actual scientifically proven health benefits of Kombucha?

The information available on the web is enormous in size, but also in anecdotal data. In this regard I tried as much as possible to distant myself from any speculative assumptions and focused entirely in direct, yet proven and referenced, scientifically-supported data. Most of these conclusions were obtained from research studies conducted in rodents and cell lines rather than immediately in human subjects. And to be fair, most of these results are only observed after a certain trial period without follow-up.

It is important to look into the original studies to understand the exact ins and outs of the mentioned observations, and also to accept that much needed human studies are not readily available (to the best of my knowledge). The lack of studies in humans must be taken into account. Regarding the listed benefits, please check [2, 4] for references:

- Mycotoxigenic,

- Hypoglycemic activity,

- Antioxidative stress against chromate,

- Longevity,

- Antistress activity against cold and hypoxia,

- Antioxidative stress against lead,

- Prevention of weight loss in diabetics,

- Prevention of postoperative intra-abdominal adhesion formation,

- Protection on chromosomal aberrations induced by γ -radiation,

- Protection on nephrotoxicity induced by trichloroethylene,

- Hypocholesterolemic effect,

- Healing property on indomethancin-induced gastric ulceration,

- Protection on phenol-induced cytotoxicity,

- Protection on mitomycin C-induced genotoxic effect,

- Hypoglycemic and antilipidemic properties against alloxan,

- Protective effects against oxidative stress-mediated damages in alloxan-induced diabetic rat,

- Amelioration of changes in trace element levels in electromagnetic field-exposed rats (950 MHz), 

- Antihyperglycemic effect in streptozotocin-induced diabetic rats,

- Attenuation of oxidative damage in electromagnetic field-exposed rats (950 MHz)

- Cytogenic activity.

A different article by Sreeramuu et al (2001) [3] analysed the antimicrobial activity of metabolites after a 14-day Kombucha fermentation period to attest of its inhibiting activity against pathogenic bacteria such as Shigella sonnei, Escherichia coli, Salmonellaenteritidis and Salmonella typhimurium, all bacteria that can cause diarrohea, stomach cramps, fever states and some other clinical manifestations due to associated infection progression.

In terms of harmful health effects the reports relate immediately to high consumption and consumption by susceptible individuals with underlying conditions [4]. The observations relate to internal lesions, perforation of the gastrointestinal tract due to acidosis and gastroenteritis (however this is easily avoided when the fermented drink is prepared under sterile conditions - VERY IMPORTANT - and left to ferment from 7 to 10 days, in that sense  the majority of spoilage pathogenic organisms will not develop as they cannot grow below a pH of 4.0 [5].

With all these in mind and considering that all my fermented brews based in Kombucha tea are performed in highly sanitary conditions, I will keep enjoying this very refreshing drink without worrying too much if its probiotic and nutritious effect is an immediate advantage. Nevertheless, animal data and studies on cell lines point towards benefits, although its also noted that it is important to limit consumption so to avoid side effects; as it is important to also limit the fermentation times so to avoid a putative production of alcohol alongside.

[1] Greenwalt, C. J., Steinkraus, K. H., Ledford, R. A. (2000). "Kombucha, the Fermented Tea: Microbiology, Composition, and Claimed Health Effects". J Food Prot, 63(7), pp. 976–981.

[2] Jayabalan, R., Malbasa, R. V., E. S., Loncar, E. S., Vitas, J. S., and Sathishkumar, M. (2014). "A Review on Kombucha Tea—Microbiology, Composition, Fermentation, Beneficial Effects, Toxicity, and Tea Fungus". Comprehensive Reviews in Food Science and Food Safety, 13, pp. 538-550.

[3] Sreeramuu, G., Zhu, Y., Knol, W. (2001). "Characterization of Antimicrobial Activity in Kombucha Fermentation". Acta Biotechnol., 21(10, pp. 49-56.

[4] Greenwalt, C. J., Steinkraus, K. H., Lefford, R. A. (2000). "Kombucha, the Fermented Tea: Microbiology, Composition, and Claimed Health Effects". Journal of Food Protection, 63(7), pp. 976-981.

[5] Jay, J. M (ed.). 1992. Modern food microbiology, 4th ed. AVI, Van Nostrand Reinhold, New York.

* In terms of denomination, Kombucha is simply the Germanised form of its original Japanese name Mo-Gu.

Images kindly obtained from Unsplash and credited via Twitter account of the Toxicologist Today.

On the management of Paediatric Vesicoureteral Reflux

For any parent/carer dealing with a child diagnosed with Vesicoureteral Reflux, the state of alarm is constant, and consequently a certain emotional burden can be identified. For having all possible variables that infer in the child's quality of life, under perfect control, can be time-consuming and quite tricky. Nevertheless, it is primordial to first have a complete understanding of the disease basics, so whoever is caring for the affected child can understand that there are clinical responses addressing the problem and that the issue itself is characterised by grey areas where agreements had to be made between experts in the area. Why? Due to lack of consensus. 

Vesicoureteral Reflux is not immediately an easily describable succession of rigid events, there are underlying little aspects that can confuse the diagnostic and bring personal opinions from clinicians to the debate table. 

What is Vesicoureteral Reflux?

This relates to a flow of urine that is contrary to normal motion. Going from the bladder into the ureter and, sometimes/eventually, depositing into the renal system (e.g., kidney). 

Can it happen to any child?

For most subjects this type of reflux derives from an existing physiological anomaly of the ureterovesical junction occurring from birth (congenital anomaly), but it can also emerge from other origins such as: 

a) from high-pressure passing urine from secondary to posterior urethral valves, 

b) due to a neuropathic bladder (where associated peripheral nerves are dysfunctional),

c) due to a voiding dysfunction (incapacity to urinate as normally expected). 

How many are affected?

About forty percent of children experiencing a urinary tract infection (UTI) show signs of reflux according to [1], thus, considering that two to five percent of girls and one to two percent of boys experience a urinary tract infection before reaching puberty [2] the numbers and their underlying inference speak for itself. 

UTIs are the commonest bacterial disease present in the first three 3 months of life in humans, according to [3]; tolling to about over 10% of reported serious febrile events of bacterial origin in infants 2 to 6 months of age [4]; reflux nephropathy is a liability factor when considering inflammation of the lining of renal pelvis and parenchyma, resulting in injury to the kidney and scarring (lesions that are irreversible and that in case of progressive kidney disease can cause kidney failure). In that sense, reflux nephropathy can result in extremely nefarious consequences such as renal insufficiency or end-stage renal disease (that when moderate to severe can then trigger renin-mediated hypertension) [5].

How is the management of disease approached?

The very first objective in the management of vesicoureteral reflux in children is to avoid pyelonephritis [a], renal injury and other complications derived from the impact of reflux in the urinary system.

Clinicians do know that vesicoureteral reflux is common, but presently there is very little consensus to the best way to manage the disease (even among clinical experts) [6]. It is exactly because of the lack of consensus in regard to how this medical issue should be treated that the American Urological Association (AUA) gathered a group of experts to produce a treatment guide directed to children diagnosed with vesicoureteral reflux, with scope on vesicoureteral reflux in children diagnosed following a urinary tract infection [7]. If you happen to visit the document online bear in mind that it is preconditioned to children aged 10 years and younger with unilateral or bilateral reflux with or without scarring. In addition, it also entails that treatment recommendations are to be made jointly with the parents of the sick child. I suspect that is because of individual behavioural patterns of the patient, day-to-day habits and the different spaces the child might be involved in. All this can impact tremendously in the practical outcome.

As stated in the document "Only a few recommendations can be derived purely from scientific evidence of a beneficial effect on health outcomes [...] Evidence of the efficacy of medical management on health outcomes is available only for Grades I–IV reflux".

What is recommended?

To maintain information as reliable as possible in regard to what is postulated in the original document, and because the document is quite long (I had to read it over the course of several weeks, see HERE). I decided to copy directly from the original. However, this is purely a summary of very important information that requires interpreting by involved clinicians. The present information is only for informative purposes to empower parents towards a more informed conversation with their children's doctors. It should not be interpreted as a priori direct medical advice towards a certain decision. Because consensus, as already discussed, is difficult in this area, even among experts, treatment options are the result of a selection by 8 out of 9 panel members and are, therefore, categorised as guidelines. As expected, treatment is advised by the panel based on a number of conditions, for example, nature of injury, grading of injury (I to IV, see end of post) and age. 

Having said all this, the available approaches are:

(1) No treatment (including intermittent antibiotic therapy); 

(2) Bladder training; 

(3) Continuous antibiotic prophylaxis; 

(4) Antibiotic prophylaxis and bladder training; 

(5) Antibiotic therapy, bladder training and anticholinergics (drugs that block the action of the neurotransmitter acetylcholine); 

(6) Open surgical repair: "although proven to cure reflux in 90–98 percent of patients, has not been demonstrated to improve health outcomes other than pyelonephritis; for this outcome, the evidence suggests that children with Grade III or IV reflux receiving continuous antibiotic prophylaxis are 2.5 times more likely to develop pyelonephritis than children who have undergone successful antireflux surgery" [...] Thus, evidence-based recommendations provide limited practical guidance for the clinician.

(7) Endoscopic repair.

"These modalities are described in Chapter 1. The recommendations assume that the patient has uncomplicated reflux (e.g., no breakthrough UTI, voiding dysfunction, duplex systems [where the ureter with the ureterocele can drain the top half of the kidney whereas the other ureter drains the lower half resulting in frequent UTIs, possibly reflux, and if not treated potential kidney damage], or other comorbid conditions); [...]

An important variable in the scope of treatment is the presence of concurrent voiding dysfunction, a common occurrence among children with reflux. Because resolution of voiding dysfunction may be accompanied by resolution or diminution of reflux such children may require more aggressive treatment with antibiotics, anticholinergics, and bladder training (e.g., timed voiding, biofeedback, parental monitoring of voided volumes). Surgical repair of reflux is less successful in children with voiding dysfunction, and thus a higher threshold is necessary before surgery is recommended in such patients. Children with reflux should therefore be assessed for voiding dysfunction as part of their initial evaluation.

[8]

[1] Bourchier, D., Abbott, G. D., Maling, T. M. (1984). "Radiological abnormalities in infants with urinary tract infections". Arch Dis Childv, 59(7); pp. 620–624.

[2] Jodal, U. and Winberg, J. (1987). "Management of children with unobstructed urinary tract infection". Practical Pediatric Nephrology, 1, pp. 647–656(1987). 

[3] Krober, M. S., Bass, J. W., Powell, J. M., Smith, F. R., Seto, D. S. (1985). "Bacterial and viral pathogens causing fever in infants less than 3 months old". Am J Dis Child, 139(9):, pp. 89-92.

[4] Allen, L. H., Lei, C., Douglas, B. (2006). "Incidence and Predictors of Serious Bacterial Infections Among 57- to 180-Day-Old Infants". Pediatrics, 117 (5), pp. 1695-1701.

[5] Martínez-Maldonado, M., (1998). "Hypertension in end-stage renal disease". Kidney International, 54(68), pp. S67-S72.

[6] Elder, Snyder, Peters, et al., 1992; International Reflux Study Committee, 1981.

[7] Management and Screening of Primary Vesicoureteral Reflux in Children (2010, amended 2017), American Urological Association, [https://www.auanet.org/guidelines/vesicoureteral-reflux-guideline], last visited on the 8th of January 2020, Last update in 2017. 

[8] Image kindly taken from Radiopaedia, [https://radiopaedia.org/cases/illustration-vesicoureteric-reflux-grading].

[a] Inflammation of both the lining of the renal pelvis and the parenchyma of the kidney especially due to bacterial infection, as per the Merriam-Webster dictionary.

Post Photo by Robina Weermeijer on Unsplash.

On the management of Paediatric: 1) Vesicoureteral Reflux and 2) Dietary-related eczema

THESE ARTICLES ARE BEING PREPARED FOR YOU AND ARE COMING SOON. STAY TUNED!

Why is there a “delayed onset” of antipsychotic action?

As a medical information specialist I am confronted with a variety of questions related to the trending therapeutic areas out there: immunoncology, cardiovascular, central nervous system, virology, orphan diseases, immunology, and so on and so forth. Every day I learn something new, from medical nomenclature to the mode of action of a certain drug, a wide range of topics pass through my eyes and I savour the opportunity to be well informed. Often, I myself, try to understand certain disease area aspects that are not so well explicit to the public or still remain a huge question mark for most of the healthcare professionals, clinicians and researchers out there. 

Recently, I have asked myself 'Why is there a “delayed onset” of antipsychotic action when changing between products?' as this is a recurrent situation to which I was never offered a clear response. Why is it so typical of treatments with antipsychotics that the patients deriving from product A to product B will quite often experience an adaptation phase? I can immediately relate to, for example, some research work I did back in the days when I graduated and my final year research project covered Cushing's syndrome. The case study I prepared did partially look through the desensitisation experienced by the patient's organism after a certain period of exposure to the very same drug. Different active substances would perform differently in terms of the body responses to the drug (pharmacokinetics) and the effects of such drugs in the different human sub-systems (pharmacodynamics). But when you consider the same basic active agents however in different products, it's very unlikely (if not almost impossible) that the aggregating/stabilising salt where these molecules 'sit' would impact that much on the efficacy of the product.

I decided to investigate a bit further, and here's what I found on the delayed onset of antipsychotic action, especially when changing between products?

Effect timings

Apparently, when considering the findings of the review article by Agid et al (2006) [1] there isn't a delayed onset, and actually the antipsychotic effect is within the first day, however the strongest more 'visible' antipsychotic effects are produced in the first two weeks after administration. Still according to this review, the most improvement is obtained in the very first month of treatment against any other period of treatment or follow up.

Even though it does not immediately respond to the question, as there is no switch between products in the previous paragraph, it already offers some nice pointers to understanding this issue. Could all this be a myth? Let's continue investigating.

A myth or a theory?

Psychotherapy is full of acquired myths as it is the norm for any therapeutic area with considerable difficulty in scientifically measuring improvement. But according to [1] it was in the 70s when this idea appeared stating that the onset of antipsychotic action is delayed in about 2 to 3 weeks. This led to investigations on what would be the underlying causes prompting such delay; and some authors arrived to a possible theory known as 'The Depolarisation Block Theory'. As per the authors two studies suggest that the explanation for a delayed onset of action is based on preclinical studies (on paralysed anaesthetised mice) involving recordings of dopamine neuron firing proposing that the effect on dopaminergic neurons in the brain after repeated administration of an antidopaminergic drug (commonly known as antipsychotic) is the inactivation of firing that usually occurs only after ~3 weeks of continuous treatment with said drug - ergo, a delay onset. Consequently, clinicians and investigators thought that this reported delay explained the delay in the therapeutic effect of the administered drugs [2] [3] [4].

The fact is that this theory was so strongly believed as factual that researchers started looking for biomarkers to actually support it. If found, no one would dare question its prevalence and thus the theory would be validated into something more clinically and scientifically accepted. The idea of its consubstantiation was to basically grow the theory into a postulate, to then grow it into an axiom.

After many different attempts this theory was 'officially' refuted as so well discussed by Agid et al (2003) [5]. The authors quite well mention that for understanding the mechanism of action of antipsychotics it is crucial to have a clear understanding of the time course over which effects take place. [5] put to test the delayed-onset hypothesis by subjecting it to a meta-analytic study, meaning by subjecting 'a large amount of data from a multitude of studies' to a statistical combinatorial arrangement that in the end informs on whether effects in different studies are equal or vary to the next one. And sometimes, it is even possible to obtain from a meta-analysis study, the underlying reason why effects were different/same. Clever, isn't it? One got to love this STATS geniuses!

So by scrutinising 42 published studies, 7450 patients 119 independent treatment response and time curves, the investigators recognised that actually an 'early onset effect' was present even beating the timeline of the estimated effect of the placebo treatment!!! In conclusion, the analysis fully rejects the 'delayed onset' theory, reinforces the idea that effects initiates at first week and grows in strength over the proceeding weeks, and that the most 'readable/visible' signs of effect are observed two weeks after treatment has initiated [5].

Big names of the neuroscience field throughout the middle of the 20th century helped propagate this idea of 'delayed onset' of antipsychotics. This helped propagate yet another theory that resulted as the possible physiological explanation, the aforementioned 'depolarisation block hypothesis'. But because the precise time course of improvement observed after administration of antipsychotics in a patient-treatment has never been solidly scientifically established, this hypothesis cannot be assumed as having enough scientific backing to support its reliability.

As extremely well presented and discussed in [5], the crucial detail in this debate is to accept and differentiate 'delayed onset' from 'delayed realisation of full improvement' as suggested by the authors. OK, many people can say - 'Well, but the idea is to know when you feel better; it doesn't really matter if it's working or not in the body if in fact one can't feel the physical effects and improve'.

I give' em that. Makes perfect sense!!! ... But then, that is what happens in all medical areas, with specific differences concerning the class of pharmaceuticals used> Nonetheless, all pharmaceuticals will take their time to act upon the subject. What really makes an incredible difference in all of this debate is, in my opinion, four very important things:

1) The level of affliction - a patient who is feeling quite poorly will urge the healthcare professionals for an immediate effect of the administered treatment (drug or drugs) on the physical system; if compliance, quality of drug or prescribed treatment as a whole is not adequate, it is possible that the patient will turn on the drugs' supposed 'delayed onset' as the one factor undermining improvement to his/her health. Add to that a multitude of disease experts making noise about the same and there you go, you have built your much wanted axiom. But one can never forget that wrongly or incompletely postulated ideas are not scientific validations, and ... a headache is a headache, a psychosis is a psychosis.

2) The seriousness of the disease - The more complex a disease the harder it is for a single pharmaceutical to respond to improvement expectancy, especially when there is concomitant medication involved. That and to an extent, considering their different biochemical natures, will affect the perceiving of efficacy of the drug under scrutiny.

3) The drug's mode of action - drugs are not all acting the same way or via the same pathways. Physiological resistances are present as they would normally be in a hyper-dynamic responsive organism as the human body is.  Where the effects might take different times to be 'concretely felt' by the patient, some drugs will operate differently or through different mechanisms even when the overall goal is the same. This will immediately impact on how rapidly their effects are observed, not only concerning its pharmacodynamics, but actual also in the sense of improvement felt by the patient.


[1] Agid, O., Seaman, P., Kapur, S. (2006). "The “delayed onset” of antipsychotic action — an idea whose time has come and gone". J Psychiatry Neurosci, 31(2), pp. 93–100.

[2] Bunney, B S., Grace, A. A. (1978). "Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity". Life Sci., 23(16), pp. 1715-27.

[3] Grace, A. A., Bunney, B. S. (1986). "Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recording". J Pharmacol Exp Ther, 38(3), pp. 1092-100.

[4] Bunney, B. S.,  (1984). "Antipsychotic drug effects on the electrical activity of dopaminergic neurons". Trends in Neurosciences, 7(6), pp. 212-215.

[5] Agid, O, Shitij, K., Tamara, A. et al (2003). "Delayed-Onset Hypothesis of Antipsychotic Action: A Hypothesis Tested and Rejected". Arch Gen Psychiatry. 60(12), pp.1228-1235. 

Post image by Laurynas Mereckas on Unsplash.

Inflammation, Good or Bad?

By working in medical communications you are presented several different questions on a daily
basis. Some are accessible and straightforward, and some others are very high profile and demand further research. Nevertheless, even after these are answered, based on the many sources of information available in-house and spread out there through official sources, now and then remaining question marks still surface. I suspect that one universal question that always pester people's minds, be them the general public or highly proficient medical professionals is the importance and relevance of inflammation.  

If you think about it we were always told that it is important to tackle inflammation to avoid it progressing and end up in febrile events and other tricky associated scenarios. However, inflammation in its pure sense and in a non-chronic autoimmune patient is a natural and necessary immune response our bodies trigger to refrain an external agent from affecting us. And this is a good thing, right? So why do we jump on to taking antiphlogistics at the very first sign of inflammation? 

My personal take on inflammation in generally healthy people has always been the same as for fever, i.e., let your body control it until you conscientiously recognise your body is either not controlling it adequately or has triggered hyper-reactive control measures. I rarely take any antipiretics if I'm not around 38 Celsius. I always let the body challenge itself. Then when I recognise it's not going to go there on its own, the pharmaceutical is at hands' reach. This is me, please do not use it as clinical guidance. I am not a healthcare professional, I am a professional in medical communications/information and this is solely my personal view as an avid science researcher. For the sake of what is your health and safety follow the advice given to you by your healthcare professionals.

Obligatory disclaimer shared, the remaining question here is actually of a double nature:

1) Is inflammation good or bad?

and

2) When do we know we must tackle the inflammatory process?

I did some literature search on this topic and was able to find some interesting information that is hereby compiled for you.

What is Inflammation?

On its own inflammation is a protocol developed by higher organisms to tackle any foreign agent of developing an invasive strategy that can undermine the stability of the system. In that sense, we humans have developed internal and external barriers that account participation of many agents, from anti-inflammatory foods, to structures like skin, nasal hair, or even mucus.

Being part of the human organism's natural defensive pathways and protective paraphernalia, inflammation is a gradual response process to infection and tissue damage as one of the primary steps of the healing process. When we consider that for producing muscle mass at the gym we need to break the muscle tissue, thus allowing it to grow and then refill it with the new generated cells, the process that encompasses it is inflammation!  But on the other hand, and so well simplified by the website Science-Based Medicine [1], when aging brings about chronic inflammation, the result, among other detrimental losses and consequences, is the cellular damage that can chronically lead to several ailments like the well known atherosclerosis (where plaque composed of fat, cholesterol, calcium ad other molecules build up in the arteries narrowing them overtime) [2] leading to very serious issues like stroke, heart attack, eventually death. There is also the almost universal example of the autoimmune condition rheumatoid arthritis, where the immune system mostly attacks synovial joints, heart and lungs and that results in swelling, stiffness and pain with devastating consequences for the quality of life of the affected patients [3]. 

In what consists the Inflammatory process?

Is Inflammation Good or Bad?

To answer this questions we must visualise an aid motion picture where one is continuously exercising and breaking muscle, not allowing the same any time to heal. Or for example, imagining the immune system sending patrol cells to destroy invaders but prolonging the destruction to such lengths that it wouldn't be even possible to discern anymore who is evil from who is good. Another figurative example can be the use of the water in a swimming pool to put down a lighting match. Unnecessary, is it not?). Water all over the place when you could have done the same with a bit of a glass of water!

Constantly hitting one's cells with a protective army of patrol soldiers can become irritating for one's organism. That is exactly what happens with people when they eat particular foods they are sensitive too, be it lactose, honey, peanuts, you name it. If your body sends out those patrol cells in a normal approach you'd have a mild inflammation and allergic reaction (let's say). If your body is as nervous as Venezuela's Maduro or Turkey's Erdogan, your body would want to send five armies to seek for two little peanut buds and then end up beating up everything they found in the vicinity and further on. And that would progress to a senseless chronic beating up if you don't eventually tackle such unnecessary and unregulated defensive mechanisms with the common sense of an antiphlogistic tablet to refrain the body's immune system's rage.

Overall, inflammation plays a vital role when as a balanced natural response to a disruptive physical imbalance in one's injured organism. However, if one lets it overwork in its functions,  one'll suffer the consequences. And these can be devastating in chronic autoimmune or immunosuppressed patients.

For a list of anti-inflammatory natural products that you can use in your normal diet, please ACCESS HERE, HERE and HERE.

1. Inflammation: Both friend and foe, Science -Based Medicine, [https://sciencebasedmedicine.org/inflammation-both-friend-and-foe/], last visited on the 6th of June 2019, last update on the 27th of December 2011.

[2]. Atherosclerosis, National Heart, Blood and Lung Institute, [https://www.nhlbi.nih.gov/health-topics/atherosclerosis], last visited on the 6th of June 2019, last update unknown.

[3]. Diet and rheumatoid arthritis, The Association of UK Dietitians, [https://www.bda.uk.com/foodfacts/diet_rheumatoid_arthritis], last visited on the 6th of June 2019, last update on September 2018.

Post picture by Cristian Newman on Unsplash.

On the neurotoxicity of caterpillars resulting in visual impairment

It was the hot dry Summer of 2018 when I got a message from a North American reader of The Toxicologist Today (right when I was sunbathing at a crowded beach whilst munching on 'Bolas de Berlim' like a very hungry caterpillar). After getting home for lunch there was a brief exchange of messages where I promised the kind reader I'd do the best I could to write a post on her afflictions, if she promised me she'd seek urgent medical advice. However, my mobile crashed. It crashed so hard that still today I cannot find the messages said person sent me, I cannot recall in what platform had we been having such brief chat, I cannot remember anything else but the fact that this person had a dog who had been playing with caterpillars and she has been (since then) with impaired vision, nausea and dizziness.

I remember expressing my deepest concern to this person and telling her time and time again that I am not a medical doctor, I am a Medical Information Specialist, a God damn good one :) but still, not a medical doctor... and definitely not a Guru Healer.

The person still asked me to inform her on any knowledge I had concerning studies covering the neurotoxicity of that specific caterpillar (still cannot precise which one) especially those with reported effects on the nervous system resulting in vision impairment.

Ai ai ai ai ai, we say in Portuguese when we are concerned about something that might prove serious. Once again I redirected the reader to her GP, stressing that if possible she should look for a speciality appointment after checking with the GP. But with very limited time in my hands and so many different projects still in progress, I could not really dedicate much time to said post... until now. I found about 30 minutes yesterday and today to do the best possible search within such time frame, even though I have no clue if the reader was talking about the Giant Silkworm Moth Caterpillar or the Oak Processionary Moth, or one of the many other that just inhabit this whole wide world. One thing I got to remember, the person was from the USA! So that will restrict the beasts to just those living and munchin' within them 3,797 million square miles that comprise the United States of America! Easy-Peasy :/

For the first time and because scientifically accurate referenced free information on the neurotoxicity of caterpillars resulting in vision impairment is not so much available out there, I had to resort to a couple of pages [1] [2] bearing no scientific references. If any of you find any inaccuracy, please let me know about it promptly so I can correct the article as best as possible. I looked for the most nasty caterpillars inhabiting the USA territory as I kind of recall the reader stating something in the lines of "my doctor told me it is unlikely that caterpillars affect our vision... it might be stress". Therefore, I decided to look for those that comprise the hardcore line of attack and I found these four:

Acharia stimulea (Eastern USA)

Megalopyge opercularis (Central America)

Automeris io (Southern US)

Lophocampa caryae (Central America)

After reducing the list of candidates to just four I had to look for any articles on envenomation causing blurry vision (and the like) that among all other symptoms was the one the reader was most concerned about. I found an article by Agarwal et al (2017) on Ophtalmia nodosa (inflammation of the eye when particles [could be caterpillar's hair] lodge in the conjunctiva, cornea or even iris. However, as the author puts it, this is a rare condition but a serious one that can result in loss of eye because of the constant inflammation within the vitreous humour. In the case-study they analysed there is a physical observation of the many caterpillar hairs that were present in the patient's eye where they used ultrasound biomicroscopy. This patient had blurring of vision and diminution of vision just like my reader reported, so the putative presence of caterpillar hairs in her vitreous humour could be another important thing for her to report to her doctor. In addition, this article also refers that their patient had some of the hairs removed and that the eye was "quiet for two months", but then the diminution of vision persisted when the inflammation returned after they stopped the anti-inflammatories (oral corticosteroids). The reason being that many other minute hairs can take months to years to be physically removed by movements of the ocular globe; moreover there are glands connected to the caterpillar's hairs that contain a toxin named thaumetopoein (an urticating protein) that induces inflammation. In this specific case, corticosteroids provided some peace but did not resolve the issue entirely as the hair still needed to be physically removed as thaumetopoein would always be causing inflammation to the area of contact. The NHS talks about the use of an antihistamine cream to antagonise the nefarious effects of thaumetopoein, as preferable approach [4].

In summary, caterpillar dermatitis (known as lepidopterism) can result in inflammatory ocular lesions when hairs come into contact with the different layers of the ocular globe, as discussed above. In fact, Rosen (1990) [5] actually discusses it so well in an article covering such matters and that deserves your uttermost attention. As the author suggests, there has been reports that these hairs can induce pruritus (itching), burning and painful dermatitis resulting in ocular lesions that can come with comorbidities such as neuropathy, convulsions, arrhytmia and dyspnea. Some of these same issues were reported by my reader!!!

It was indeed extremely difficult to find free information available in the Internet on these matters, but on Medscape one can read that when the ocular globe comes into contact with hairs from the M. opercularis (the puss caterpillar I already told you about) the resulting erucism (envenomation by caterpillars) might be counteracted by H1 and/or H2 blockers (antihistamines), but if there's pain the doctors might have to use narcotic analgesics [6].

That is the information I hope my reader is now glancing her eyes through. I honestly hope she is feeling much better and that she visited her doctor for a professional observation. For all of you who just reached this post, whatever reason brought you here, I hope you found useful info.

[1] 5 of the world's most toxic caterpillars, SunnyScope, [https://www.sunnysports.com/blog/5-worlds-toxic-caterpillars/], last update unknown, last visited on the 20th of September 2018.

[2] Stinging caterpillars of the United States, The Ark in Space, [http://www.arkinspace.com/2011/05/stinging-caterpillars-of-united-states.html], last visited on the 21st of September 2018, last update on the 12th of June 2016.

[3] Agarwal, M., Acharya, M. C., Majumdar, S., Paul, L. (2017). "Managing multiple caterpillar hair in the eye". Indian Journal of Opthalmology, 65(3), pp. 248-250.

[4] Health warning over invading moth, NHS, [https://www.nhs.uk/news/heart-and-lungs/health-warning-over-invading-moth/], last updated on the 4th of August 2010, last visited on the 21st of September 2018.

[5] Rosen, T. (1990). "Caterpillar dematitis". Dermatologic Clinics, 8(2), pp. 245-252.

[6] Caterpillar envenomation, Medscape, [http://misc.medscape.com/pi/iphone/medscapeapp/html/A772949-business.html], last visited on the 21st of September 2018, last update unknown.

On the health benefits of Pimenta racemosa

A reader (Lary Hirabedian) left me with a question as a comment "On the allergenic potential of bay leaf" about two months ago. I have been so busy with work and my children that it was almost impossible to dedicate any time whatsoever to researching properly and responding to Lary. He asked me if I could comment on Pimenta racemosa vs bay laurel, i.e., establishing a comparative efficacy, health benefits against, for example, cholesterol reduction, diabetes, pain reduction, antiviral and antibacterial effects, etc. He also suggested that Pimenta racemosa in the shape of oil or infusion can be more effective than bay laurel.

I'd like to reinforce that I am not a plant biotechnologist and I am not a plant physiologist, actually I am quite far from enjoying the study of plants per se. My interest lays on the different substances that exist in the world (plant, animal or inorganic) as a scientist interested in those that have a toxicological potential or health benefit to all of us. Having said that, I think I'd like to contribute with a few lines to help responding to this question without presenting a dispute between these two plants. I prefer to provide you with what is out there, literature-wise, concerning the different molecules present in Pimenta racemosa.

But to start with, let's try and understand exactly what plant are we talking about. Pimenta racemosa is the scientific name for the plant that is commonly known as Bay-rum tree, others call it malagueta, and I am sure other people worldwide call it different names for this plant is quite widespread through Asia and Africa. The plant belongs to the Myrtaceae family and is famous for its essential oil with 'alleged' curative properties. That is what we will try to unfold in the coming lines.

In the article by Contreras (2014) [1] one can find a long list of different research studies on the  putative pharmacological effects and biochemical agents of the different Pimenta species, like for example the capacity to repel insects and its mosquito larvicidal and nematicidal properties, the capacity to reduce/inhibit pain (for example pain associated to dysmenorrhea), anti-inflammatory effects (possibly due to flavonoids, tannins, polyphenols), the capacity to counteract fever (possibly due to quinones), antimicrobial properties (e.g., flavonoids, tannins, triterpenes, steroids), antioxidant properties (e.g., flavonoids, saponins, polyphenols), antimutagenic effects (e.g., flavonoids, tannins, saponins), as an antidote against cobra venom and so on and so forth to a very detailed biochemical level. It is just a matter of getting that article and read thought the other references for the specific effect one is trying to learn more about.

Another very composed article [2] identified 52 components (where 1,8-cineole was the major one) present in the flower itself of this plant, after gas chromatography assays.  But the most interesting observation I could personally identify in this article was the cytotoxic activity against a panoply of human cell lines and the antimicrobial activity against Geotrichum candidum and bacillus subtilis - part of the human microbiome, and where the identified minimum inhibitory concentration  [MIC] is exactly the same as for the common antibiotics applied against these bacteria, Ampicillin and Amphotericin B, respectively. Actually, this article is a great add-up to the Alitonou et al (2012) [3]  where essential oils compositions of Pimenta racemosa from two different sites in Benin were studied thus unveiling the same antimicrobial, antioxidant and even acaricide properties, but only this time no anti-inflammatory effects were recognised.

In fact, great literature is starting to emerge on this topic and it is just a matter of looking in the right articles for gaining the adequate knowledge. Finally, the food industry will definitely want to look into this essential oils for its antioxidant properties, as well as the phamaceutical industry into all the different pharmacological effects identified.

Image kindly taken from Plantogram, Leon Bay Rum Tree, [https://plantogram.com/product/bay_rum_lemon/], last visited on the 10th of April 2018, last update unknown.

[1] Contreras, B. (2014). "Preliminary phytochemical screening of pimenta racemosa var. racemosa (Myrtaceae) from Tachira - Venezuela". Pharmacologyonline, 2, pp. 61-68.

[2] Al-Gendy, A. A., Moharram, F. A., Zarka, M. A. (2017). "Chemical composition, antioxidant, cytotoxic, and antimicrobial activities of Pimenta racemosa (Mill.) J. W. Moore flower essential oil". Journal of Pharmacognosy and Phytochemistry, 6(2), pp. 312-319. 

[3] Alitonou, G. A., Noudogbessi, J-P., Sessou, P. et al (2012). "Chemical composition and biological activities of essential oils of Pimenta racemosa (Mill.) J. W. Moore from Benin". International Journal of Biosciences, 2(9), pp. 1-12.

On the allergenic potential of Bay Leaf

It has been a long time since I had any time available at all to update the blog with my own text and ideas. The reason behind it is quite simple, and to a certain extent quite positive - I have been very busy with additional responsibilities related to my profession. From early November to this day my days have been consumed by work, and I am a bit of a workaholic, not so much in the obsession sense of the concept, but definitely on the pleasure I take from doing what I love the most - working in science.

However, I pride myself in always responding to my readers and I have had this stone stuck to my shoe with a pending question from Lee Scholl. This reader left a question in the bay leaf post concerning a change of regimen his girlfriend decided to perform, more specifically and I quote:

"My girlfriend is planning to start a regimen of ingesting bay Laurel oil for cardiovascular health. It sounds like this isn't an issue as long as she isn't allergic?"

Well, to start off it is also important to explain that no blog writer, regardless of how professionally accredited he/she is will ever be capable of determining if something isn't an issue for a certain person for there is always the need to know the health status of the individual. What I mean is medical advice can only be given by medical professionals that know the clinical records of said patient, the best person to offer a professional opinion on a health hazard to a determined person is therefore the healthcare professional familiar to said person's medical history.

I am not a medical doctor, I have a doctorate! I am a medical information specialist that happens to hold academic qualifications in Molecular Microbiology (PhD), Toxicology (MRes) and Biotechnology (BSc), and about 10 years of research experience. With this blog I only provide what can be taken as an informal second line search to articles and information available out there, and combine it to my knowledge on the different scientific areas I am proficient on. Ergo, I provide information for people to make their own decisions, I do not provide medical advice.

Now, jumping directly to the meat in bone that is requested here. What have I found that can help this couple decide whether this change of regimen or this dietary decision can represent danger, from the many free relevant articles that can be found online?

1) To start with I found this really nice book that might have incredible additional information on many aspects involving essential oils and their putative dangers to human health. The name is "Essential Oil Safety" [1]. Looks like a good easy read and from the index sounds like the authors did a great job! In this very same book on page 323 there is a summary of  the bay Laurel toxicity that tested for adverse skin reactions at a 1%, 2% and even 10% concentration in different animals and human volunteers with different outcome reactions (but overall nothing tremendously serious below the 10% threshold). However, there are indications of contact dermatitis, especially at a 10% concentration level. But the triggering molecule is not clear to be costunolide (the sesquiterpene lactone that can be obtained/isolated from Laurel).

2) I could come up with a million articles on the putative toxicity of Bay Laurel, but I have already written so much about it that it is just a matter of revisiting the previous articles here, here, here and  also here, here, here, here, here, and finally here. However, in regards to the benefits I would like to stress this article found on the Indian bay leaf (Cinnamomum tamala Nees.) where the authors explore that the leaves extract can prevent the increase of serum levels of total cholesterol, low- and very low-density lipoprotein cholesterol, prevent the formation of fat deposits in the arteries (known as the atherogenic effect) and increase the levels of the so called 'good cholesterol' (meaning high-density lipoprotein-cholesterol) [2].

Sorry for such a late post but it has been crazy over the past three months.

Have a nice read.

[1] Tisserand, R . and Young, R. (2014). "Essential Oil Safety". 2nd edition. Churchill Livingstone Elsevier.

[2] Dhulasavant, V., Shinde, S., Pawar, M., Naikwade, N. S. (2010). "Antihyperlipidemic activity of Cinnamomum tamala Nees. on High Cholesterol Diet Induced Hyperlipidemia". International Journal of PharmTech Research. 2(4), pp. 2517-2521.

Post image kindly taken from alibaba.com

I have a question, or actually three... on bay leaf

Bay leaf and more bay leaf. A million questions...! 

It took me quite a while to find sometime to research on these matters. That, and the fact that I don't want to make this blog talk exclusively of bay leaf. There is loads of important toxicology issues to debate, inform and learn about; why focusing so much on bay leaf.

But the audience likes the topic, I like the audience, matching 2 and 2 together results in 3. Yes, today and only today 2+2 = 3 questions answered on bay leaf.

1) From an anonymous person who's asking us about the properties of bay leave for curing bunions. For those who aren't familiar with the term, a bunion is, according to the NHS website a 'bone deformity of the joint at the base of the big toe'. Considering that I'm no medical doctor and that any patient suffering with such ailment should definitely seek treatment with one, all I can say is that as a home-remedy I have not found scientific information on bay leaf curing bunions. Anecdotal reports??? Loads of them, they're all over the web and you can do with such information whatever you feel like. My personal advice is that for an issue that often derives from autoimmune complications, like rheumatoid arthritis, or emerges from genetic proneness traced back through one's family tree, a simple assessment is not the brightest approach. In addition, these websites base their results on bay leaf as drinking tea and oil as ointment, and on the anti-inflammatory properties of the plant itself. Bay leaves contain Eugenol that is a chemopreventive substance [1], meaning this chemical has the potential to inhibit/stop a certain disease process. In that sense, it might induce anti-inflammatory responses, like when one is afflicted with bunions. 

2) Lolo Gibbins, a reader of The Toxicologist Today, presented me with a very different question concerning the use of bay leaves to get rid of rats. I will not prolong this one request for long. Using specifically bay leaf as a pesticide against rats... or rodents... I never heard of. Not meaning it's impossible, but I never heard of. What I heard about is of a quite recent article by Chaudhary et al (2017) [2] that discusses the advances in the knowledge gained on the potential of Azadirachta indica (also known popularly as neem leaves  - post image) as a biopesticide. As you may know biopesticides also encompass rodenticides (a substance capable of killing rodents). It's worth reading. And if you are willing to pay me for the time invested, I can read  itand summarise it for you ;) 

3) And the last one comes from an unknown reader who have questioned me on if bay leaves combustion fumes are toxic for cats. My answer couldn't be blunter and humbler. I simply do not know and found no information whatsoever on the matter. Probably the best advice is indeed for the reader to revisit that post on the toxicology of burning bay leaf wood as a source of fuel that can be accessed HERE.

1) Hussain, A., Brahmbhatt, K., Priyani, A., Ahmed, M., Rizvi, T. A., Sharma, C. (2011). "Eugenol enhances the chemotherapeutic potential of gemcitabine and induces anticarcinogenic and anti-inflammatory activity in human cervical cancer cells". Cancer Biotherapy and Radiopharmaceuticals, 26(5), pp. 519-527.

[2] Chaudhary, S., Kanwar, R. K., Sehgal, A., Cahill, D. M., Barrow, C. J., Sehgal., R., Kanwar, J. R. (2017). "Progress on Azadirachta indica based biptesticies in replacing synthetic toxic pesticides". Frontiers in Plant Science, 8(610), pp. 1-13.

Post image kindly taken from Neem, Dr. Haushcka, [https://www.dr.hauschka.com/en_DE/knowledge-base/medicinal-plant-facts/neem/].

Why does my head hurt when I drink avocado leaves tea?

The first thing that I feel when someone complaints of headaches and inquires about the reasons behind it, is - I don't know, it could be a million different things. And in reality it could indeed be a million different things. The brain and its mysteries still to unfold, from a common headache to the overwhelming migraine. However, if one states that whenever one has something specific a headache surfaces, then we can restrain to a thousand, rather than a million, different reasons.


An anonymous person asked me, through the avocado leaves tea for cancer and osteoarthritis post (read here), why her/his head always heart when drinking avocado leaves tea. I must be honest, I never heard such thing before. My curiosity got even stronger when after a very quick search through a few science articles, I immediately got confronted with several other reports from other complaints pointing in the same direction.

Nonetheless, I gave it a lot of thought and found some interesting scientific facts that 'might', to a certain extent, point towards the causality in this headache complaint from one of my readers. A complaint of headaches after drinking avocado leaves tea.

Fact 1) Avocado is anecdotally linked to chronic headache due to the presence of two biochemicals, namely, histamine and tyramine. And you can even find it on the web as a NO-NO food in this novel headache-free diet based on information adapted from [1].

Fact 2) Avocados are related to hypertension incidents due to monoamine oxidase inhibitors (MAOIs) that ultimately interfere with the metabolism of the previously mentioned agents (see fact 1). Even though it is also reported that hypertensive episodes cannot immediately be related to the presence of tyramine in avocados, as I suggest in the opening paragraph, I was able to find actually a case-report for a 35 year old white male who ate avocados and guacamole. And guacamole is based on ripen avocado that due to its maturity is likely to have an increased content, tyramine-wise. In that same report [2] they let us know that the patient is dealing with a fair amount of other health issues, but also state that "The amount of tyramine that is dangerous for a patient being treated with MAOIs is not known precisely, although it has been reported that 6 mg is sufficient to produce adverse reactions, and that 25 mg is dangerous", as stated in [3]. These values are based on a fairly old article from 1965, one that needs to be taken with a pinch of salt even though the human body is still a human body, but the analytical methods have improved tremendously.

Fact 3) It is important to be aware that tyramine on its own, may or may not be the cause for hypertension-based headaches. But molecular interactions between tyramine and certain pharmaceuticals (e.g., MAOIs for depression) can determine a low breakdown rate of the former. Thus, resulting in an strong tyramine effect on the vascular system. So, it is also very important to know if indeed some medicine one is taking can be behind a lower metabolic 'digestion' of the tyramine content.

Fact 4) Tyramine is the metabolic product of the breakdown of amino acid Tyrosine that is also present in several other types of food. But in avocados there is also histamine, a potent neurotransmitter with a crucial role in our immune system, therefore allergies and the like. Histamine intolerance is known to be more frequently reported these days (estimated 1% of adults may be histamine-intolerant with 80% of these being females) according to [4], and since histamine is a vasoactive amine, as tyramine also is, these reported headaches after drinking avocado leaves tea could be due to histamine rather than tyramine. I must plea ignorance on the real content of histamine and tyramine in avocado leaves, I just couldn't find it anywhere, I'm afraid. Vasoactive amines can trigger allergy-like symptoms, such as headaches, rashes, hot flushes, etc etc etc [5]. Usually these symptoms occur around half an hour after consumption and vary from individual to individual.

Based on the extremely limited amount of information provided by the reader I can only say that one can be present to one of these facts, be it a histamine intolerance/sensitivity, an interaction between tyramine and medication or an excessive intake of tyramine/histamine. My opinion is that a nutritionist can help any of you unveil the source of the problem - if you also have it.

But in the meantime to help those who are always seeking for advice on food intolerance, I added to the list of links here in the blog, right on the Toxic Databases (see image below), a link that will take you straight to the Food Intolerance Diagnostics web page. There you can actually get to know so much more about loads of other food intolerance issues.Hope it helps!

***

[1]. The American Council for Headache Education Tyramine Restricted Diet & Theisler CW: Migraine Headache Disease: Diagnostic and Management Strategies. Austintown: Aspen Publishers; 1990, pp. 111–112.

[2]. Generali, J. A., Hogan, L. C., McFarlane, M., Schwab, S., Hartman, C. R. (1981). "Hypertensive crisis resulting from avocados and a MAO inhibitor". Drug Intelligence and Clinical Pharmacy, 15, pp. 904-905.

[3]. BlackweIl, B., Mabbitt, L. A. (1965). "Tyramine in cheese-related hypertension crisis after monamine oxidase inhibition". Lancet, 1, pp. 938-40.

[4]. Histamine, tyramine and other biogenic amines, Food intolerance diagnostics, [http://foodintolerances.org/intolerances/histamine-biogenic-amines-intolerance/], last visited on the 10th of February 2017, last updated on the 16th of August 2016.

[5]. Histamine intolerance, Allergy UK, [https://www.allergyuk.org/common-food-intolerances/histamine-intolerance], laast visited on the 10th of February 2017, last updated on October 2015.

Post image kindly taken from "Everyday Health" - 8 Smart Food Swaps for a Healthy Heart, [http://www.everydayhealth.com/atrial-fibrillation/diet/food-swaps-for-healthy-heart/].