Showing posts with label anosmia. Show all posts
Showing posts with label anosmia. Show all posts

Tuesday, November 28, 2023

Hope for Long Covid Parosmia Sufferers


Not one but two:

New Treatment Restores Sense of Smell in Patients with Long COVID
Nov 2023, Radiological Society of North America

Parosmia, a condition where the sense of smell no longer works correctly, is a known symptom of COVID-19. Recent research has found that up to 60% of COVID-19 patients have been affected. While most patients do recover their sense of smell over time, some patients with long COVID continue to have these symptoms for months, or even years, after infection.

The research team used a stellate ganglion block, which includes injecting anesthetic directly into the stellate ganglion on one side of the neck to stimulate the regional autonomic nervous system. The minimally invasive procedure takes less than 10 minutes, and no sedation or intravenous analgesia is necessary. CT guidance was used to position a spinal needle at the base of the neck for injection into the stellate ganglion. The researchers added a small dose of corticosteroid to the anesthetic in the pharmacologic preparation, suspecting that the COVID virus may be causing nerve inflammation. 

Follow-up was obtained for 37 patients (65%), with 22 (59%) of the 37 reporting improved symptoms at one week post-injection. No complications or adverse events were reported…

via the Radiological Society of North America and Jefferson Health in Philadelphia: New Treatment Restores Sense of Smell in Patients with Long COVID (press release). Nov 20 2023.


New clinical-trial data suggest that an antiviral pill called ensitrelvir shortens the duration of two unpleasant symptoms of COVID-19: loss of smell and taste
Nov 2023, Nature

From Japan - The medication is among the first to alleviate these effects and, unlike other COVID-19 treatments, is not reserved only for people at high risk of severe illness. The antiviral drug molnupiravir speeds recovery of these senses, but generally only the most vulnerable people can take it.

That is not true for ensitrelvir. In Japan, where it received emergency approval last year, the drug is available to  individuals with mild to moderate symptoms, regardless of their risk  factors. Its developer, Shionogi in Osaka, Japan, is continuing to conduct clinical trials of the drug, which has not yet been approved outside Japan.

In one such trial, people with mild or moderate COVID-19 symptoms were given either 125 or 250 milligrams of ensitrelvir or a placebo. At the start of  the study, 20% of participants reported some level of smell or taste loss. After the third day of treatment, the proportion of participants reporting such symptoms in the ensitrelvir groups started dropping more sharply than 
did the proportion in the placebo group.

“Most people will eventually recover on their own, but we know that some people have had 
long-term issues with smell and taste” 

via Shionogi in Osaka, and Fujita Health University: Nature. New pill helps COVID smell and taste loss fade quickly. Oct 17 2023. doi: https://doi.org/10.1038/d41586-023-03244-7 

Partially unrelated image credit: AI Art - The Human Condition is a Paradox - 2023

Further Reading:
Smell for Life: The Campaign to Tackle Smell and Taste Disorders
Apr 2023, Monell Center for Advancing Discovery in Taste and Smell

Friday, February 10, 2023

Hyper-Hypo-Nose


Sounds like a big deal. Also sounds like a great explanation for the phantom "Iso E Super" anosmia that isn't a full anosmia.

Researchers reveal an added layer of nuance in our sense of smell
Jan 2023, phys.org

They've discovered something called a depolarization lock to add to the standard combinatorial coding model used for odor detection, and it turns off the receptors when presented with high concentrations of an odor. 

You might already be familiar with this phenomenon for odors like violet and hydrogen sulfide (H2S). In the case of H2S, this receptor-deactivating behavior can be life-threatening, which is why you're supposed to wear a supplemental gas monitor, in addition to your nose, when entering areas suspected to contain high concentrations of the gas. 

^This write-up does a good job of explaining the fruit fly experiment that led to this discovery, as well as possible reasons why this would be needed for olfaction. 

via UC Santa Barbara: David Tadres et al, Depolarization block in olfactory sensory neurons expands the dimensionality of odor encoding, Science Advances (2022). DOI: 10.1126/sciadv.ade7209


Post Script:
In addition to Iso E Super, Hedione is another perplexing odorant that's in almost every fragrance formulation from floor cleaners to face cream, and yet most people can't actually smell it. Well, you can smell when it's NOT there, but you can't smell when it is. (Old post mentioning Hedione)

And if I'm reading this correctly, it sounds like someone with a hypersensitive nose might be more likely to lose their sensitivity altogether. I seem to have some kind of hyperosmia myself, and yet when I go out to sample perfume, I often can't smell anything at all. Take the same perfume, put it on a strip of paper and leave it on a table in my house for the next 3 weeks, and I will smell the whole bouquet revealed one at a time as the mixture breaks down. The theory being that if you're hypersensitive to a specific odorant, or all odorants for that matter, your "depolarization lock" will kick in at low concentrations. 

Post Post Script:
Hella synonyms for the musky odorant referred to above, in fact so many that I just wanted to list them here: Iso E Super, Tetramethyl acetyloctahydronaphthalenes is a synthetic ketone fragrance also known as octahydrotetramethyl acetophenone (OTNE) and by other commercial trade names such as: Iso E Super, Iso Gamma Super, Anthamber, Amber Fleur, Boisvelone, Iso Ambois, Amberlan, Iso Velvetone, Orbitone, Amberonne. It is a synthetic woody odorant and is used as a fragrance ingredient in perfumes, laundry products and cosmetics.
-Hall, John B. & Sanders, James Milton, "Perfume composition and perfume articles containing one isomer of an octahydrotetramethyl acetonaphthone", issued 1975

Friday, January 13, 2023

Smells Like Covid Part 2


It's been a couple years since the world learned the word "anosmia," so here's some updates:
(but don't forget this post about how parosmia worked with covid)

The first mass screening system for COVID cases has been developed with a sensitivity of 97%
Dec 2022, phys.org

Washing your hands with hydroalcoholic gel, smelling it and using a QR code to answer a short questionnaire. These very simple actions make up the world's first patented mass screening system for COVID cases.

Citrus fruits and apples are two of the first aromas that people with the SARS-CoV-2 virus stop detecting.

"Citrus" -- I don't remember seeing this at all, so I looked further into the report: "Based on the literature and habits of our Mediterranean study population, it was determined that the most suitable odoriferous substance was lemon." via Institute for Research in Fundamental Sciences in Iran and R DOty at U Penn: Moein, S. T. et al. Smell dysfunction: A biomarker for COVID-19. Int. Forum Allergy Rhinol. 10, 944–950 (2020). https://pubmed.ncbi.nlm.nih.gov/32301284/  -- This study used the University of Pennsylvania Smell Identification Test (UPSIT) which has 40 odorants; I can't read the paper because paywall, but I guess "citrus" or "lemon" is one of those odors. The paper wasn't meant to find the most prevalent non-detectable odor, but I guess it was just sitting there in the data?

"The antigen tests on the market have an average sensitivity of 80%, which means that the number of false negatives is 20%. What we have developed is not a diagnostic test, but a screening system that aims to detect the maximum possible number of positives and prevent false negatives," explained the researchers.

via Youcef Azeli et al, A machine learning COVID-19 mass screening based on symptoms and a simple olfactory test, Scientific Reports (2022). DOI: 10.1038/s41598-022-19817-x

Image credit: Stainless steel climate chamber at the Technical University of Denmark, Mikal Schlosser, 2022


Loss of smell following COVID linked to a person's immune reaction to the infection
Dec 2022, phys.org

They studied antibody levels in people infected during the early days of the pandemic—in all, they studied blood samples of 306 people who had donated blood for study after recovering from a COVID-19 infection. In comparing the antibody levels with other data provided by the donors and their doctors, the researchers determined that those people who had higher antibody levels tended to be the same people who had reported losing their sense of smell or taste. They found that such patients were twice as likely to lose one or the other sense as those who did not have higher-than-average levels of antibodies in their blood.

via Columbia University Irving Medical Center, the University of Pennsylvania, the National Institute of Alcohol Abuse and Alcoholism and the New York State Psychiatric Institute: Jonathan B. Overdevest et al, Chemosensory deficits are best predictor of serologic response among individuals infected with SARS-CoV-2, PLOS ONE (2022). DOI: 10.1371/journal.pone.0274611


Scientists find key reason why loss of smell occurs in long COVID-19
Dec 2022, phys.org

The reason some people fail to recover their sense of smell after COVID-19 is linked to an ongoing immune assault on olfactory nerve cells and an associated decline in the number of those cells, a team of scientists led by Duke Health report.

via Duke University Medical Center: John Finlay et al, Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium, Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.add0484.

Post Script:
Nasal injections could treat long-term COVID-19–related smell loss
Jan 2023, phys.org

Using injections of platelet-rich plasma derived from a patient's own blood. In a trial of 26 participants, those who received the treatment were 12.5 times more likely to improve than patients who received placebo injections. 

"It's a nerve damage and nerve regeneration issue that we're dealing with," she said.

via Stanford: Carol H. Yan et al, Use of platelet‐rich plasma for COVID‐19–related olfactory loss: a randomized controlled trial, International Forum of Allergy & Rhinology (2022). DOI: 10.1002/alr.23116


Thursday, June 9, 2022

Covid's Parosmia Uncovered


Covid has a smell. Not that you can smell sick people, although you can actually. Dogs have proven that it's possible; only that humans have never been trained, and for obvious reasons.

Instead, we mean that things "smell like Covid." That's because everyone who got pre-Omicron Covid also got hit with a neuroplastic time bomb where their olfactory neurons got attacked and then reconfigured. Half the people who got Covid, and its anosmic introduction, knew they had it, and the other half didn't. (This according to a May 2022 study, linked here, and repasted below.)

Lost of people would argue with that stat. And I would have to argue back. The absolute worst source of data for testing anosmia etc is the subjective reporting of the people themselves. We don't even know we have a sense of smell in the first place, nevermind detecting that it's been removed. There are congential anosmics (can't smell from birth) who don't realize they're anosmic until they're teenagers! How do you not realize that? Because we don't talk about smells. They're outright lingua-phobic. And so when we lose it, especially in the midst of a respiratory infection that messes with our breathing, we don't even notice. We also think it's our sense of taste, so when someone asks "have you experienced any change in your sense of smell," you say no, but I did lose my sense of taste. In that study, they used Sniffin' Sticks, so an objective measure, and so they got the 100% stat. 

Next, things "smell like Covid" because after a bout of anosmia, your olfactory system needs to reboot, retrain, pick your computer analogy, and in the process, there's some bugs in the code. Eggs smell like Covid, coffee smells like Covid. Shit? Smells like biscuits. Wait, what? Yes, the Faeces Paradox, see below, it's all been explained for us. Thanks, Flavor Center at University of Reading:

Researchers find cause of disordered smell
May 2022, phys.org

Among the 29 volunteers with post-viral parosmia, scientists found 15 commonly identified compounds that triggered parosmia. They also found reduced sensitivity in some people, via lower TDI scores from Sniffin’ Sticks, although some who were considered functionally anosmic could still detect some of the trigger smells...

Some of the most cited food and drinks that set off parosmia in sufferers include:
  • Coffee
  • Onions
  • Garlic
  • Chicken
  • Green peppers

The most common trigger molecules are grouped into four distinct categories based on structure: 
  • thiols
  • trisubstituted pyrazines
  • methoxypyrazines
  • disulfides
  • (and as always with smell-things: some less common triggers did not fall into any one of these categories)
  • (these molecules tend to be potent, have very low olfactory detection thresholds and, in isolation, are neither distorted nor unpleasant for nonparosmics)

Trigger Molecules and their Parosmic Descriptions:
  • 2-furanmethanethiol ("coffee") is the most frequently reported trigger. Whereas NONPAR (non-parasmics) used a range of food-related terms to describe it (coffee, roasty, popcorn, smoky), PAR (parosmics) often struggled to find suitable descriptors, as they were unable to relate it to anything they had smelled before. PAR typically used words describing its hedonic quality (disgusting, repulsive, and dirty) or new coffee (relating to the altered smell of coffee since onset of parosmia) as described previously. Four PAR described it in the same way as NONPAR (biscuit, toasty or roasty) indicating that it is not universally parosmic, but certainly an important and frequent molecular trigger of parosmia.
  • 2-methyl-3-furanthiol and its corresponding methyl disulfide  ("meaty") were detected but reported less frequently as distorted. 
  • 2-Ethyl-3,6-dimethylpyrazine (also "coffee") was the second most frequent trigger in coffee; described with a variety of food terms by NONPAR, but by “new coffee”, “unpleasant” and “distorted” by PAR.
  • 2,3-diethyl-5-methylpyrazine, 2-ethyl-3,5-dimethylpyrazine and trimethylpyrazine (found in roasted, fried and baked goods) were common triggers. These compounds also triggered a parosmic response to cocoa, grilled chicken, and peanut butter
  • 2-Ethyl-3-methoxypyrazine, 2-isobutyl-3-methoxypyrazine and 2-isopropyl-3-methoxyprazine (green peppers) were common triggers in coffee.
  • 3-methyl-2-butene-1-thiol (pungent and weedy) was reported as a trigger 9/29 times.
  • 3-mercapto-3-methylbutanol and its formyl ester are potent aroma compounds in coffee, and were detected in half the cases, but only reported as distorted 5 or 6 times.

Exceptions:
  • The unknown compound has been tentatively identified as 4-methylthio-4-methyl-pentan-2-one, but this is yet unconfirmed. (What the heck is "the unknown compound?)
  • Although thiols and disulfides seem to effectively trigger a parosmic response, there are two notable exceptions.
  • Methanethiol, detected by some NONPAR, was not detected by any PAR. Likewise, dimethyl trisulfide is detected by 12/15 NONPAR but only by 4 PAR, and only reported once as a trigger.
  • A few compounds were detected but never reported as triggers.
  • 4-Ethylguaiacol was detected by 7 PAR and always described as spicy, sweet and smoky, but never parosmic.
  • Similarly, (E)-β-Damascenone, a key odour-active compounds in coffee, was detected by 6 PAR and always described as jammy and fruity.

The Faeces Paradox
  • Foods smell of faeces yet faeces smell of food (biscuity or pleasant)
  • Two parosmic researchers did not detect these compounds in a faecal slurry and were unaware of any foul smells.
  • However, they detected several other compounds, many of which they had also detected in coffee, and only some of which triggered parosmia.
  • In comparison, a normosmic scored the intensity of indole and skatole as close to the strongest imaginable. 
  • This provides a neat explanation as to why the changes in valence for faecal samples is reversed. 

How did they do it?
They GCMSd different sources, like coffee or onions, so that the individual molecules could be separated and presented one-at-a-time to the volunteers, so they could detect the specific molecules in the source that repulses them.

Why did they do it?
Prior to the global pandemic caused by COVID-19, parosmia was a rare condition known to occur after infections such as cold, flu or sinus infections, with very little awareness about the causes and treatments for the disease.

During the pandemic COVID-19 symptoms included loss of smell and taste in 50–60% of cases, of which about 10% developed parosmia. Since the omicron variant, loss of smell and taste has become a less common symptom (estimated to occur in about 10–20% of cases) and parosmia cases are likely to be fewer in number, parosmia is still estimated to affect 2 million people in Europe.
Not exactly. See below.

via the Flavor Center at University of Reading: Jane K. Parker et al, Insights into the molecular triggers of parosmia based on gas chromatography olfactometry, Communications Medicine (2022). DOI: 10.1038/s43856-022-00112-9


Study finds sensory loss in ~100% of active COVID infections, which is twice as high as self-reports
May 2022, phys.org

In participants with active infections during the delta surge, a majority (22 of 25) had been vaccinated. Objective screenings found that 100% were experiencing a diminished or lost sense of smell—but only 54.5% self-reported any problem with odor detection.

via Ohio State University: Kym Man et al, Chemosensory losses in past and active likely Delta variant break-through COVID-19 cases, Med (2022). DOI: 10.1016/j.medj.2022.05.004

Image credit: Free Photos at img freepic dot com [link]

Post Script:
Can 'smell' trigger tumors?
May 2022, phys.org
 
"Now that glioma preferentially emerges in the OB, will neuronal activity in the olfactory circuit affect the emergence of glioma?" the researchers wondered. This "mind-blowing" flash of inspiration became a turning point in this study. The research team attested to this hypothesis through a series of experiments.

In this study, they employed a cutting-edge chemogenetic technology to specifically manipulate the neuronal excitability of ORNs. They found that inhibiting the activity of ORNs reduced the size of the tumor significantly, whereas activating their activity increased the size of the tumor. It was therefore concluded that the neuronal excitability of ORNs was the root of gliomagenesis.

To further verify this conclusion, the researchers suppressed olfactory inputs through naris occlusion by using small plugs. They found that with naris occlusion, tumors were significantly hindered in the olfactory bulb, indicating that olfactory stimuli could regulate gliomagenesis.

via Zhejiang University: Pengxiang Chen et al, Olfactory sensory experience regulates gliomagenesis via neuronal IGF1, Nature (2022). DOI: 10.1038/s41586-022-04719-9

Post Post Script:
Clinical trial led by Thomas Jefferson University Hospital paves the way for innovative topical treatment
Mar 2022, Jefferson Hospital

Platelet-rich plasma (PRP) is a common restorative therapy used to regenerate cells, heal tissue, and address an array of medical conditions from healing injured muscles and tendons to increasing hair growth and reducing the appearance of scars. Animal studies have shown that PRP helps regenerate the olfactory epithelium, which may be the site affected in COVID-19 induced olfactory dysfunction (OD). As smell and taste are closely interrelated, improved sense of smell can help with sense of taste as well. Until now, PRP has been used as a nasal injectable in several small clinical trials for smell loss. Although the results were promising, nasal injections can be uncomfortable and invasive for patients.

A recent phase I clinical trial of eight patients who had at least six months of olfactory disturbance has shown preliminary success with 50 percent of participants (4 people) experiencing clinically significant improvements in smell and taste.

Also:
Autopsies suggest COVID’s smell loss is caused by inflammation, not virus
Apr 2022, Ars Technica

via Johns Hopkins: Ho C, Salimian M, Hegert J, et al. Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19. JAMA Neurol. Published online April 11, 2022. doi:10.1001/jamaneurol.2022.0154

Friday, March 11, 2022

Pan-Anosmia



Mechanism behind loss of smell with COVID-19 revealed
Feb 2022, phys.org

  • For more than 12 percent of COVID-19 patients, olfactory dysfunction persists 
  • SARS-CoV-2, indirectly dials down the action of olfactory receptors
  • The new study may also shed light on the effects of COVID-19 on other types of brain cells, and on other lingering neurological effects of COVID-19 like "brain fog," headaches, and depression
  • Presence of the virus near nerve cells in olfactory tissue brought an inrushing of immune cells, microglia, T cells, and cytokines that changed the genetic activity of olfactory nerve cells
  • They used infected golden hamsters and olfactory tissue from 23 human autopsies [hamsters are more susceptible to nasal cavity infections]

Reminder of why it's such a big deal when you start messing with smell:
"Other work posted by these authors suggests that olfactory neurons are wired into sensitive brain regions, and that ongoing immune cell reactions in the nasal cavity could influence emotions, and the ability to think clearly (cognition), consistent with long COVID."

The talk on gene behavior and downregulation of receptor building is lost on me (not a geneticist, not a neurologist), but one of the main points I am reminded of when reading this is -- for those who experienced a change in taste or smell, for any reason, but especially after a COVID infection, long-term brain damage is possibly ongoing, but it's the kind to go undetected for another 20-30 years, depending on how old you are, of course. 

They also seem to suggest that this is an explanation for why people experience brain fog, and even emotional disturbance, all of which makes a lot of sense, because your sense of smell is connected to the all those brain areas -- the hippocampus for memory and the amygdala for emotion, both integral parts of the limbic system. 

via NYU Langone Health Department of Microbiology, NYU Grossman School of Medicine and Columbia University: Marianna Zazhytska et al, Non-cell autonomous disruption of nuclear architecture as a potential cause of COVID-19 induced anosmia, Cell (2022). DOI: 10.1016/j.cell.2022.01.024


WHERE CAN I GET MORE INFORMATION ON SMELL LOSS?

Monell Anosmia Project - US Organization studying smell and taste

AbScent - UK Organization raising public awareness of smell loss

National Institute on Deafness and Other Communicable Disorders (NIDC) - Smell Disorders

ENT UK - Loss of Smell as Marker of Covid-19 Infection


Post Script:


Tuesday, February 1, 2022

You Don't Know What You're Missing


Attention and memory deficits persist for months after recovery from mild Covid
University of Oxford News, Jan 2022

"Although our Covid-19 survivors did not feel any more symptomatic at the time of testing, they showed degraded attention and memory."
-Dr Sijia Zhao of the Department of Experimental Psychology, University of Oxford
Repasted from above article:
All the participants had previously suffered from Covid-19 but were not significantly different from a control group at the time of testing on factors such as fatigue, forgetfulness, sleep patterns or anxiety.

But, they displayed significantly worse episodic memory and a greater decline in the ability to sustain attention over time than uninfected individuals for 6-9 months.

Note, the COVID-19 survivors in this study were young, mean age around 28, n=136.

How bad was it? Here is a measurements for context: Over the course of the 9-minute experiment, control participants’ accuracy dropped from 78.5% to 75.4%, whilst COVID survivors started with a similar baseline at 75.5%, reducing to 67.8% ... For a 30-minute memory test, COVID-19 survivors showed a significant memory decrement which was larger than in controls by 9.2%.

And to be specific: The larger episodic memory decrement amongst COVID-19 survivors was driven by errors in which the wrong orientation was chosen for a correct item. This difference suggests that the deficit in episodic memory in the COVID group might be associated with a deficit in binding information in memory. 

Interesting: word-memory tasks showed no change. 

How it might happen, if you're interested: One investigation of COVID-19 survivors demonstrated that the most severely cognitively affected patients demonstrated a degree of cognitive impairment accompanied by hypometabolism in the frontoparietal regions. These brain regions are implicated in sustained attention as well as in episodic memory. Reassuringly, the follow-up study of Hosp et al. showed slow but evident improvement after 6 months.

Last thing: The good news is that COVID-19 survivors performed well in most cognitive abilities tested, including working memory, executive function, planning and mental rotation. 

via University of Oxford: Rapid vigilance and episodic memory decrements in COVID-19 survivors. Zhao et al. Brain Communications. Jan 2022. https://academic.oup.com/braincomms/article/4/1/fcab295/6511053


How Is This Related to Smell?
We already know that changes in our ability to smell were the primary symptom of the initial varieties of covid. Some of us still deal with these changes. But something we also know, regardless of any pandemic, is that smell is tightly linked to episodic memory -- "grandma's attic" or "first boyfriend's cologne" -- and a subset called autobiographical memory. These type of memories tie together people, places, feelings and smells into the olfactory cluster. Chemosensation enabled the first navigation, as primordial protists sniffed their way through the soup of early Earth. Chemosensation enabled the first social experience, when you detected your mother's immunity profile via her amniotic fluid. And chemosensation enabled your primate ancestors to remember where that really ripe fruit tree was. 

So it does seem appropriate that a virus attacking your olfactory neurons would also affect your episodic memory.

Image credit: Just astrocytes, upsplash

Post Script:
For those who haven't heard about this enough already, here's a good reminder of what Long Covid is: People who survive COVID-19 infection present a significantly higher risk of major neurological and psychiatric conditions, particularly if they were hospitalized. These include acute cerebrovascular events such as ischaemic stroke and intracerebral haemorrhage. In addition to severe neurological conditions, there can also be more chronic, longer-term consequences such as fatigue, low motivation, disturbed mood and poor sleep—all commonly reported symptoms amongst survivors, the so-called long-COVID (see recent review). -source

Friday, September 10, 2021

Olfactory Training for Olfactory Dysfunction


Parking this here for future reference, and for anyone still having trouble getting their sense of smell back:

Hura N, Xie DX, Choby GW, Schlosser RJ, Orlov CP, Seal SM, Rowan NR. Treatment of post-viral olfactory dysfunction: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2020 Sep;10(9):1065-1086. doi: 10.1002/alr.22624. Epub 2020 Jun 25. PMID: 32567798; PMCID: PMC7361320. https://pubmed.ncbi.nlm.nih.gov/32567798/

Background: Post-viral olfactory dysfunction (PVOD) is one of the most common causes of olfactory loss. Despite its prevalence, optimal treatment strategies remain unclear. This article provides a comprehensive review of PVOD treatment options and provides evidence-based recommendations for their use.

Methods: A systematic review of the Medline, Embase, Cochrane, Web of Science, Scopus, and Google Scholar databases was completed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies with defined olfactory outcomes of patients treated for PVOD following medical, surgical, acupuncture, or olfactory training interventions were included. The Clinical Practice Guideline Development Manual and Conference on Guideline Standardization (COGS) instrument recommendations were followed in accordance with a previously described, rigorous, iterative process to create an evidence-based review with recommendations.

Results: From 552 initial candidate articles, 36 studies with data for 2183 patients with PVOD were ultimately included. The most common method to assess olfactory outcomes was Sniffin' Sticks. Broad treatment categories included: olfactory training, systemic steroids, topical therapies, a variety of heterogeneous non-steroidal oral medications, and acupuncture.

Conclusion: Based on the available evidence, olfactory training is a recommendation for the treatment of PVOD. The use of short-term systemic and/or topical steroids is an option in select patients after careful consideration of potential risks of oral steroids. Though some pharmacological investigations offer promising preliminary results for systemic and topical medications alike, a paucity of high-quality studies limits the ability to make meaningful evidence-based recommendations for the use of these therapies for the treatment of PVOD.

And don't forget:
Monell Center Scientists Find that Insulin is Necessary for Repairing Olfactory Neurons: Findings Point to Possible Treatment for Smell Loss
May 2021 - Monell Center

Thursday, August 5, 2021

Diabetes x Anosmia

Interesting theme here; anosmia, insulin and Covid:

It appears that long-Covid has more to do with the pancreas and insulin regulation than we thought, and this has implications for the health of our olfactory receptors.

Research from the Monell Center found that insulin may be able to treat smell loss:
1. Insulin plays a critical role in the maturation, after injury, of immature olfactory sensory neurons (OSNs). 

2. The research team induced diabetes type 1 in mice to reduce levels of circulating insulin reaching the OSNs. The reduced insulin interfered with the regeneration of OSNs, resulting in an impaired sense of smell. 

3. In addition, the team injured OSNs, which have a unique ability to regenerate in mammals. This approach allowed the investigators to ask whether OSNs required insulin to regenerate, which they found to be true. What’s more, they discovered that OSNs are highly susceptible to insulin deprivation-induced cell death eight to 13 days after an injury. This time window indicates that during a critical stage newly generated OSNs are dependent on insulin. They also found that insulin must be applied to regenerating OSNs at this critical time point in the neurons’ growth to be able to restore a mouse’s sense of smell.

4. Insulin promotes regeneration of regenerating OSNs in both type 1 diabetic and nondiabetic mice.

Monell Center Scientists Find that Insulin is Necessary for Repairing Olfactory Neurons: Findings Point to Possible Treatment for Smell Loss, May 2021
Post Script:
July 2021, phys.org
An increase in new-onset hyperglycemia and abnormal hormone levels lasting months after Covid infection in Italy; "This study is one of the first to show that COVID-19 has a direct effect on the pancreas," says Fiorina.

via Children's Hospital Boston: Laura Montefusco et al, Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00407-6

Sebastiano Bruno Solerte et al, Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study, Diabetes Care (2020). DOI: 10.2337/dc20-1521

Saturday, August 1, 2020

The Tree of Heaven

The ghetto palm in its natural habitat

The Tree of Heaven* is also known by its international colloquial name, the Ghetto Palm,  because it thrives in the worst conditions. It's been intentionally brought to the New World from Asia for centuries, both for its exotic ornamental qualities, and its basic use as a fast-growing shade tree that reaches up to the vast ecosystem in the sky at an exceptional rate.
*Also called ailanthus, varnish tree, and chouchun (Chinese, foul-smelling tree).

Now it's considered an invasive species. Its unstoppable juggernaut root system crumbles anything made of concrete, from sewers to foundations to highways and bridges. It also crowds out indigenous species by releasing a toxin (ailanthone) into the soil via its roots and fallen leaves. It isn't affected by herbicide; it is the herbicide.

At this time of year, in the heat of summer, it's spreading like wildfire. Not only does it produce an extraordinary amount of seeds, but it sprouts from its indomitable lateral roots, and almost 100 feet away from the source tree. You don't even have to look for it; you will know it's there by its smell. If you don't know, you will in a minute.

The Tree of Heaven smells bad. Like what? "Bad," that's what.

Can you be a little more descriptive?

Not really. We are so bad at describing bad smells. In fact, the corpus of words used in olfactory science is skewed way to the good. We have many more words for good smells than we do for bad. There's a few reasons for this, one being that we don't like to think about bad smells long enough to generate descriptors. When it comes to bad smells, "objectionable" "disagreeable" "noxious" "offensive" and "smells like shit" will suffice.

We already don't talk about smells much as it is; why waste that precious sensory indulgence on things that smell bad? We also don't like to talk about bad smells, because it can get socially complicated. You're not going to mention a bad smell while with your boss, and that's in case they are the source of it! We don't want to make them look bad. It's also too personal. It's just good social etiquette in general to not talk about bad smells, at all.


We also don't stop and take a second whiff when something smells bad. Flowers yes, the Tree of Heaven no. It will activate your disgust response, you'll reflexively twist your head back, flare your nostrils, and curl your upper lip. And you will not be going back for seconds.

Unless you're me. I've been trying to smell the Tree of Heaven for years now. It was introduced to me circa 2008 by a friend who lived on a farm; we were touring his property. "We call it the jizz tree," he said with a nervous giggle, him and his girlfriend. I don't remember smelling it, maybe it wasn't in season, who knows. I don't remember seeing it either. I don't remember anything except that there's a tree that smells like semen.

Later on I wrote a book about the language of smell, and shortly after that I came to the realization that I'm anosmic to putrescene, which means I cannot smell semen. Smellblind. People are smellblind to all kinds of things, bad things more often it seems, and roughly half of us are anosmic to something (natural gas and rotten fish will come up a lot, because they're talked about a lot, because it's a safety issue, right?).

I'll bet there's less people that know they're anosmic to putrescene. There are some people who are completely anosmic to everything, from birth, and don't realize it until they're ten years old. Kids don't even know that they have a sense of smell, and they certainly don't notice if it goes away temporarily, as in the case of those infected with the novel coronavirus of 2019 (the condition will present as them skipping meals and not being hungry, but it's likely because they can't smell).

Back to the tree. I started to notice the Tree of Heaven invading my extended neighborhood once I began taking the train for school. They grow along the train tracks really well, and they grow fast. After an extreme weather event, like drought, flood or fire, they are the first to pop back up, because they go dormant into their roots, conserve resources, and wait. They looked strange to me only because they were growing so fast. Within the first year of my taking the train, they had already grown from 5 to 20 feet. I started to notice them elsewhere, and once I started to look, there they came; these things are everywhere.

I looked them up, and found this notable characteristic -- this is the famed semen tree I've been hearing about, but never smelled. But it could be sumac, they look pretty darn close. In fact, the easiest way to identify it is to break off a leaf at the stem and smell it. If your head snaps back, it's the Tree of Semen, I mean Heaven. I went outside and grabbed a leaf, and as expected, couldn't smell anything. It could also be sumac; although it turns out I was wrong. 

Months later, I see one on the street and decide to try again, and rip off a leaf. It smells, kind of bad, maybe not, definitely not noxious, is it chocolate? Bad chocolate? What does that even mean? I must investigate further, because there's something there, although it's faint. Maybe it's just the beginning of the right season, who knows. Maybe it's still sumac.

A couple weeks later, it's getting hotter, a 12-day heat wave which is rare where I live, and I'm waiting in a parking lot for my laundry to finish (you can't wait inside, because of the virus). I'm in the back of the parking lot, against the train tracks, where there's shade, from the shade trees... There, I see it again... and now it's everywhere, I take a piece, break it off, and my goodness. My head snaps back. Terribly offensive.

I look it up again -- sumac makes red bunches of fruit, tree of heaven makes neutral colored and later in season pink to reddish-colored seed pods that kind of like maple tree "helicopter" seeds. I now confirm it is in fact the Tree of Heaven. And so is that what semen smells like? I call it pungent burnt rancid oily and dare I say, nutty, like peanuts?
Ailanthus samara seed pod, The Pennsylvania Flora Project of Morris Arboretum, 2011

How come when I look this up, in the more reputable sources such as the New Jersey Audubon Society or the Ecological Landscape Alliance, they use words like rancid peanut butter, burnt rubber, pungent, foul, and the the indispensable "smelly."

Is it because they're so "reputable" that they can't say "semen?" I think this may be half of it.

But as I go further into the informal investigation of the internet rabbit hole (this is called gray literature research, although you should probably call it reading urban dictionary entries, VICE articles and horticulturist blogs), and it starts to dawn on me. These descriptors are a mess; they're all over the place:
Rancid peanut butter, rancid peanuts, rancid cashews, cross between peanut butter and cat urine, well-used gym socks, yucky cooked meat, objectionable, disagreeable to humans, fetid-smelling, bitter, acrid, pungent, strong, and any word that refers to semen, and which can be described as a "chlorine musk," but is more directly associated with the molecule putrescene ... there's something in here about amines and ammonia also. You could also refer to it in your most prudent Victorian manner and call it simply "a man smell."
*Only the male flower smells, but both smell when their branches or stems are broken.
When I look at that list I am reminded of two things -- we are really bad at describing bad smells, and half of us are anosmic to something, and usually to bad smells.

So not only do we NOT talk about or think about the names to call bad smells, but for some of them, we can't even smell them in the first place.

When you don't talk about something, and you don't generate either a personal or a shared vocabulary for something, you will be really bad at identifying it, at discriminating it from similar things, or at categorizing it in your autobiographical database. This means you're more likely to mis-assign a name to the smell, calling plant-semen "dirty gym socks" instead. I may need some help here, because again, I'm smellblind to it, but does semen smell like dirty gym socks?

Furthermore, when you're presented with a cocktail of bad smells, as would be expected emanating from a living biochemical reactor*, you may be missing a major component of the mixture due to smellblindness to one of the molecules, and that could change your impression dramatically.
*A plant's essential oil is not the same as an isolated synthetic compound, because olfaction is a combinatorial affair, shown from about 2015 research and on.

If you combine all these factors together, you get one dirty mess of a database. There is no absolute, no discrete points. If you could manage to ask 10,000 people around the world  (or 1.5 million in the National Geographic Smell Survey) to describe 10 different bad smells, each a natural biologically-generated smell cocktail, what would that list look like?

That list would tell you something about the overall distribution of genetic diversity in the study population based on olfactory receptor genes, or it could tell you something about the cultural milieu of a sub-sample (like the Victorians!), but it won't tell you any better what the Tree of Heaven "really" smells like, or stink bugs for that matter.

When it comes to making sense of the world as an olfactory phenomenon, you're on your own. Olfactory reality is not a consensual reality. And that's unsettling, because in the Information Age, approximation seems like failure, no?




Post Script: 
Within days of my most recent experience with the potent odor of this tree, I can now smell it as a drive down the highway, from the trees on the side of the road. In my typical self-induced pseudo-hyperosmic fashion, I have become very sensitive to it.

This reminds me of an idea about regeneration of olfactory neurons and combinatorial perception, and as it relates to people recovering from the novel coronavirus of 2019. After some traumatic disturbance to your olfactory neurons, like from being attacked by a virus, you may experience changes in smell or taste. This is also called anosmia, partial anosmia, or phantosmia, the last referring to not a loss of smell but a change in the way things smell.

Phantosmia, like all phenomena in olfactory science, is not understood enough to say much from an evidenced-based point of view. I'm making a broad speculation here, not to explain, but to make someone interested enough that they will investigate further for themselves, and maybe even initiate more research into the topic.

The change in smell that comes from phantosmia is common, but its origins are often overlooked. It likely signals a change in the structure of neurons used to smell. These are the only part of your brain that pass the blood-brain barrier and rest outside your skull, in the mucous atop the epithelium skin way up in the top of your nostril canal (right where they swab that sample for your PCR test by the way, and not a coincidence). These neurons are thus both very vulnerable to damage, and able to regenerate indefinitely.

Combine this with another fact about olfaction -- it is combinatorial. That means when you smell "apple," there are a bunch of different receptors all lighting up in a pattern that means "apple." There is no Apple gene. For some there are, but for the most part, no. No single gene codes for any single cell. Olfaction is all gestalt. Take one piece out, and the entire picture gets weird as hell. Something's wrong but you can't tell what. So your brain misfires, it says "cigarette smoke" when it's really something else entirely. But after damage to your system, it is re-learning how to smell. Your nose-brain is a deep learning neural network that requires countless iterations to "learn" what a smell is. And while it's relearning after an infection, it gets confused.

In a very mild manner, and for reasons I will attribute to having been infected myself, my Tom Ford Italian Cypress lost its depth and presented as cinnamon and bubblegum, for about three days. If you've ever smelled Italian Cypress (and if not good luck it's discontinued since 2014), you would know that it does NOT smell like cinnamon and bubble gum. That's happened to me once before, and I will now assume it was because I was then also infected with a virus. But I got lucky, it wasn't bad, just weird.

And another thing -- when faced with new smells, we tend to call them bad. After repeated exposure, we can start to see them as good, but it's more likely we call them bad at first. So if your system is relearning how to smell, then lots of typical odor exposures will present as "bad" to you, simply by their being new, that is, new to your newly developing system. And all of the sudden, anything that doesn't compute properly on your new system will become "cigarette smoke," for example. Rotten meat is another good one for this, but it could be anything really (and it could also be really debilitating, just imagine.)

Eventually, the system will recalibrate and relearn how to smell, and you'll be back to normal. But that doesn't always happen. Blunt trauma can kill those neurons forever. Really bad infections too. Sometimes it doesn't come back because you're not using it, like therapy after a stroke, it only comes back if you try really hard to use it.

And some of us, well, we're just getting older. Things don't work like they used to. And not only that, changes in smell can predict all kinds of neurological diseases decades in advance (Parkinson's, Alzheimer's, etc.).

All this being said, my system has apparently, and finally, learned how to smell the Tree of Heaven.



Some good recent research on genetic variation in olfactory receptors:
Did You Smell That No I Didn't
Jan 2020, limbicsignal.com

And the most relevant among them for today:
Any two individuals differ by ∼30% of their olfactory receptor subtype genome.
Mainland JD, et al. (2014) The missense of smell: Functional variability in the human odorant receptor repertoire. Nat Neurosci 17(1):114–120.
https://www.ncbi.nlm.nih.gov/pubmed/24316890
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990440/

The human olfactory genome contains 418 intact odorant receptor genes and their 912,912 intact odorant receptor alleles.
The 1000 Genomes Project (2008-2015), the largest public catalogue of human variation and genotype data.
https://www.internationalgenome.org

Pop Search Trivia:
"Tree of heaven smells" like peanut butter, #1 search result. (July 2020)

What is the tree that smells like dead fish?
(Callery pear trees)

What is the tree that smells like peanut butter?
(Butterfly tree or peanut butter shrub)

What are other trees that smell?

  • Callery pear, Bradford pear tree - flowers emit dead rotten fish semen trimethylamine dimethylamine
  • Maidenhair, Ginkgo bioloba tree - female fruit produces putrid rotten eggs vomit
  • Chinese chestnut tree - male flowers emit "off-putting" smell; again I think this smells like semen and it's just not said that way because it's uncouth!
  • Linden tree - smells like semen? How could it smell like semen and yet someone else says it smells like the most powerful fragrance in the plant kingdom, of honey and lemon peel?

Notes:

Best source of information on this topic:
Ecological Landscape Alliance - Tree of Heaven, An Exotic Invasive Plant Fact Sheet - May 2014

Identify and Disambiguate:
New Jersey Audubon Society - How to Correctly Distinguish Invasive Tee-of-Heaven from Native Sumac - July 2018

Post Post Script:
This gal is trying to decode the bad smell network; I made an odor descriptor-molecule network graph of her research with a regional air quality odor complaint database, interesting work, under-explored territory.

In word-searching the list from the Curren's study, "amine" turns up "fishy" and "pungent" via trimethylamine, and "pungent" via ammonia; no mentions of semen ever.

"Pungent" then brings up pentanal, 2-pentanone, formaldehyde, ammonia, trimethylamine. And  "rancid" connects to butyric acid. "Rotten" brings the expected hydrogen sulfide and dimethyl trisulfide from "rotten eggs" and "rotten vegetables."

A Case Study of Odor Nuisance in the South Coast Air Quality Management District 
Curren, J. 2012. Characterization of Odor Nuisance. UCLA.

What the Hell Does a Stink Bug Smell Like?


Thursday, July 2, 2020

Healthy Brains


An interest in olfaction has me following the anosmic effects of this disease. A career as an industrial hygienist has me posting public health information on this olfactory awareness weblog:

Our sense of smell is a secret weapon in the fight against the 2019 novel coronavirus.

1. Loss of smell (anosmia) is a primary symptom of Covid-19.
2. Covid-19 may cause neurological damage.
3. This is not a coincidence.

Most people don't realize it but your sense of smell offers very sensitive diagnostics for complex brain activity, like how it can predict Alzheimer's decades in advance. This is because our sense of smell has special connections with the brain that other senses don't have. This also gives us an opportunity to monitor our own "brain health," and that's the main reason I'm sending this.

I'll let this recent BBC article on the topic fill-in the details; it's not long:
How Covid-19 can damage the brain - BBC Future


SEE UPDATE (7/25) ON NEW INFORMATION FROM HARVARD SPH BELOW


If you don't read that article, and if you're about to stop reading this, please:

  • Pay attention to changes in smell or taste, both for you and those around you.
  • Changes in smell and taste are a primary symptom for Covid-19.
  • Changes in smell and taste, in general and aside from a Covid infection, could be a sign of neurological issues and may warrant attention from a professional.
  • The sooner you recognize neurological issues the better.


WHERE CAN I GET MORE INFORMATION?

Monell Anosmia Project - US Organization studying smell and taste

AbScent - UK Organization raising public awareness of smell loss
https://abscent.org

National Institute on Deafness and Other Communicable Disorders (NIDC) - Smell Disorders
https://www.nidcd.nih.gov/health/smell-disorders

ENT UK - Loss of Smell as Marker of Covid-19 Infection
https://www.entuk.org/sites/default/files/files/Loss%20of%20sense%20of%20smell%20as%20marker%20of%20COVID.pdf

[x] image source link

Post Script:
The ability to detect smells predicts recovery and long-term survival in patients who have suffered severe brain injury, a new study has found. A simple, inexpensive 'sniff test' could help doctors to accurately diagnose and determine treatment plans for patients with disorders of consciousness.

Published in the journal Nature, ...

Simple sniff test reliably predicts recovery of severely brain injured patients
May 2020, phys.org
https://medicalxpress.com/news/2020-04-simple-reliably-recovery-severely-brain.html

Olfactory sniffing signals consciousness in unresponsive patients with brain injuries, Nature (2020). DOI: 10.1038/s41586-020-2245-5 , www.nature.com/articles/s41586-020-2245-5


UPDATE ON NEW INFORMATION
Eric Song et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20202135

David H. Brann et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia, Science Advances (2020). DOI: 10.1126/sciadv.abc5801

Trying to Make Sense of Long COVID Syndrome, Dr. Francis Collins. NIH Director's Blog, January 19th, 2021. https://directorsblog.nih.gov/

Harvard Medical School, coming with all the hot smell data these days, figures out what's going on with the covid smell loss problem.

I'm pretty sure you already know this, but just in case -- covid-19 can cause changes in smell or taste. It's a primary symptom, and the number one symptom for identifying infection (also the earliest; others may not show up until days later). The problem is that most people don't even know they have a sense of smell in the first place, so they don't notice that it's missing.

We thought it was the actual neurons themselves getting attacked and damaged by the virus. This is certainly possible, because your olfactory neurons, which are like little brain fingers with special neuron cells at the very tips, and are the only part of your brain that reach across the blood-brain barrier, outside the body envelope, and into the world. 

Imagine a piece of your brain reaching, creeping, crawling outside your skull to sniff the world firsthand. That's your olfactory neurons. That's where they stick the swab when taking your covid test sample. Sounds pretty vulnerable. I can see the line of reasoning here.

Well we were wrong (and when I say we, I mean them, because I'm not a scientist). It's not the neurons themselves being attacked, but their "supporting cells." These nonneuronal cells are described as sustentacular cells which wrap around the neurons for structural and metabolic support, and also basal cells which are regenerative stem cells responding to damage.

The thing is, I'm not sure of the implications here. Do we actually know what causes non-obstructive virus-induced anosmia prior to this? And what are the associations between people who have it and people who later develop neurodegenerative symptoms like Alzheimer's etc.? I don't think the new information from this study lets us put our guard down. Using the precautionary principle, I would say that your sense of smell is deeply connected to core areas of your brain, and any dysfunction there should prompt you to investigate potential neurological damage. With the brain, as plastic as it is, and important to quality of life, anything out of the ordinary should be taken seriously, and as quickly as possible. 

Notes:
David H. Brann et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia, Science Advances (2020). DOI: 10.1126/sciadv.abc5801

This lab also just released one of the more groundbreaking reports on how olfaction works,  basically in the same week: Stan L. Pashkovski et al, Structure and flexibility in cortical representations of odor space, Nature (2020). DOI: 10.1038/s41586-020-2451-1

Thursday, April 23, 2020

Normosmia Has No Name



I have really met my match. In the world of smell, where language is a game more than a utility, there is one group of researchers who have finally said f*** it. They took all the words out, smashed all the molecules together, presented a bunch of people with their sniff panel, and recorded the responses. (This study is from 2013, but still worth writing about, since this is pretty important point in smell science.)

And it worked. They found that we don't smell molecules; we smell mixtures of molecules. In their words: "The algorithm that worked best was one that treats the odor-mixture as a single value, rather than a bunch of values reflecting each of its components."

They also found that "Pleasantness is the primary odor dimension in human olfactory perception," but we already knew that.

The Study
They use mixtures of 1 to 43 different components, making each 191 mixture-pairs in total, each having 1433 physiochemical descriptors (via the Dragon dataset), and gave them to 48 people.

The Findings: Pairwise Distance Model for Predicting Odorant-Mixture Similarity
They pit the molecular mixtures against each other and have people rate their similarity.
Again, "We found that the mean pairwise Euclidean distance over all the descriptors of all mono-molecular components comprising any two mixtures was a poor predictor of perceptual similarity between the two mixtures." But it gets even better, because apparently they're saying that the weak predicting capacity is because the data is screwed up by the monomolecules' comparisons to themselves! Maybe I'm wrong here, but I think they're saying  people gave different ratings for the same pairs of molecules at different times in the test, and those ratings changed so much from time to time, that they make the model no good.

The Findings: Angle Distance Model for Predicting Odorant-Mixture Similarity
This is the meat of the study. They came up with a statistical regime to turn the odor mixtures into a perceptual whole, that way it could be manipulated as if they it was an individual odor.

Just about every smell-science experiment like this will use odors that have been very carefully isolated – single molecules with single names (let's not kid anyone here, any particular molecule can have a dozen different names, from the local vernacular to the formalized IUPAC designation). The point is that molecules are typically isolated. Because science likes that. Lumping molecules together is messy. But that's also how we interface odors in the real world.

So they made this study more like the real world. They take all the physiochemical components of each molecule, add them together, and divide by the norm. That makes the mixture-odor as if it were a single odor, with a single vector (a single point in multi-dimensional odor-space). And this was the model that worked.

If you take its higher logical plateau, you end up with Olfactory White, one of the most mindbending osmological facts you'll ever comprehend: if you add enough molecules together, it doesn't make "brown paint" like colors do, it makes the mixture smell like nothing. Sure enough, these researchers found that the more components you add to the mixture, the closer the mixture gets to every other mixture (approaching 30 components).

A very important note here is that these odor mixtures were made to be all the same intensity. (This was done in the Olfactory White study as well.) Odors can have very different perceived intensities, and it's more than unlikely that this would ever happen in the wild. I can't help but get into some quick industrial hygiene here: the odor detection threshold for Ammonia is 50ppm; Acetone 100ppm, Trimethyl Amine (rotten fish) 0.0002ppm, Hydrogen Sulfide (rotten eggs) 0.005ppm.

Another extension of this study is maybe not so logical, but certainly an important point in smell science: we can't identify individual components of a mixture of only 4 components. You think you know what peanut butter smells like. And pineapples, and cinnamon. But if you add one more thing to that mixture, they all fall away, losing their identify on your great epithelial equalizer.

Conclusion
"The olfactory system treats odorant-mixtures as unitary synthetic objects, and not as an analytical combination of components."

Limitations
Being that they have three clear limitations, they should be included here:

1. The mixtures were intensity-normalized. This is not natural, because perceived odor-intensity changes drastically across odors. See mention above.

2. The odorants represent only a limited portion of olfactory perceptual space (not much we can do about that, since it's kind of infinite).

3. Many physicochemical features such as boiling point or vapor pressure remain unrepresented (they narrowed down the features from ~4,000 to 25).

Post Script
If you don’t know what the word steganography means, you do know: camouflage. Think about it – you don’t like broccoli? Blend it with enough other smells and you won’t even notice!

Olfactory White also its own name, and it’s called Laurax.

Notes
Semantic free approach to structure-odor prediction, general perceptual primaries rather than individual odorant primaries:
Predicting odor perceptual similarity from odor structure.
Snitz K, Yablonka A, Weiss T, Frumin I, Khan RM, Sobel N
PLoS Comput Biol. 2013; 9(9):e1003184.

Olfactory White:
Weiss T, Snitz K, Yablonka A, Khan RM, Gafsou D, et al. (2012) Perceptual convergence of multi-component mixtures in olfaction implies an olfactory white. Proc Natl Acad Sci USA 109: 19959–19964.

Odor Thresholds:
Gregory Leonardos , David Kendall & Nancy Barnard (1969) Odor Threshold Determinations of 53 Odorant Chemicals, Journal of the Air Pollution Control Association, 19:2, 91-95, DOI: 10.1080/00022470.1969.10466465