Are plastic constituents of foods containers and medical devices safe?

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Many chemical compounds are used as a plasticizer to improve the flexibility and moldability of polymers such as PVC, making the material soft even at low temperatures. Phthalates, particularly phthalate esters (PEs), among these latter components, are released into any liquid and solution from all PVC materials used for alimentary and/or medical purposes, including pockets for blood transfusions, parenteral nutrition, dialysis tubes, devices for extracorporeal circulation (CEC) and membrane oxygenation (ECMO), etc… PEs are the most abundant man-made pollutants and increase the risk of developing an allergic respiratory disease or a malignancy.

 

Since 2003, these chemicals were considered potentially hazardous to health with consequences still under discussion: some studies seem to demonstrate that phthalates can produce effects similar to those of the estrogen hormones, causing a feminization of male babies and developmental disorders and maturation of testes. Breast milk is also found to contain detectable levels of phthalates, as well as infant formula and baby food. Europe, for instance, legislated in order to limit use of these compounds and hence prevent adverse effects in development [1]. Recently, a few studies have demonstrated that phthalates could cause oxidative stress which would contribute to the development of insulin resistance which is believed to be the underlying mechanism of metabolic syndrome and type 2 diabetes mellitus [2].

Even though effects, directly correlated to phthalates ingestion, seem to be quite clear but are still under investigation, it is well strengthened that these are harmful when released by several type of plastic surfaces, in contact with blood, of medical devices in prolonged use. The leaching of PE’s in donated packed red blood cells during storage was assessed provoking oxidative stress and increasing the level of pro-inflammatory cytokines [3].

The same effects could be detected in patients where dialysis and extracorporeal circulation devices were used.

Rodent studies also showed that high exposure to phthalates causes damage to some internal organs including liver, kidneys and lungs [4]. All these assumptions led recently FDA to issue a document certifying harmfulness of such chemical agents, concluding that a real risk exists to human health, especially for pediatrics and pregnant women.

The aim of this post is not to create scaremongering in people but to just help diffusion of news so that everyone can create personal and independent opinions.

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References

[1] Human Elimination of Phthalate Compounds: Blood, Urine, and Sweat (BUS) Study.

SJ Genuis, S Beesoon, RA Lobo, D Birkholz – ScientificWorldJournal, 2012: 615068 – doi:10.1100/2012/615068

 

[2] Diethylhexyl Phthalates Is Associated with Insulin Resistance via Oxidative Stress in the Elderly: A Panel Study

JH Kim, Hy Park, S Bae, YH Lim, YC Hong – PLoS One, 2013 19;8(8):e71392

 

[3] Phthalate esters used as plasticizers in packed red blood cell storage bags may lead to progressive toxin exposure and the release of pro-inflammatory cytokines.

LT Rael, R Bar-Or, DR Ambruso, CW Mains, DS Slone, ML Craun, D Bar-Or – Oxid Med Cell Longev, 2009;2(3):166-71.

 

[4] Presence of Plasticizer Di-2(ethylhexyl)phthalate in Primed Extracorporeal Circulation Circuits

Burkhart HM, Joyner N, Niles S, Ploessl J, Everett J, Iannettoni M, Richenbacher W – ASAIO Journal 2007; 53:365–367.

 

 

Current bioprosthetic heart valves substitutes: 100% biocompatible?

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Over 400.000 heart valves are replaced worldwide every year. Distrophic calcification and inflammation lead these prostheses to failure in the middle-long term in over 50% of patients, especially in the youngers that require recurrent re-operations [1]. When an aortic valve must be replaced, 80% of the times a biological heart valve substitute (BHVs) is used. These valves are engineered using porcine aortic valves or pericardium from different animal species like pig, sheep and horse that is properly assembled to build a prosthesis. Biological valves are of course different from mechanical valves that are made of pyrolytic carbon or other different materials.

BHVs are subjected to a treatment, called fixation, before being commercialised and implanted into humans. This process, performed with a chemical agent named glutaraldehyde (GLU), is fundamental for many reasons, for example in order to increase tissue mechanical strength, to sterilize the prostheses and preserve it prior to use but mainly to act as a shield for molecules that, if not suitably inactivated, cause a rejection of implanted tissue. Despite its importance, GLU is not able to mask completely these molecules and in the mid-long term it faces a chemical binding degeneration due to the mechanical stress to which bioprostheses are subject when implanted and put into operation. Multiple factors lead to the replacement of GLU-treated BHVs approx. after 10 years following the original implant due to tissue calcification and consequent stenosis of the valve, i.e. a narrowing of the internal diameter of the valve preventing an effective blood flow. BHVs degeneration was recently confirmed to be correlated to GLU masking efficiency of xenogeneic tissues which contain proteins, sugars and molecules that are proper of derivation species, whose complete elimination or inactivation is necessary to meet the requirements for clinical use. Particularly, the residual presence of a specific molecule called alpha-Gal (epitope), significantly increases the level of antibodies against galactose, starting from day 10 following BHV implantation, reaching a maximum peak at around 3 months after it [3].

This sugar moiety is expressed in most mammalian tissues, except humans and higher primates. In humans, continuous antigenic stimulation by the gastrointestinal flora (expressing the epitope) ends with the production of anti-alpha-Gal antibodies accounting for 1-3% of the total amount in the blood stream. A new developed test demonstrated that around 30% of alpha-Gal epitopes in BHVs are still reactive even after fixation with GLU, prior to be implanted. It’s likely the time to try to produce alpha-Gal free BHVs that are likely to longer-lasting, resulting in a better quality of life for patients. The removal of the alpha-Gal molecules detected in a tissue might also provide new insight of deleterious effects possibly related to the presence of secondary substances whose role is currently overshadowed by the preponderant reactions of the alpha-Gal [4].

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References:

1. Zilla P et al. – Prosthetic heart valves: catering for the few. Biomaterials 2008;29(4):385-406.

2. Bloch O et al. – Immune response in patients receiving a bioprosthetic heart valve: lack of response with decellularized valves. Tissue Eng Part A 2011;17(19-20):2399-2405.

3. Naso F et al. – First quantitative assay of alpha-Gal in soft tissues: presence and distribution of the epitope before and after cell removal from xenogeneic heart valves. Acta Biomater. 2011;7(4):1728-1734.

4. Naso F et al. – First quantification of alpha-Gal epitope in current glutaraldehyde-fixed heart valve bioprostheses. Xenotransplantation. 2013;20(4):252-261.

Cardiovascular disease: an economic phenomenon

shutterstock_149573669Cardiovascular disease (CVD) can be defined as a group of disorders affecting coronaries (coronary heart disease),

blood vessels of the brain (cerebrovascular disease), peripheral arteries (peripheral arterial disease),  deep veins and

lungs (deep vein thrombosis and pulmonary embolism), pathologies damaging heart and valves due to rheumatic fever

(rheumatic heart disease) or malformations present at birth (congenital heart disease).

Data available to date defines a possible future scenario regarding the prevalence of CVD in developed

countries: smoking rates are now steady, risk factors are supposed to increase, and despite the augmented control on

them could enhance a lower mortality of CVD, the decline in mortality observed in the last decades from CVD  is

now leveling (1).

The pattern of changes of disease prevalence among world population, according to the so-called “epidemiological

transition”, are predicting the future also of developing countries, that are now supposed to be in stage 3

(the age of degenerative and man-made diseases). In fact, the next step should be stage 4, as to say the situation

of developed countries, where life expectancy is greater than 70 years. In stage 4 CVD and cancer are the main

causes of death and premature cardiovascular events occur mainly to lower socioeconomic classes, while richer people

faces the CVD mainly in their old age.

By year 2020, it is estimated that Chinese and Indian economies will worthy account for almost 40% of the total value.

The average annual incidence rate of stroke in India in 2009 were 145 per 100,000 population, which is higher than in

the western nations (3). Also in China it is markedly important the prediction of CVD considering that Chinese population

(35-84 age range) trend in CVD risk factors, as systolic blood pressure, total cholesterol, smoking,  body mass index (BMI)

and diabetes, were projected forward over the period 2010-2030. The expected aging and growing of Chinese people

will be sufficient to determine a consistent increase in the absolute value of coronary heart disease and stroke in the world (4).

Consumption of animal fats and sugar is declining in the western world but it is going to be introduced, even if

at low levels, in developing countries. Billion people will have soon access to new resources at their first and are going to

change their life style. Food consumption will increase and shift in dietary patterns will have considerable health

consequences  as emerged from data derived by FAO food balance sheets (FBSs).

Therefore, despite the impressive decline in mortality from CVD during the latter half of the 20th century, CVD remains the

leading cause of death in the world and political, economic, social, and medical strategies and interventions are urgently

needed to prevent the increase of CVD prevalence.

In the so-called low and middle income countries (LAMI – know more looking at figure 1), 80% of worldwide deaths

caused by CVD occurs, as these countries present more risk factors together with less possibility to prevention and

less access to health services.

What seems to be clear is that the economic development is the major factor driving the epidemiological transition,

and vice versa, cardiovascular pathologies can affect the economic development, lowering the economic in growth of

nations. The burden of CVD is particularly high in LAMI, where stroke and diabetes reduce the gross domestic product

(GDP) of a percentage ranging from 1 to 5% (5).

To confirm data presented, it is important to mention The American Heart Association forecast for the healthcare costs

of CVD in USA, which will likely increase to 17% of the current national health expenditures and 15% of GDP by year 2030

(data of 2008). Considering no changes in the government politics, together with aging and increasing of the population,

by 2030 over 40% of Americans will likely present some kind of CVD and medical direct costs will probably

triple from $273 billion to $818 billion, while the indirect costs will increase of 61% due to less productivity (6).

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 Immagine

Fig. 1. Countries by 2011 GDP (PPP) per capita, based on World Bank figures (7).

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References:

  1.  Capewell SJ, Ford ES, Croft JB, Critchley JA, Greenlund KJ and Labarthe D – Cardiovascular risk factor trends and potential for reducing coronary heart disease mortality in the United States of America – Bull. World Health Organ. (2010);88(2):120-130.
  2. Gersh BJ, Sliwa K, Mayosi BM, and Yusuf S – The epidemic of cardiovascular disease in the developing world: global implications – European Heart Journal (2010);31:642–648.
  3. Kaul S, Bandaru VC, Suvarna A, Boddu DB – Stroke burden and risk factors in developing countries with special reference to India – Indian Med. Assoc. (2009);107(6):367-70.  3(3): 243–252.
  4. Moran A, Gu D, Zhao D, Coxson P, Wang YC, Chen CS, Liu J, Cheng J, Bibbins-Domingo K, Shen YM, He J and Goldman L –  Future cardiovascular disease in China: Markov model and risk factor scenario projections from the Coronary Heart Disease Policy Model-China – Circ Cardiovasc Qual Outcomes (2010);3(3):243–252.
  5. The Long-Term Budget Outlook – Congressional Budget Office. Nonpartisan analysis for the U.S. Congress (2010);http://www.cbo.gov/doc.cfm?index11579.
  6. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW, Woo YJ – Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association – Circulation (2011)1;123(8):933-44.
  7. http://data.worldbank.org/indicator/NY.GDP.PCAP.PP.CD/countries/1W?order=wbapi_data_value_2011%20wbapi_data_value%20wbapi_data_value-last&sort=desc&display=default – image author in Wikipedia: Quandapanda (http://en.wikipedia.org/wiki/File:Gdpercapita.PNG)

Is rejection of human transplanted animal tissues avoidable?

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The demand for organ and tissue transplantation (heart, kidney, cardiac valves, cartilage) already far surpasses the number of available donors. The lack of resources has led biomedical researchers to explore the use of animal donors as an attractive and unlimited source for biological devices (xenotransplantation). Xenogeneic tissues, the tissue that are harvested from common animals such as pigs, sheep, cows, horses, are currently employed in clinical practice to create biological prostheses for the substitution of specific structures like heart valves, ligaments, pericardium etc.. and in the repair of various damaged body costituents (gastric-mucosa, nerves, cartilage). It is well know by many scientific studies that xenogeneic tissues express superficial molecules, called epitopes, alpha-Gal in primis, but also the major histocompatibility complex (MHC), capable of triggering hyperacute and acute vascular rejection phenomena. An epitope is definied as an antigenic determinant, something that it is not recognized as a “personal effect” by the immune system cells (B cells, T cells) and antibodies of the recipient organism. Once a tissue is recognised as non-self, a series of events are triggered ending in vascular thrombosis.

Currently, commercially available xenogeneic bioprosthes are processed with treatments which have not been proven able to completely mask or inactivate such epitopes. Most common methods involves the use of chemicals to stabilize matrices (the main component of tissues); these agents penetrate deep into the substrate and cover it quite permanently like a molasses. Glutaraldehyde fixative is one of them and even if it allows the clinical use of tissues, it is toxic for cells sorrounding the site of implantation and for the graft itself, therefore prostheses biological integration is not possible.

The ability to ascertain alpha-Gal and MHC epitopes removal from a xenogeneic tissue is closely related to the possibility of its quantitative determination. Recently, a new patented test has been processed by prof. Gino Gerosa’s research team at the Cardiac Surgery Reserch Lab of the University of Padova. The test developed assesses the presence of still unmasked alpha-Gal epitopes that rather than triggering a hyperacute rejection, due to reduction in number, lead to a chronic phlogosis that have dramatic effects in the mid-long term after the bioprostheses has been implanted, especially when this xenogeneic tissue is used to construct heart valves substitutes.

Analysis of currently commercial heart valve bioprosthes assessed, for the first time, the presence of the alpha-Gal
epitope used for about 40 yrs for surgical reasons. Such quantification might provide indications of biocompatibility relevant for the selection of bioprosthetic devices and an increase in the confidence of the patient. It might
become a major quality control tool in the production and redirection of future investigation in the quest for alphaGal-free long-lasting substitutes.

These are the first scientific results that shed light on one of the most critical cause for mid-long term failure of heart valve bioprosthese.

Related article:

First quantification of alpha-Gal epitope in current glutaraldehyde-fixed heart valve bioprostheses by Naso F e al. Xenotransplantation. 2013 doi: 10.1111/xen.12044