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Denver TMAU Test Lab survey click here
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USA survey for anyone who wants to improve Denver TMAU test

begun : Dec22
end : no ending for now

A trainee genetic counselor is working at the Denver TMAU test lab. Probably as part of her training. As a project she wishes feedback on any aspect of the Denver TMAU test and process. You can fill in the survey and/or email her (email address is in survey). It's meant for USA people, but perhaps others can give their view too (as we have so few opportunities).

quote from her rareconnect post

"Hello all! I wanted to make you aware of a research study being conducted to better understand the experience and needs of individuals with trimethylaminuria with a goal of being able to create improved patient and healthcare provider education materials. Any participation is completely voluntary and all responses remain confidential. Feel free to use the contact information within the link with any questions or share the survey with others with TMAU."

see this post for more details

https://www.meboblog.com/2023/01/denver-tmau-test-survey-tbc-who-it-is.html

Thursday, August 26, 2010

‘Unaffiliated’ systemic body odors, A patient advocacy group’s viewpoint by MEBO Research staff

Recently, MEBO Research was invited to write an article about systemic body odor for the American Academy of Pediatrrics (AAP) monthly Adolescent Newsletter which is read by member pediatricians. We wrote an article in 3 parts, the 1st part being MeBO's discussion of 'unaffiliated' systemic body odor (unaffiliated as in no other apparent symptom). The 2nd part is an overview of TMAU by Dr Ronald Hines, and the 3rd part being 3 sufferer's stories. The final version is still to be determined by the editor of the publication. Below is a copy of the 1st part. Even though we do not know if this copy will be accepted, we thought the community would be interested in reading it. Your comments are welcome.


‘Unaffiliated’ systemic body odors

Part One

A patient advocacy group’s viewpoint
by MEBO Research staff
email : info@meboresearch.org

Introduction
At this stage in modern medicine, one would imagine all health problems obvious to the senses would have been characterized. However, one pungent complaint seems to have eluded the clinician’s nose: that of unaffiliated systemic body odors, including a form that can smell fecal or gas-like, as well as other bowel odors, emitted from the body as a whole. This article attempts to raise awareness of the concept of unaffiliated (as in ‘no other apparent symptom’) systemic body odors such as trimethylaminuria. These types of body odors may be the most common type of ‘unsolvable’ body odor, and far more common than realized. The odor problem typically starts in childhood or teenage years, especially around puberty, making it a problem that pediatricians may especially encounter.

Who is MEBO Research?
MEBO Research is a fledgling patient advocacy group of body odor sufferers and their families with the help of experts whose goal is to raise awareness and promote research into systemic body odors and is currently applying for charity status in the US. We are grateful for the opportunity to raise awareness of unaffiliated systemic body odors from the sufferers’ viewpoint. MEBO Research is writing this part of the article as a voice for the body odor community. We believe that unaffiliated systemic body odor may not be rare, with most still to be defined in medical literature.

Spectrum of Systemic Body Odors
Pediatricians are familiar with systemic body odors associated with serious medical conditions, including inborn errors of metabolism, such as the ‘sweaty feet’ smell of isovaleric acidemia. However, unaffiliated systemic body odors may be a new concept in which the person seems healthy other than presenting with an unusual odor complaint, although one form is already characterized, trimethylaminuria (TMAU).

The Internet, Trimethylaminuria and Fecal Body Odor syndrome
With the maturing of the internet, it has become clear in the online body odor and halitosis community, that many believe they do not have the classic localized body odor/halitosis problem (e.g. underarm body odor), but rather, an uncontrollable unusual odor problem that emanates from within. Although TMAU, which used to be commonly known as ‘fish odor syndrome’, is the only reasonably documented unaffiliated systemic body odor, the most common complaint on forums even by persons diagnosed with TMAU is known as ‘fecal body odor’ (FBO), an odor emitted from the whole body. In addition, others describe their unusual body odor to also be of bowel odors, gas, garbage, sewage, rotten egg, rotten fish, and burning rubber amongst other unpleasant odors. Before the internet, most sufferers thought they had a unique problem.

The main reason this disorder may have gone unnoticed by clinicians may be that in most cases it tends to be intermittent, and frequently, curiously enough, neither the sufferer nor close genetic relatives can detect it; making demonstrating the symptom to a clinician difficult. A common pattern is for sufferers to say they start smelling in childhood or in their teens and especially around puberty, with their parents not believing them since close relatives normally are somehow anosmic to it.

Introduction to Trimethylaminuria
Trimethylaminuria, known by its acronym TMAU, was first documented in 1970 link, but has generally been a neglected disorder. A PubMed search of ‘trimethylaminuria’ recovers only 106 papers, written mainly by the same few researchers. As depicted in these papers, the primary form, TMAU1, is classically portrayed as an genetic autosomal recessive condition with a mutant gene from both parents, and thus thought to be rare. The primary form is classed as having subnormal activity of the flavin mono-oxygenase 3 (FMO3) enzyme, that normally oxidizes trimethylamine (TMA) to its odorless form of TMA-oxide. Curiously, in most cases, the odor is intermittent and undetectable by the sufferer, so the patient may not know when symptoms will present, while in rarer severe cases, symptoms present constantly for years. While ‘severe’ cases may be rare, ‘mild’ genetic cases are likely far more common. It may even include carriers, as well as genetically ‘mild’ variant cases link. The secondary form, TMAU2, is an acquired non-genetic condition due to excess trimethylamine (TMA). Essentially, the TMAU phenotype test looks for reduced FMO3 function via the ratio of TMA and TMA-n-oxide link link (TMAU1), and/or the excess TMA level (TMAU2).

A differential diagnosis classification scheme for TMAU has been proposed [Mitchell & Smith 2001, Mitchell 2005], primary genetic TMAU, acquired TMAU, transient childhood TMAU, transient TMAU associated with menstruation, precursor overload, and diseases states link.

Dr. Ronald Hines, who has previously conducted TMAU/FMO research link link link, has kindly written an accompanying text for us, which depicts the current TMAU overview and advice.

Dimethylglycinuria (DMGU)
Another documented unaffiliated systemic body odor is dimethylglycinuria. However there is only one reported case, even though some have been tested for DMGU with negative test results. It seems to imply that there may be other hitherto undocumented idiosyncratic systemic body odors still to be characterized. MEBO Research believes broad-spectrum biogenic volatile organic compound (VOC) phenotype testing is a good starting point to discovering most systemic body odors, along with genetic testing.

TMAU or Fecal Body Odor syndrome?
While most saturated enzymes may produce one particular odor, one can only speculate, and much research is required, to explain how someone can smell of such a wide range of odors, such as in FBO. A suspicion is that a drug-metabolizing enzyme may be implicated, since these enzymes deal with a wide range of substrates. Of these, FMO3 is a prime suspect, given that it detoxifies a wide range of odorous sulfur and nitrogen compounds in particular.

Currently, TMAU is the only medically recognized odor problem associated with this enzyme. However many patients positive for TMAU complain of having fecal/gas odors, rather than only, if at all, a rotting fish odor. One theory MEBO Research has is that FBO may be a ‘saturated FMO3 substrates body odor’ due to either sub-standard enzyme function or substrate overload. Since TMA is an FMO3 substrate, a positive TMAU test result is likely. Perhaps TMA is a baseline/signature FMO3 odor. Only much needed research will clarify these matters.

Comments on TMAU diagnosis
Presently, it is not known if TMAU and FBO are the same, similar or overlapping disorders. Researchers anticipate TMAU sufferers may in theory have issues with FMO3 substrates, but not that they smell of anything other than TMA. Many, though not all, who have FBO get a positive TMAU phenotype test result. So, testing for TMAU in cases of claimed unusual body odors seems a current sensible initial plan of action.

It appears there is currently no international standardized reference range for the TMAU phenotype test. The three known labs in the US that currently perform the TMAU phenotype test are the Human BioMolecular Research Institute (HBRI) in San Diego, the Arkansas Children’s Hospital (ACH) in Little Rock, and the University of Colorado Denver (UCD) Biochemical Genetics Laboratory, Department of Pediatrics. The Mayo Clinic provides instructions to the physician for the Trimethylaminuria urine test (Mnemonic -WILD105/Mayo Unit 90544) covered by most major medical insurance carriers, and the urine specimen is then referred to the ACH Lab. MEBO Research also keeps a list of known worldwide TMAU test labs on its website link

While ACH tests for TMA concentration level only, the other two labs test for TMA and TMA-oxide (TMAO), arriving at a diagnosis using the percent of TMAO/(TMAO+TMA)x100. For labs worldwide that perform the phenotype test, there may be different levels set as to what indicates TMA excess (if this is taken into consideration alone), or under which percentage point a positive diagnosis is indicated from the equation above.

A curious anomaly is that a number of positive phenotype cases go on to test negative for the genotype test (DNA test) link. One possible explanation for this is that more variants/mutants may exist and are yet to be discovered through more extensive research. With his permission, an email reply was posted in MEBO’s blog from Richard Kirk MSc FRCPath Lead Clinical Scientist, who tests for FMO3 variants. His view on this was :
...Although our test will pick up all the mutations that have been described in this gene, we cannot exclude rare mutation mechanisms such as mutations deep within introns (the non-coding DNA between the exons) or mutations affecting the controlling mechanisms for the gene. There is also a theoretical possibility that other related proteins/enzymes could be affected... link

Although primary TMAU is expected to start at a young age, there are a sizable number of patients whose systemic odor symptoms begin in their 20s, 30s, 40s, or even older, who then test positive for primary TMAU. This raises the notion that an environmental factor could play a large role in some cases, with the gut ecology being a possible obvious suspect. Many with TMAU or FBO do complain of mild gut issues such as bloating, constipation, or mild IBS types of complaints.

Secondary TMAU, generally regarded as an acquired excess TMA-production, seems to be a common TMAU diagnosis in the UK, but customarily rarely diagnosed in the US.

Estimated percentage of persons at risk for TMAU
The estimated percentage of population ‘at risk’ for primary TMAU is yet to be conclusively determined. A concern is that those potentially prone to TMAU may be greatly underestimated. The classic severe type, where the person has two mutant copies is generally regarded as very rare, which is possibly accurate. However, it is a spectrum that goes from a ‘severe’ classic ‘mutant’ case, to those with TMA excess while having no apparent FMO3 deficiency, with variant cases or ‘mild’ combinations somewhere in between. It seems likely that most on the forums will be ‘mild’ genetic cases, though the odor produced, even if intermittently, is just as pungent as that of a severe case, with the added problem that sufferers usually cannot detect their own odor. Given the amount of polymorphisms that may diminish FMO3 function to some degree, even if only mildly, there could be a sizable number ‘at risk’ for TMAU. Estimates of all forms of genetic TMAU could be approximately 1-3% of the population being potentially affected to some degree link. This does not include the secondary TMAU type (TMAU2), which is considered to be due to a TMA overload.

In a 1999 letter to the Lancet, Dr SC Mitchell wrote,


Over the past decade we have encountered many patients who have odour problems on a mild, transient, and periodic basis. These otherwise healthy individuals are presumably heterozygotes, or compound heterozygotes, who can cope with the daily burden of trimethylamine, but have little, if any, reserve capacity when stressed by other factors and may fail to metabolically remove trimethylamine. To raise the general awareness of this disorder and reiterate that it “is not merely a rare recessive disorder but rather a spectrum of phenotypes of transient or mild malodour” is important, but it is also imperative to realise that fish-odour syndrome is not a simple genetic problem and that heterozygotes (carriers) may have to endure a transient and more elusive form of this complaint initiated by various, less obvious, and more ephemeral, factors.link

Why can’t some people smell it ?
A cruel irony of systemic body odor is that usually close genetic relatives or the sufferer cannot smell the odor. One can only speculate as to why this is. Theories in the forums are often based around either acclimatization or desensitization, or a ‘genetic carrier’ connection. Some believe that some people have a specific anosmia to some of the odors involved.There is evidence that some people have specific anosmia to TMA and other tertiary amines in particular: In a 1975 study, 7% could not detect TMA link. One possible theory MEBO has is that those who are ‘carriers’ may have a specific anosmia or hyposmia due to some sort of genetic ‘immunity’.

Other possible causes of systemic body odors ?
Other speculative causes of unaffiliated systemic body odors are whether any other enzymes could be saturated or deficient, or anything could inhibit an enzyme, causing an odor problem similar to how TMAU occurs. Similar to the FBO complaint, there was a documented case of a neonate with a ‘cabbage’ odor in 1999 link. Some may be anecdotally aware that after eating curry or garlic, their armpit may later smell of the food. This seems to confirm VOCs can be circulating systemically and be excreted unmetabolized. An example is asparagusuria, where after eating asparagus, the urine becomes odorous. Interestingly, this is regarded as an ‘autosomal dominant’ action link, whereas TMAU is regarded ‘recessive’.

DMGU implies there may be other idiosyncratic enzyme body odors that cause one particular smell, rather than a multitude of smells. One question is whether it may be possible that carriers of serious genetic disorders such as isovaleric acidemia may be prone to transient ‘sweaty feet’ body odor and otherwise healthy. Only testimony along with research would answer this question.

Psychosocial consequences of uncontrollable unaffiliated body odor conditions
While those with unaffiliated systemic body odors seem otherwise healthy, the psychosocial impact is profound, particularly since the sufferer usually cannot smell himself or herself, and thus is not aware or in control of the odor pattern. Most feel they smell all the time, which may be far from the truth. To compound the problem, when the patient presents with a body odor complaint which is usually intermittent, it is unlikely they would smell at the doctor’s office visit. To further confuse matters, a study demonstrated that a small minority of the population, which would also include the physicians, may have anosmia or hyposmia to TMA, as mentioned above link.

If the patient then expresses extreme anxiety that arises from seeing that there is no solution at hand, the physician often refers the patient for mental health therapy rather than testing for TMAU and other VOCs and discussing the TMAU odor-reducing protocol recommended by the National Institutes of Health with the patient and family. Most physicians are currently unlikely to be aware of TMAU or the concept of systemic body odors; however, it is imperative that the physician first test the patient for TMAU and other VOCs to arrive at the physical cause before referring to a mental health therapist. The purpose of this article is to raise awareness of TMAU and other odor conditions so that physicians will help their patients by prescribing these tests.

As noted on the forums, patients with a positive diagnosis for TMAU who have transient symptoms (some of which have been a fecal odor and not only fish odor) have been told in the past that the odor was all in their minds. This medical approach only confuses patients who face overt social ridicule by some people about their odor while the family and therapist try to tell them the odor and social ostracism is not real.

Since most of the medical establishment is generally unfamiliar with TMAU or any other type of “benign” body odor condition, a physician may not take the complaint seriously and refer the patient for psychiatric treatment. As a result, the patient may end up with a psychiatric diagnosis of Olfactory Reference Syndrome (ORS), and treated for delusional symptoms. Curiously enough, documented ORS cases claim to have unusual body odors such as fecal, gas, garbage, burnt rubber, and other unusual smells. link link As noted on the forums, patients with a positive diagnosis for TMAU who have transient symptoms have been told in the past that the odor was all in their minds.

Without proper treatment based on body odor diagnostic testing, the primary goal in the life of a sufferer becomes to avoid humiliation, and typically many persons affected with uncontrollable odor conditions are inclined to become isolated, unemployed, and paranoid.

Amazingly, some are highly educated, have good jobs, and/or go on to have long-term partners and children, despite the constant concern about their odor problem, although the pattern in this group may be that their partner usually cannot smell them. Perhaps most in this group develop their body odor condition later in life, but not always. However, many do not accomplish these goals primarily due to the psychological consequence of their condition.

Possible other symptoms
If a metabolic enzyme deficiency was culpable, one could speculate there may be health implications other than just an odor. FMO3, for example, is a xenobiotic metabolic enzyme, metabolizing many substrates including endogenous amines and drugs. It is common to read of adverse reactions to medications, herbs and spices among those with TMAU or FBO. Often the person may have IBS-type issues, such as bloating, pain or tenderness, and irregular bowel movements. Although sufferers may often feel ‘not 100% healthy’, the health problems tend to be vague, such as general malaise, chronic fatigue, or mild ADHD. It is questionable whether this may be the result of stress or whether there is a connection with subnormal enzyme function causing mild toxicity or, for example, with a mild yet abnormal gut ecology causing excess toxicity. Sufferers often feel there is a connection between odor episodes and strong emotions, with emotions triggering the odor. Some, especially women, believe hormonal changes can be a factor in increasing odor levels, as is the case of transient trimethylaminuria associated with menstruation link.

Possible roles for pediatricians in unaffiliated systemic body odor cases
A typical scenario pediatricians may encounter in an unaffiliated systemic body odor case follows:

Whilst a baby, child or teenager with an unusual body odor will be obvious to the pediatrician, this paper will highlight the typical pattern of the mild transient unaffiliated systemic body odor case, i.e., a youth not obviously smelling who claims that he does. What would likely happen is that the youth may insist he smells of ‘gas’ or ‘feces’, or another unusual odor, but the parents are unable to confirm this. The youth will be unlikely to smell anything himself, but claim people keep telling him that he does, and may believe that he permanently smells. The pediatrician likely will not smell anything either, most likely due to the youth having a transient problem, but also possibly due to having the specific anosmia or hyposmia as mentioned above, but this is less likely since only 7% had anosmia to TMA in the study mentioned above.

If diagnostic tests were used, standard amino acids and organic acids would almost definitely be normal. A diagnostic option would be to test the youth for TMAU, which seems the nearest ‘fit’ available, since there is no current test for FBO. The TMAU phenotype test is usually done as a choline or diet challenge test to provoke the symptom, or when the patient is known to be smelling. Pediatricians may be surprised at how many show positive or borderline for this diagnosis. Currently, however, there is a greater chance the youth would be referred to a psychiatrist as opposed to being tested for TMAU.

A caveat when testing youths for phenotype TMAU is that until birth FMO1 is the main functional form of FMO in humans, and full FMO3 expression may not fully occur until age 18, as explained by Dr Hines in his article following.

Research into systemic body odors
Systemic body odor is generally an ignored area due to lack of awareness or perceived unimportance, including TMAU, which was characterized 40 years ago. Only a handful of researchers have had an interest in TMAU and most in the medical community may be unaware of it, despite common knowledge of FMO3 being a drug-metabolizing enzyme. MEBO would like to see research, especially involving the two most obvious areas of testing: broad-spectrum volatile organic acid testing (phenotype), and DNA testing (genetic). Hopefully this line of testing would reveal the cause of most systemic body odors. In addition, MEBO Research would like to see the TMAU test added to the newborn DNA screening program and to the standard list of metabolic disorders pediatric units test for. Two International TMAU workshops were held in 1999 and 2002link, which MEBO would like to see revived.

MEBO Research goals
MEBO Research hopes to promote research into unaffiliated systemic body odors to identify the various causes of each condition and to find treatment and a cure. In the interim, efforts will be made to develop effective management strategies, including the use of monitoring devices, for example as transdermal monitors or TMA reagent papers, to assist affected individuals to detect and control their own odor in an independent fashion. By raising awareness of these conditions, MEBO Research hopes to not only promote scientific research and proper medical treatment, but also to raise social consciousness in order to prevent further misunderstanding and mistreatment of all body odor sufferers. MEBO would particularly like to see the founding of an international body odor and halitosis research center and clinic. We welcome any feedback to this article.

General Reference links on TMAU :
Gene Reviews TMAU article
Genetics Home Reference TMAU article Gene Reviews TMAU article
Trimethylaminuria: The Fish Malodor Syndrome
Eugène M. Trimethylaminuria; Orphanet encyclopedia, August 2002
2006 paper : Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children
Trimethylaminuria and a human FMO3 mutation database
Dr Eileen Treacy overview of TMAU for OMMBID
Sheffield Children’s Hospital TMAU phenotype testing overview and procedure (pdf document)
1991 paper : The identification of trimethylamine excess in man: quantitative analysis and biochemical origins

Interesting TMAU case studies :
2006 case study : trimethylaminuria in an adolescent
2007 paper : Human breath odors and their use in diagnosis
1970 case study : First reported case of TMAU
2003 paper : TMAU related to the choline concentration of infant formula

FMO3 Reference:
2005 paper : Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism
2006 paper : Mutation, polymorphism and perspectives for the future of human flavin-containing monooxygenase 3
2008 paper : Flavin mono-oxygenase (FMO)--the 'other' oxidase

Links alluding to commonality of those at risk of TMAU due to FMO3 enzyme deficiency:
2008 dissertation case study : 8/12 positive for TMAU phenotype test did not show any mutants in DNA test
2007 case study : Transient trimethylaminuria related to menstruation
1999 paper : Mild trimethylaminuria caused by common variants in FMO3 gene
1999 Dr SC Mitchell letter to lancet : Trimethylaminuria: susceptibility of heterozygotes
2001 paper : In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene
2000 paper : Biochemical and molecular studies in mild flavin monooxygenase 3 deficiency
1996 case study : 3.8% of 421 random volunteers are <90% in TMAU urine test
1997 case study : 11 of 100 random New Guineans are <80% in TMAU urine test
2000 : A Kashyap and S. Kashyap letter to lancet

Other possible issues with FMO3 deficiency
2000 paper : Population-Specific Polymorphisms of the HumanFMO3 Gene: Significance for Detoxication
1997 case report : TMAU associated with seizures and behavioural disturbance
2007 paper : Genetic polymorphisms of human flavin-containing monooxygenase 3
2002 paper : Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolism

Possible Fecal Body Odor cases ?
1973 case report : possible FBO case. Systemic cause not regarded
1997 : neonate with a pungent odor

María

María de la Torre
Founder and Executive Director

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maria.delatorre@meboresearch.org
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3 comments:

Anonymous said...

VERY WELL WRITTEN, PLAIN SPEAKING ARTICLE.

I enjoyed it and felt like I got a better understand so that I could come up with my own theories.Well done!!!!!

Jan 18, 2011, 8:23:00 AM
Unknown said...

How do you fix this problem?? What can be done to remedy the issue with the patient??

Jan 24, 2015, 11:00:00 AM
Maria de la Torre said...

IT's MEBO's goal to seek the answer to your questions by pursuing research. Meanwhile, we discuss as a group what we try and works or doesn't work.

Jan 24, 2015, 11:41:00 AM
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