Tagged: Ldopa

Oleh Hornykiewicz (1926-2020)

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This week it was announced that Oleh Hornykiewicz had passed away.

I appreciate that most readers will not know who he is, but understand that his contribution to Parkinson’s research was important.

Not only was he instrumental in the discovery that dopamine is significantly reduced in the Parkinsonian brain, but he also demonstrated that levodopa treatment can help restore function.

In today’s post, we remember Oleh Hornykiewicz.

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It was sad to hear of the passing away of Oleh Hornykiewicz this week.

Most readers will have little clue as to who he was, but he played a very important role in the development of the Parkinson’s treatment we know of as levodopa therapy.

Very early in the 20th century, a chemical called dopamine was discovered, but no one really knew anything about it until a young Swedish research named Arvid Carlsson started to play with it.

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Prof Arvid Carlsson. Source: Alchetron

In 1957, Carlsson discovered that when he injected a drug called reserpine into the brains of rabbits, the animals exhibited limited ability to move. He found that reserpine depleted levels of dopamine in the brains of the rabbits. He also discovered that by injecting the dopamine precursor – levodopa (more on this below) – into those same animals, he was able to rescue their motor ability. Importantly, he found that the precursor (called 5-hydroxytryptophan) to another chemical called serotonin, it was not capable of reversing the reduction in motor ability, indicating that the effect was specific to levodopa and dopamine.

He published this amazing result in the prestigeous scientific journal ‘Nature’:

avid

Title: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.
Authors: Carlsson A, Lindqvist M, Magnusson T.
Journal: Nature. 1957 Nov 30;180(4596):1200. No abstract available.
PMID: 13483658       (the article on the Nature website – access required)

This was a fantastic discovery.

But what to do with it?

And that is where an Austrian researcher named Oleh Hornykiewicz becomes part of the story.

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Direct dopamine delivery

     

In the Parkinsonian brain, there is a severe reduction in a substance called dopamine. Reduced levels of this chemical are associated with the appearance of the motor features of Parkinson’s.

Dopamine replacement therapies has been the front line therapy for the condition for the last 50 years. But long-term use of drugs like L-dopa are associated with the rise of motor complications, like dyskinesias.

In the an effort to correct this, researchers in France have recently developed a method of continuously and directly delivering dopamine to the brain. They have now published the results of a study evaluating the safety and feasibility of this approach in a primate model of Parkinson’s.

In today’s post, we will discuss what dopamine is, review the results of this new research, and explore what might happen next for this new potential treatment method.

 


Prof David Devos. Source: Youtube

This is Dr David Devos.

He is Professor of medical pharmacology at University of Lille (France), world-renowned Parkinson’s researchers, a passionate advocate for the Parkinson’s community, and on top of all that he’s a really (and I mean REALLY) nice guy as well.

Recently, his research group (in collaboration with other scientists) published a report presenting a novel way of treating Parkinson’s, that he is now hoping to take to the clinic.

Here is the report:

Title: Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson’s disease.
Authors: Moreau C, Rolland AS, Pioli E, Li Q, Odou P, Barthelemy C, Lannoy D, Demailly A, Carta N, Deramecourt V, Auger F, Kuchcinski G, Laloux C, Defebvre L, Bordet R, Duce J, Devedjian JC, Bezard E, Fisichella M, David D.
Journal: Neurobiol Dis. 2020 Mar 20:104846.
PMID: 32205254                    (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers wanted to explore how to directly deliver a chemical called dopamine to the brain.

What is dopamine?

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When disco-needs-ya, can gene therapy help ya?

 

With the recent announcement that the STEADY-PD III/Isradipine clinical trial did not reach its primary end point (that of slowing the progression of Parkinson’s), the winds of change have shifted with calls for a focus on biomarkers and better treatments, rather than disease modification.

Recently, researchers at Michigan State University have reported a novel experimental gene thearpy method for dealing with one of the most debilitating aspects of Parkinson’s – dyskinesias.

Ironically, their approach involves the same calcium channels that Isradipine blocks.

In today’s post, we will look at what dyskinesias are, what gene therapy is, and how this new approach could be useful for people currently burdened by these involutary movements.

 


Dyskinesia. Source: JAMA Neurology

There is a normal course of events following a diagnosis of Parkinson’s.

Yes, I am grossly over-generalising.

And no, I’m not talking from personal experience (this is based on listening to a lot of people), but just go with me on this for the sake of discussion.

First comes the shock of the actual diagnosis. For many it is devastating news – an event that changes the course of their lives. For others, however, the words ‘you have Parkinson’s‘ can provide a strange sense of relief that their current situation has a name and gives them something to focus on.

This initial phase is usually followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial). It depends on each individual.

The emotional rollercoaster. Source: Asklatisha

And then comes the period during which many will try to familiarise themselves with their new situation. They will read books, search online for information, join Facebook groups (Click here for a good one), etc.

That search for information often leads to awareness of some of the realities of the condition.

And one potential reality that causes concern for many people (especially for people with young/early onset Parkinson’s) is dyskinesias.

What are dyskinesias?

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Is there NOP hope for Parkinson’s?

Please do not misread the title of this post!

Compounds targeting the Nociceptin receptor (or NOP) could provide the Parkinson’s community with novel treatment options in the not-too-distant future.

In pre-clinical models of Parkinson’s, compounds designed to block NOP have demonstrated neuroprotective properties, while drugs that stimulate NOP appear to be beneficial in reducing L-dopa induced dyskinesias. 

In today’s post we look at exactly what NOP is and what it does, we will review some of the Parkinson’s-based research that have been conducted so far, and we will look at what is happening in the clinic with regards to NOP-based treatments.


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Source: LUMS

On the surface of every cell in your body, there are lots of small proteins that are called receptors.

They are numerous and ubiquitous.

And they function act like a ‘light switch’ – allowing for certain biological processes to be initiated or inhibited. All a receptor requires to be activated (or blocked) is a chemical messenger – called a ligand – to come along and bind to it.

An example of a receptor on a cell. Source: Droualb

Each type of receptor has a particular structure, which is specific to certain shaped ligands (the chemical messenger I mentioned above). These ligands are floating around in the extracellular space (the world outside of the cell), having been released (or secreted) by other cells.

And this process represents one of the main methods by which cells communicate with each other.

By binding to a receptor, the ligand can either activate the receptor or alternatively block it. The activator ligands are called agonists, while the blockers are antagonists.

Agonists_and_antagonists

Agonist vs antagonist. Source: Psychonautwiki

Many of the drugs we currently have available in the clinic function in this manner.

For example, with Parkinson’s medications, some people will be taking Pramipexole (‘Mirapex’ and ‘Sifrol’) or Apomorphine (‘Apokyn’) to treat their symptoms. These drugs are Dopamine agonists because they bind to the dopamine receptors, and help with dopamine-mediated functions (dopamine being one of the chemicals that is severely in the Parkinsonian brain). As you can see in the image below the blue dopamine agonists can bypass the dopamine production process (which is reduced in Parkinson’s) and bind directly to the dopamine receptors on the cells that are the intended targets of dopamine.

Source: Bocsci

There are also dopamine antagonists (such as Olanzapine or ‘Zyprexa’) which blocks dopamine receptors. These drugs are not very helpful to Parkinson’s, but dopamine antagonist are commonly prescribed for people with schizophrenia.

Are there other receptors of interest in Parkinson’s?

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O’mice an’ men – gang aft agley

This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.

The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.

In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.


The humble lab mouse. Source: PBS

Much of our understanding of modern biology is derived from the “lower organisms”.

From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.

Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.

You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.

Nor do mice. Or snails.

Or yeast for that matter.

So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.

We work with the best tools we have, but it those tools are flawed…

What did the new research report find?

This is the study:


Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
PMID: 28882997

The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.

What are induced pluripotent stem cells?

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Voyager Therapeutics: phase Ib clinical trial results

 

This week a biotech company called Voyager Therapeutics announced the results of their ongoing phase Ib clinical trial. The trial is investigating a gene therapy approach for people with severe Parkinson’s disease.

Gene therapy is a technique that involves inserting new DNA into a cell using a virus. The DNA can help the cell to produce beneficial proteins that go on help to alleviate the motor features of Parkinson’s disease.

In today’s post we will discuss gene therapy, review the new results and consider what they mean for the Parkinson’s community.


Source: Joshworth

On 25th August 2012, the Voyager 1 space craft became the first human-made object to exit our solar system.

After 35 years and 11 billion miles of travel, this explorer has finally left the heliosphere (which encompasses our solar system) and it has crossed into the a region of space called the heliosheath – the boundary area that separates our solar system from interstellar space. Next stop on the journey of Voyager 1 will be the Oort cloud, which it will reach in approximately 300 years and it will take the tiny craft about 30,000 years to pass through it.

Where is Voyager 1? Source: Tampabay

Where is Voyager actually going? Well, eventually it will pass within 1 light year of a star called AC +79 3888 (also known as Gliese 445), which lies 17.6 light-years from Earth. It will achieve this goal on a Tuesday afternoon in 40,000 years time.

Gliese 445 (circled). Source: Wikipedia

Remarkably, the Gliese 445 star itself is actually coming towards us. Rather rapidly as well. It is approaching with a current velocity of 119 km/sec – nearly 7 times as fast as Voyager 1 is travelling towards it (the current speed of the craft is 38,000 mph (61,000 km/h).

Interesting, but what does any of that have to do with Parkinson’s disease?

Well closer to home, another ‘Voyager’ is also ‘going boldly where no man has gone before’ (sort of).

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Helicobacter pylori: Unwanted passengers?

helicobacter-pylori


Whether we like it or not, we house a great deal of microbes.

Many of these tiny creatures aid us in our daily living by conducting important functions. Some of these microbes, however, may not be helping us, getting a free ride, and potentially causing trouble.

In today’s post we will review recent research regarding one particular family of bacteria, Helicobacter pylori, and what they might be doing in relations to Parkinson’s disease.


yong

Source: ScienceFriday

In his magnificent book, I contain multitudes, science writer/journalist Ed Yong writes that we – every single one of us – release approximately 37 million bacteria per hour. By talking, breathing, touching, or simply being present in the world, we are losing and also picking up the little passengers everywhere we go.

Reminds me of that Pascal Mercier book “Night Train to Lisbon” – We leave something of ourselves behind when we leave a place,… I’m not sure if this is what he was referring to though.

Yong also points out that: 80% of the bacteria on your right thumb are different to the bacteria on your left thumb.

It’s a fascinating book (and no, I am not receiving any royalties for saying that).

12-microbes.w710.h473.2x

Microbes. Source: NYmag

We have discussed microbes several times on this blog, particularly in the context of the gut and its connection to Parkinson’s disease (Click here, here and here to read some of those posts). Today we are going to re-visit one particular type of microbe that we have also discussed in a previous postHelicobacter pylori.

helicobacter-pylori-1

Helicobacter pylori. Source: Helico

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Tetrabenazine: A strategy for Levodopa-induced dyskinesia?

Dyk

For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.

Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa

In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.


Dysco

Dyskinesia. Source: JAMA Neurology

There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).

First comes the shock of the diagnosis.

This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).

Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.

One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.

What are dyskinesias?

Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.

As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).

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Sinemet is Levodopa. Source: Drugs

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Juvenile-onset Parkinson’s disease

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A community in New Brunswick (Canada) was recently shocked to discover that a 2 year old boy in their midst had been diagnosed with Parkinson’s disease (Click here to read more).

Yes, you read that correctly, it’s not a typo: a 2 year old boy.

Juvenile-onset Parkinson’s disease is an extremely rare version of the condition we discuss here at the Science of Parkinson’s. It is loosely defined as being ‘diagnosed with Parkinson’s disease under the age of 20’. The prevalence is unknown, but there is a strong genetic component to form of the condition. In today’s post we will review what is known about Juvenile-onset and look at new research about a gene that has recently been discovered to cause a type of Juvenile-onset Parkinson’s disease.


Henri_Huchard

Dr Henri Huchard. Source: Wikipedia

In 1875, Dr Henri Huchard (1844-1910; a French neurologist and cardiologist) described the first case of a child who, at just 3 years of age, presented all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has become known as ‘juvenile-onset Parkinson’s disease’.

What is juvenile-onset Parkinson’s disease?

Basically, it is a form of Parkinson’s disease that affects children and young people under the age of 20. The defining feature is the age of onset. The average age of onset is approximately 12 years of age (with the majority of cases falling between 7 and 16 years) and males are affected by this condition more than females (at a rate of approximately 5:1).

The actual frequency of juvenile-onset parkinson’s is unknown given how rare it is. When researcher look at people with early onset Parkinson’s disease (that is diagnosis before the age of 40; approximately 5% of the Parkinson’s community), they have found that between 0.5 – 5% of that group of people were diagnosed before 20 years of age. This suggests that within just the Parkinson’s community, the frequency of juvenile-onset parkinson’s is at the most 0.25% (or 2.5 people per 1000 people with Parkinson’s). Thus it is obviously a very rare condition.

It is interesting to note that Lewy bodies (the clusters of aggregated protein that classically characterise the brains of people with Parkinson’s disease) are very rare in cases of juvenile-onset parkinson’s disease. To our knowledge there has been only one case of Lewy bodies in juvenile-onset parkinson’s disease (Click here to read more on this). This suggests that the juvenile-onset form of Parkinson’s disease may differ from other forms of the condition in its underlying biology.

Do we know what causes juvenile-onset parkinson’s disease?

There is a very strong genetic component to juvenile-onset parkinson’s disease. In fact, the incidence of Parkinsonism in relatives of people with juvenile-onset parkinson’s disease is higher than in the general public AND in the relatives of people with other forms of Parkinson’s disease.

Genetic mutations in three genes are recognised as causing juvenile-onset Parkinson’s disease. The three genes are known to the Parkinson’s world as they are all PARK genes (genetic variations that are associated with Parkinson’s). Those three genes are:

  • Parkin (PARK2)
  • PTEN-induced putative kinase 1 (PINK1 or PARK6)
  • DJ1 (PARK7)

In juvenile-onset Parkinson’s disease, all of these mutations are associated with autosomal recessive – meaning that two copies of the genetic variation must be present in order for the disease to develop.

Parkin mutations account for the majority of juvenile-onset Parkinson’s disease cases. Affected individuals have a slowly progressing condition that is L-dopa responsive. Dystonia (abnormal muscle tone resulting in muscular spasm and abnormal posture) is very common at the onset of the condition, particularly in the lower limbs.

Can the condition be treated with L-dopa?

The answer is: ‘Yes, but…’

L-dopa (or dopamine replacement) treatment is the standard therapy for alleviating the motor features of Parkinson’s disease.

The majority of people with juvenile-onset parkinson’s respond well to L-dopa, but in the Parkin mutation version individuals will typically begin to experience L-dopa-induced motor fluctuations (dyskinesias) early in that treatment regime.

What research is currently being done on this condition?

Given that cases are so very rare and so few, it is difficult to conduct research on this population of individuals. Most of the research that is being conducted is focused on the genetics underlying the condition.

And recent that research lead to the discovery of a new genetic variation that causes juvenile-onset Parkinson’s disease:

Juvenile

Title: Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.
Authors: Sudhaman S, Prasad K, Behari M, Muthane UB, Juyal RC, Thelma BK.
Journal: Journal Med Genet. 2016 Jul;53(7):450-6.
PMID: 26864383           (This article is OPEN ACCESS if you would like to read it)

The researchers who wrote this article were presented with a 10 member Indian family from Aligarh, Uttar Pradesh. Of the 8 children in the  family, 3 were affected by Parkinsonian features (tremor, slowness, rigidity and gait problems) that began between 13 and 17 years of age. The researchers conducted DNA sequencing and found that none of the three affected siblings had any of the known Juvenile-onset Parkinson’s disease genetic mutations (specifically, mutations in the genes PARK2, PINK1and DJ1).

They then compared the DNA from the three siblings with the rest of the family and found a genetic variant in a gene called podocalyxin-like (or PODXL). It must be noted that PODXL is a completely novel gene in the world of Parkinson’s disease research, which makes it very interesting. PODXL has never previously been associated with any kind of Parkinson’s disease, though it has been connected with two types of cancer (embryonal carcinoma and periampullary adenocarcinoma).

The researchers then turned to their genetic database of 280 people with Parkinson’s disease have had their genomes sequenced. The researchers wanted to determine if any genetic variants in the PODXL gene were present in other suffers of Parkinson’s disease, but had not been picked up as a major contributing factor. They found three unrelated people with PODXL mutations. All three had classical Parkinson’s features, and were negative for mutations in the Parkin, PINK1 and DJ1 genes.

The researchers concluded that the PODXL gene may be considered as a fourth causal gene for Juvenile-onset Parkinson’s disease, but they indicated that further investigations in other ethnic groups are required.

 


The banner for today’s post was sourced from ClipArtBest

The Autistic spectrum and Parkinson’s disease

The word Autism on a cork notice board

In August of 2015, groups of scientists from North Carolina and Perth (Australia) published a report together in which they noted the high occurrence of Parkinson’s-like features in aging people with Autism.

In this post we will have a look at what links (if any) there may be between Autism and Parkinson’s disease.


Recent estimates suggest that the prevalence of Autistic Spectrum Disorders in US children is approximately 1.5 %. Autism is generally associated with children, and in this way it is almost a mirror opposite of Parkinson’s disease (which is usually associated with the elderly). A fair number of people who were diagnosed with Autism early in their lives are now reaching the age of retirement, but we know very little about what happens in this condition in the aged.

What is Autism?

This is one of those questions that gets people into trouble. There is a great deal of debate over how this condition should be defined/described. We here at SoPD will chose to play it safe and provide the UK National Health System (NHS)‘s description:

Autism spectrum disorder (ASD) is a condition that affects social interaction, communication, interests and behaviour. In children with ASD, the symptoms are present before three years of age, although a diagnosis can sometimes be made after the age of three. It’s estimated that about 1 in every 100 people in the UK has ASD. More boys are diagnosed with the condition than girls.

Wikipedia also has a very thorough page Autism

So what was reported in the study finding a connection between Autism and Parkinson’s disease?

Last year two groups of researchers (from North Carolina, USA and Perth, Australia) noticed an interesting trend in some of the aging Autistic subjects they were observing.

They published their findings in the Journal of Neurodevelopmental disorders:

Autism-title1

Title: High rates of parkinsonism in adults with autism.
Authors: Starkstein S, Gellar S, Parlier M, Payne L, Piven J.
Journal: Journal of Neurodev Disord. 2015;7(1):29.
PMID: 26322138         (This report is OPEN ACCESS if you would like to read it)

The article reports the findings of two studies:

Study I (North Carolina) included 19 men with Autism (with an average age of 57 years). When the researchers investigated the cardinal features of Parkinson’s disease, they found that 22 % (N = 4) of the subjects exhibited bradykinesia (or slowness of movement), 16 % (N = 3) had a resting tremor, 32 % (N = 6) displayed rigidity, and 15 % (N = 2) had postural instability issues.

In fact, three of the 19 subjects (16 %) actually met the criteria for a full diagnosis of Parkinson’s disease (one of who was already responding well to L-dopa treatment).

Study II (Perth) was a larger study, involving 32 men and 5 women (with an average age of 51 years). 46 % (N = 17) of the subjects in this study exhibited bradykinesia, 19 % (N = 7) had a resting tremor, 19 % (N = 7) displayed rigidity, and 19 % (N = 7) had postural instability problems. In study II, 12 of the 37 subjects (32 %) met the full diagnostic criteria for Parkinson’s disease.

Given this collective result, the researchers concluded that there may well be an increased frequency of Parkinsonism in the aged people with Autism. They emphasize, however, the need to replicate the study before definitive conclusions can be made.

So how could this be happening?

The short answer is: we don’t have a clue.

The results of this study need to be replicated a few times before we can conclusively say that there is a connection. There are, however, some interesting similarities between Autism and Parkinson’s disease, for example (as the NHS mentioned above) males are more affected than females in both conditions.

There are genetic variations that both Parkinson’s and Autism share. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one of the PARK genes (we have discussed these before – click here to read that post). The genetics of Autism are less well understood. If you have one child with Autism, the risk for the next child also having the condition is only 2-6% (genetically speaking, it should be a 25-50% level of risk).

There are, however, some genes associated with Autism and one of those genes is the Parkinson’s associated gene, PARK2. it has previously been reported that variants in the PARK2 gene (Parkin) in children with Autism (click here for more on this).

It would be interesting to have a look at the brains of aged people with Autism. This could be done with brain scans (DAT-SCAN), but also at the postmortem stage to see if their brains have alpha synuclein clusters and Lewy bodies – the pathological characteristics of Parkinson’s disease. These studies may well be underway – we’ll keep an eye out for any reports.

Alternative explanations?

There are alternative explanations for the connection between Autism and Parkinson’s disease suggested by this study. For example, 36 of the 56 subjects involved in the two studies were on medication for their Autism (the medication is called neuroleptics). Those medications did not appear to explain the rates of parkinsonism in either study (after excluding subjects currently on neuroleptic medications, the frequency of parkinsonism was still 20 %). Most of the subjects in both studies have been prescribed neuroleptics at some point in their lives. Thus it is possible that long-term use of neuroleptics may have had the effect of increasing the risk for parkinsonism later in life. This is pure speculation, however, and yet to be tested. Any future studies would need to investigate this as a possibility.


EDITOR’S NOTE: If you have a child or loved one on the Autism spectrum, it is important to understand that the study summarised here are novel results that are yet to be replicated. And if it turns out that adults with Autism do have a higher risk of developing Parkinson’s disease it does not necessarily mean that they will – simply that they are at greater risk than normal. It is best to consult a medical practitioner if you have further concerns.


The banner at the  today’s post was sourced from Sailing Autistic Seas.