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Showing posts with label Cetirizine. Show all posts
Showing posts with label Cetirizine. Show all posts

Wednesday 4 May 2022

High dose Betaine/TMG, Low Dose Ponstan, Galavit, Humira, HMB (β-hydroxy-β-methylbutyrate) and Cetirizine for Palilalia/Scripting

 


Our reader in Canada, AJ, did highlight a case series from Norway that showed that high dose Betaine/TMG was effective in improving functioning in people with autism due to creatine transporter deficiency.  The use of Betaine/TMG was really just stumbled upon and the authors considered what the beneficial possible mode of action could be. 


Betaine (TMG) and Gene Therapy as potential alternatives to Bumetanide Treatment in Autism? 

The effect was only present at high dose (7-10 g a day) not the much lower dose used by some DAN/MAPS doctors, who do prescribe TMG and the closely related DMG.

The paper suggested that one possible effect might have been lowering chloride levels within neurons.  This is also the effect of Bumetanide.

AJ suggested that Betaine/TMG might be an alternative to Bumetanide and one that does not need a prescription.

Our reader Nancy reported a benefit in her adult son.

The question is not whether or not high dose TMG is a useful therapy, we already know that it is, in some cases. The question is whether it is a bumetanide alternative.

My conclusion is that high dose TMG does not seem to be a bumetanide alternative.  If it was an effective alternative then I would be suggesting everyone using bumetanide should go and buy some.

I did try TMG for s couple of weeks and did not see any additional effect over the continued therapy of 2mg of bumetanide.  In our case there is a benefit from additional bumetanide/Azosemide. If TMG shared the same mode of action as Bumetanide then 7g TMG + 2mg Bumetanide should show some improvement over 2mg Bumetanide.  It did not.

There is a long list of other modes of action to explain why Nancy’s son and the two Norwegians improved.

 

Low dose Ponstan for sound sensitivity

Low dose Ponstan (Mefenamic Acid) was proposed as a treatment for sound sensitivity.  Within Europe it seems that Greece is the place to buy Ponstan; it is sold OTC and cheap.  One pack (15 x 500mg) costs less than 2 USD/EUR.

In some people the effect of 250mg lasts all day, while for others it lasts for a few hours.

Ponstan is also widely used as a syrup to reduce fever in young children (antipyretic).

In the US the common brand name is Ponstel, but the price is dramatically higher.

Galavit + Cromolyn Sodium

The combination of the common mast cell stabilizer Cromolyn Sodium, used by many readers, with a Russian drug called Galavit is used by at least two readers. Dragos recently told us that the combination has put an end to his adult son’s aggressive behaviors.

Galavit has multiple anti-inflammatory modes of action.  It is not a mast cell stabilizer like Cromolyn Sodium.

Galavit is not expensive, but may hard to get hold of.

It does look like there is an overlap between responders to Verapamil and responders to Galavit.  So, if you respond well to Verapamil but get one of the rare side effects, like Maja’s daughter, it might be worth investigating further. 


Humira 

Humira is a TNF alpha inhibitor normally used to treat auto-immune conditions like rheumatoid arthritis, Cohn's disease, ulcerative colitis, psoriasis and juvenile arthritis.

I was recently contacted by an Aspie lady with auto-immune conditions, who found Humira not only controlled those conditions but moderated her autism symptoms, notably sound sensitivity.  One injection produced a benefit that lasted 7 weeks.

Kanner’s subject #1 went on to develop juvenile arthritis and this made his autism much worse.  There was no Humira back in his day, but his arthritis did respond to treatment.

Apparently, many children with autism and GI problems are taking Humira. 

IVIG seems to be the “go-to” therapy for immunomodulation in autism.  It is now quite commonly used in the US, but much less so elsewhere due to the cost.

I wonder if Humira might be an alternative for some?

 

HMB (β-hydroxy-β-methylbutyrate)

Our reader Natasa did mention the sports supplement HMB to me.

It has many interesting modes of action and it is a precursor to the ketone BHB, which has been covered in great depth in this blog.

Ketone Therapy in Autism (Summary of Parts 1-6)


In Europe ketone supplements like BHB fell foul of the rules on supplements and have been banned. In the US they are widely sold.

If you want to try BHB, by cannot buy it in Europe, you might want to look into HMB (β-hydroxy-β-methylbutyrate).

 

Cetirizine for Palilalia/Scripting 


I am a big fan of the OTC antihistamine Cetirizine/Zyrtec and I was interested to read the recent comment below about its effect on one 12-year-old boy.


“I realize this is 5 years old, but as a result of this blog, I tested cetirizine on my 12 yo yesterday. He has a nonstop palilalia (obsessive speaking that is nonsense or only makes sense to him). It's his "chief feature" and inhibits social development. For 4 glorious hours, it went away. Today, I gave him 5 mg of Zyrtec again. Yet again, the palilalia went away, AND he had strong focus on school (he has serious attention issues).”

 

Many people’s autism gets worse when auto-immune conditions flare up.  In some cases, the auto-immune condition is very mild, but the consequences are not.  For one person the result is aggressive behavior, while in another it is talking nonsense.







Sunday 14 June 2020

Summertime Autism Raging and Dumber in the Summer


By far the most read post in this blog is one about histamine and allergies, which means many people are searching on Google for “histamine, allergy and autism”.

Our reader Kei recently commented that his daughter, without allergy, was again showing signs of summertime raging and that his neurologist confirmed that summertime raging does indeed happen and nobody knows why.

I did figure out how to deal with our version of “summertime raging” and the post-bumetanide “dumber in the summer” phenomena.  There were several posts on this subject.  The lasting solution was to treat the raging as if it was caused by inflammation driven by pollen allergy and to note that inflammation will further worsen the KCC2/NKCC1 imbalance in Bumetanide-responsive autism, making those people appear “dumber in the summer”.  This also accounts for the “Bumetanide has stopped working” phenomenon, reported by some parents.  You need to minimize inflammation from allergy and increase Bumetanide (or add Azosemide).  My discovery was that Verapamil was actually more effective than anti-histamines and actual mast cell stabilizers. Mast cells degranulate via a process dependent of the L-type calcium channels that Verapamil blocks. Mast cells release histamine and inflammatory cytokines like IL-6.

This spring when Monty’s brother asked why Monty was acting dumber, it was time to implement the “dumber in the summer” therapies.  Add a morning tablet of cetirizine (Zyrtec) and a nasal spray of Dymista (Azelastine + Fluticasone).

Dymista is inexpensive and OTC where we live, but I see in the US it is quite an expensive prescription drug.  It is a favourite of Monty’s pediatrician and his ENT doctor. 



Summertime Regression in the Research Literature

I recently came across two very relevant papers on this subject by a proactive American immunologist called Dr Marvin Boris.  If you live in New York, he looks like a useful person to know.

In his first study he investigated whether the onset of the allergy season caused a deterioration in behavior of children with autism or ADHD; in more than half of the trial subjects, it did.

In his second study he went on to make a double‐blind crossover study with nasal inhalation of a pollen extract or placebo on alternate weeks during the winter.  This was his way to recreate the pollen season during winter.

Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms.

In other words, half of children with autism regress when exposed to pollen, even though they may not show any symptoms of allergy, or test positive for allergy.  This should be of interest to Kei and his neurologist.



Purpose: To determine whether children with autistic spectrum disorders (ASD) or attention deficit hyperactive disorder (ADHD) exhibit neurobehavioral regressive changes during pollen seasons.
Design: A behavioral questionnaire‐based survey, with results matched to pollen counts; an uncontrolled, open non‐intervention study.
Materials and Methods: Twenty‐nine children identified with ASD and 18 children with ADHD comprised the study population. The parents of the study children completed the Allergic Symptom Screen for 2 weeks during the winter prior to the pollen allergy season under investigation. The parents of the ASD children also completed the Aberrant Behavior Checklist and the parents of the ADHD children completed Conners' Revised Parent Short Form for the same periods. The parents completed the respective forms weekly from 1 March to 31 October 2002. Pollen counts from the geographical area of study were recorded on a daily basis during this period.
Results: During natural pollen exposure, 15 of 29 (52%) children with ASD and 10 of 18 (56%) children with ADHD demonstrated neurobehavioral regression. There was no correlation with the child's allergic status (IgE, skin tests and RAST) or allergy symptoms.
Conclusions: Pollen exposure can produce neurobehavioral regression in the majority of children with ASD or ADHD on a non‐IgE‐mediated mechanism. Psychological dysfunction can be potentiated by environmental exposures. 


Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge 

Purpose: In a previous study it was established that children with attention deficit hyperactive disorder (ADHD) and autistic spectrum disorders (ASD) had regressed during pollen seasons. The purpose of this study was to determine if these children regressed on direct nasal pollen challenge. 

Design: A double‐blind crossover placebo‐controlled nasal challenge study. Materials and Methods: Twenty‐nine children with ASD and 18 with ADHD comprised the population. The study was a double‐blind crossover with nasal instillation of a pollen extract or placebo on alternate weeks during the winter. The pollens used were oak tree, timothy grass and ragweed. The dose insufflated into each nostril was 25 mg (±15%) of each pollen. 

Results: Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. 

Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms. There was no correlation to the child's IgE level, positive RAST pollen tests, or skin tests.


Conclusion

When I was figuring out Monty’s summertime raging and cognitive decline, several years ago, there were no significant signs of allergy present.  Nowadays there are far more visible signs of allergy.

Dr Boris does not suggest any therapy for summertime raging, but he did show that it can be driven by pollen in half of those with autism, even children who have no signs of having any allergy.

His studies were published more than a decade ago and seem to have been forgotten.  This seems a pity, but it says a lot.

I only stumbled upon his papers because I was reading another of his decade old papers.  That paper is based on his early use of Pioglitazone in autism, which resulted in several hundred children being successfully prescribed this drug.  Pioglitazone selectively stimulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.

There was a bladder cancer scare, lots of hungry lawyers and I suppose people stopped prescribing Pioglitazone for autism a decade ago.  The numerous subsequent safety studies and meta-analysis show either a small increased risk, or no increased risk, very much dependent on who financed the research.  Pioglitazone is given to people with type 2 diabetes, and they are already at an increased risk of bladder cancer.  In those people, that risk increases between 0 and about 20%, depending on the study.  We are talking about 0.07% to 0.1% of people with T2 diabetes taking Pioglitazone later developing bladder cancer.

A decade later and Pioglitazone is again back in fashion with trials in humans with autism and studies in mouse models of autism. The current autism research does not see cancer risk as reason not to use Pioglitazone.  I agree with them. 

It looks like a minority of people taking Pioglitazone are more likely to suffer upper respiratory tract infections.  That is the risk that I consider relevant.  I also note that in trials even the placebo can appear to cause upper respiratory tract infections.

Pioglitazone was covered in earlier posts, 


but there will soon be a new post.  For most people I think histamine, allergy and summertime raging will continue to be of more interest.






Tuesday 13 June 2017

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism  


There are many comorbidities associated with autism.  I have long held the view that these comorbidities hold the key to understanding each particular case of autism.  In many cases this may be far more useful than genetic testing, which only seems to help in a minority of cases.

“Ringed esophagus” aka “Corrugated esophagus”


This then allows you to put people into sub-groups that may well respond to the same therapy.  This may all sound like common sense, but apparently is not.

Eosinophilic esophagitis (EoE) is a relatively new diagnosis and it is applies to a certain type of reflux/GERD/GORD that might be associated with a difficulty in swallowing and may not respond well to the standard stomach acid lowering therapies.

It is likely that most people with Eosinophilic esophagitis have never been correctly diagnosed. Many people have taken several years to get the correct diagnosis.

It is known that Eosinophilic esophagitis is much more common in autism than the general population. One study showed that EoE is four time more likely to be diagnosed in someone with autism. I suspect many people with autism never have their GI problems fully diagnosed.

We now have to add some new science to this blog


Granulocytes

There is a great deal already in this blog about mast cells.  Many readers have children who have allergies, mast cell activation, or even mastocytosis.  Mast cells are the ones (but not the only ones) that release histamine.

Mast cells are just one type of a class of cells called Granulocytes, that are produced in your bone marrow.

Granulocytes are a category of white blood cells characterized by the presence of granules, which release their contents when they degranulate.

The four types of granulocytes are:- 


·        mast cells

These have been well covered in the past. These are what cause problems for people with pollen allergy.


·        eosinophils

Eosinophils play a crucial part in the killing of parasites because their granules contain a unique, toxic basic protein and cationic protein. Eosinophils regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils), they are involved in the destruction of tumor cells, and they promote the repair of damaged tissue. Interleukin-5 interacts with eosinophils and causes them to grow and differentiate; IL-5 is produced by basophils.

Note that some people with autism find that the TSO helminth parasites modify their immune system and improve their autism. This may relate to what is contained in the granules of eosinophils.  


·        basophils 

Basophils are similar to mast cells, in that they contain prestored histamine within their granules. Unlike mast cells they circulate in your blood . Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting.

There is research underway to try to develop basophil stabilizers.


·        neutrophils

Neutrophils are normally found in the bloodstream. During the beginning phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.

Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection.


An obvious question would be, if you know you have a problem with mast cells are you likely to have an issue with the other types of granulocytes?

One role of eosinophils is to regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils).

The subject is highly complex and again not fully understood, but it is clear that granulocytes are all interrelated and so a problem with one may well be associated with a problem with others.

In the case of Eosinophilic esophagitis (EoE), both eosinophils and mast cell are directly involved.

Basophils, like mast cells, release histamine among other things when they degranulate.

Mast cells usually do not circulate in the blood stream, but instead are located in connective tissue.  Circulating granulocytes, like basophils can be recruited out of the blood into a tissue when needed.

So in addition to mast cell stabilizers perhaps, we might benefit from basophil and eosinophil stabilizers.

Surprisingly, the antihistamine cetirizine has Eosinophil-stabilizing properties, as does the asthma drug Montelukast. Both drugs are widely used in children.

Another substance, curine, also inhibits eosinophil influx and activation and is seen as a potential new treatment for asthma.  Interestingly the drug curine, is an alkaloid, that blocks L-type Ca²⁺ channels.

Regular readers may recall that I proposed the L-type calcium channel blocker Verapamil to control my son’s mast cell degranulation. Mast cells degranulate in a very complex fashion that involves the flow of Ca²⁺.

This may or may not be a coincidence. 

Fullerene nanomaterials are being developed as both mast cell and peripheral blood basophil stabilizers.



L-type calcium channels and GI disorders in Autism

There are many types of GI disorder in autism, however I suggest that a large group can be categorized as being broadly Granulocyte Disorders, which may well all respond to L-type calcium channel blockers, to some extent.

Indeed this may be a better solution than the widely used cromolyn sodium.

Perhaps people with autism, and their family members have certain calcium channels that are either overexpressed, or do not close fast enough, leading to a higher level of intracellular calcium.  This of course ties back in with Professor Gargus and his theories about IP3R and the calcium store inside the endoplasmic reticulum”.

This all gets extremely complex.

My rather simple suggestion would be that if you have autism and any GI problem from the esophagus downwards, a three day trial of verapamil just might change your life.  As is almost always the case, there are some people who do not tolerate verapamil.



Interleukin 5

Interleukin 5 (IL-5) is an inflammatory cytokine produced by type-2 T helper cells  (Th2), mast cells, basophils and eosinophils.

IL-5 interacts with eosinophils and causes them to grow and differentiate.

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, where a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.

You might expect high levels of IL-5 in people with Eosinophilic esophagitis (EoE)



Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3+ blood cells) in patients with EE and improved clinical outcomes.


Not surprisingly the same anti-IL-5 therapy has been approved to treat severe asthma.


Patients are given mepolizumab by injection every four weeks. It costs £840 per dose.



Mepolizumab for autism?

It is very expensive, so I doubt many people will think of Mepolizumab for autism.  If you have EoE, or severe asthma, you may be able to access this IL-5 therapy, my guess is that it would also reduce the severity of any comorbid autism.


Back to Eosinophilic Esophagitis

I was writing a while ago about food allergy in my book and came across the opinion that food allergy is no more common in autism than in typical people, but what is more common is Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of digestive system (gastrointestinal) illness.  In many cases it likely remains undiagnosed. If it continues, after a few years swallowing becomes difficult, in part because a “ringed esophagus” develops that impedes the passage of food.

As seems to be often the case there are plenty of contradictions in the diagnosis and treatment, as you will find as you read on.

The symptoms are broadly what would normally be diagnosed as reflux/GERD/GORD. This is very often found in people with autism and I expect in their relatives.

It is relevant to autism because it will be yet another comorbidity that when treated should improve autism, but it is also another marker of a particular sub-group of autism.

There are numerous other GI conditions comorbid with autism - colitis, IBD, IBS etc.  In the end I imagine that the molecular basis of some of these diagnoses is actually the same, so you will find the same therapies may be effective.

It looks like that one common factor is the mast cell and, just as in pollen allergy and asthma, stabilizing mast cells yields great benefit. Stabilizing mast cells is complex but involves the flow of calcium ions, Ca2+.  By modifying the flow of Ca2+ you can prevent mast cells degranulating.  This was one of my earlier discoveries, but there is now research showing the L type calcium channels “open” mast cells.  Keeping these channels closed is actually quite simple.

It would seem logical that the same approach could be therapeutic to other conditions that are, at least in part, mediated by mast cells.

According to the Mayo Clinic these are symptoms of eosinophilic-esophagitis


Adults:

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         Chest pain that is often centrally located and does not respond to antacids

·         Persistent heartburn

·         Upper abdominal pain

·         No response to gastroesophageal reflux disease (GERD) medication

·         Backflow of undigested food (regurgitation)


Children:

·         Difficulty feeding

·         Vomiting

·         Abdominal pain

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         No response to GERD medication

·         Failure to thrive (poor growth, malnutrition and weight loss)


The diagnosis of EoE is typically made on the combination of symptoms and findings of diagnostic testing.


Prior to the development of the EE Diagnostic Panel, EoE could only be diagnosed if gastroesophageal reflux did not respond to a six-week trial of twice-a-day high-dose proton-pump inhibitors (PPIs) or if a negative ambulatory pH study ruled out gastroesophageal reflux disease (GERD).

Treatment strategies include dietary modification to exclude food allergens, medical therapy, and mechanical dilatation of the esophagus.

The current recommendation for first line treatment is PPI in lieu of diet as a significant portion of EOE cases respond to this, and it is a low risk, low cost treatment.

The second and third line therapies are an elimination diet of either the 6 or 4 most common triggers, or topical corticosteroids, including both fluticasone, and topical viscous budesonide.

Elimination diets would be followed by re-introduction of foods under supervision if the first diet is successful. Allergy evaluation has not been found to be an effective means to determine what foods to eliminate.

  


MAST CELL STABILIZERS

In a small case series, Cromolyn sodium failed to show any clinical or histologic improvement in EoE patients

LEUKOTRIENE INHIBITORS

Montelukast is an eosinophil stabilizing agent. It improved clinical symptoms in EoE but there was no histological improvement

PROGNOSIS

As mentioned earlier, EoE is a chronic inflammatory disease of the esophagus. The inflammation leads to remodeling, fibrosis and stricture. Fortunately, no case of esophageal malignancy has been reported in EoE. Patients are generally diagnosed after several years of their symptoms. Although symptomatic improvement occurs after treatment, recurrence is common after discontinuation of treatment. So maintenance therapy is needed to prevent recurrences. At the present time there is no head to head study to suggest the best maintenance treatment. Continuation of swallowed corticosteroid and/or dietary therapy should be done in all EoE patients particularly in those with history of food impaction, dysphagia, esophageal stricture, and in those with rapid symptomatic and histologic relapse following initial treatment



Eosinophilic esophagitis and Mast Cells

Eosinophilic esophagitis is called Eosinophilic because it is mediated by Eosinophils, however it has been established that mast cells also play a role. 



Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Herein we have identified local mastocytosis and mast cell degranulation in the esophagus of EE patients; identified an esophageal mast cell associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome with CPA3 mRNA levels serving as the best mast cell surrogate marker; and provide evidence for the involvement of KIT ligand in the pathogenesis of EE.


One possible explanation for eosinophilic esophagitis:















A potential immunological mechanism involved in the pathogenesis of EoE. An uncontrolled TH2 immune response initiated by an allergic insult results in the transition of the esophagus from a normal (NL) to EoE phenotype through enhanced IL-13 production that induces highly elevated CCL26 (eotaxin-3) expression by esophageal epithelium. Dysregulated TH2 immune response and enhanced CCL26 secretion together promote the infiltration of CD4+TH2 cells, eosinophils, and mast cells, and potentially, type-2 innate lymphoid cells (ILC2) and CD4+TH9 cells; into the esophagus. TGF-β and IL-4 produced by the activated mast cells and CD4+TH2 cells may induce eosinophils, ILC2, and/or CD4+TH9 cells to produce IL-9, which in turn, promotes esophageal mastocytosis that contributes to the development of EoE pathophysiology.



Possible Eosinophil stabilizers


CONCLUSIONS Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been well-tolerated in our patient population, with incoming data about efficacy expected over the coming months




·        Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum.

·        Curine inhibits eosinophil influx and activation and airway hyper-responsiveness.

·        Curine mechanisms involve inhibition of Ca2+ influx, and IL-13 and eotaxin secretion.

·        No significant toxicity was observed in mice orally treated with curine for 7 days.

·         Curine has the potential for the development of anti-asthmatic drugs.

  

Conclusion

Non conventional therapies for eosinophilic esophagitis might include:-


·        Cetirizine

·        Verapamil

·        Montelukast

·        Curine

The very expensive therapy is Mepolizumab.

If you have one type granulocyte causing a disorder, is seems almost inevitable that the other types of granulocyte are also involved.

Treating granulocyte disorders should improve autism and left untreated they may mask the effect of otherwise useful autism therapies. 

One reader did previously suggest a bone marrow transplant for autism. A rather radical solution, but if someone with autism was given donor bone marrow as part of another therapy, you might well see their autism improve.