\r\n\tGoverning equations of the flows and heat transfer with EHD consist of the Navier–Stokes equations, thermal effects, and additional EHD forces. Due to the complex nature of EHD, only a limited number of publications concerning modeling of the effects of EHD on laminar flows, without numerical solutions, can be identified.
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1. Introduction
Environmental problems have a deep impact on public health, the economy, and society at large. Plastics top the list among other types of solid waste pollutants due to their properties and tenacity [1]. Plastic littering is a violation of several local and international agreements; it travels in sea water spreading its damaging effects on marine fauna and flora. Environmental valuation requires accounting for environmental damage and the resulting social costs. In many countries, the absence of environmental valuation combined with lack of policies exacerbates the problem. Weakness in public management, at both levels of legislation and implementation, are other salient factors of major concern. To compensate for weaknesses in local policies across nations and to combat negative littering practices, international agreements were created to impose prohibitions against plastic littering in the marine environment. The London Dumping Convention created in 1972 (MARPOL Convention, Annex V) and MARPOL Protocol of 1978 declared plastics in international waters as unlawful. The 1982 Law of the Sea Convention mandates preservation of the marine environment. Several other United Nations agreements ban dumping plastic substances in the ocean. Many states committed themselves legally to such agreements. The weakness, however, resides in implementation and enforcement [2, 3, 4, 5]. In a country like Lebanon where data were collected in the present research, non-governmental organizations and ecological movements took the lead over public sector services to close this policy gap. International organizations and environmental activists argue that the establishment of dump sites and landfills on the shore, as it has been practiced in Lebanon in the last two decades, is a straight violation of the Barcelona Convention, a 1995 legislation designed to protect and preserve the marine environment in the Mediterranean [6].
Previous studies by the author gauged public attitudes towards marine plastic litter with an emphasis on the nexus between engineering and public policy. It was argued that engineering solutions on their own could be developed and may prove to be effective. However, such solutions cannot be implemented if they are not supported by public policy. The separate study by the author is briefly reviewed to emphasize the results of a linear regression model with a dependent variable, Y, which represented the need to develop regional strategies for natural resource management. The independent variables were defined as (1) the establishment of national policies specific to marine protection against pollution, (2) use of technology as remedial solutions, (3) use of engineering innovation as preventive solutions in the private sector, and (4) local enforcement. The third variable was based on the premise that radical innovative solutions would be required to transition into a plastic-free end-use. A statistically significant and positive correlation was found with the first, third, and fourth variables, while there was no statistical significance with the second variable. In the following sections, we illustrate the dire need for policies focused on solid waste management and in particular marine plastic litter. We then draw on policy examples from other countries and recommend local adaptation and adoption. Still, local policy development may be solely a small component of the problem offering only a patchwork of piecemeal solutions. Plastic pollution requires a broader and long-term outlook where teamwork, cooperation, and scientific knowledge-sharing in the Mediterranean region are a firm prerequisite.
2. Plastic pollution is a regional and global problem
Literature shows that coastal areas of developing countries which lack waste management policies and remedial infrastructure are of primary concern. However, the status of plastic pollution in the world’s oceans poses a challenge to both industrialized and developing countries alike. Large plastic items released in the ocean do not degrade but rather degenerate into very small pieces—microplastics—which are particles smaller than 5 mm. These particles are mobile over hundreds of acres on the ocean surface and within lower layers. The spread of microplastics is caused by currents and oceanographic mixing processes. The Mediterranean is particularly vulnerable to polluting activities including plastic debris [7, 8].
In the last few decades, plastic accumulation reached remote offshore areas and formed trash gyres, islands, and vortexes [9]. Harmful effects of plastics on marine life include starvation, suffocation, and entanglement. Thousands of marine fauna and hundreds of species have been affected thus far. Floating plastics help transport non-indigenous marine species to intrude on other native colonies, causing a threat to marine biodiversity and the food chain. Floating plastic particles become vehicles to toxic pollutants that stick on their surface causing concentrated sources of environmental pollution in ocean gyres. With this visible recognition that drifting plastic debris cause adverse effects on ecosystems, innovative techniques are required [10]. A major challenge is to quantify plastics in the oceans because there is a lack of accurate information about sources, quantities, trajectories, accumulation, and final status.
3. Vulnerability of the Mediterranean
3.1 History and biodiversity
The Mediterranean Sea is considered to be the cradle of civilization. This pond is seriously affected by marine litter because its geometry forms a closed basin with limited mixing with other oceans. Due to their weather, beauty, and history, countries around the Mediterranean are densely populated with an active tourism industry. Lebanon’s coast houses some of the most ancient cities including Tyre (2750 BC), Sidon (4000 BC), Beirut (3000 BC), and Byblos (5000 BC). Other countries on the Mediterranean rim have long-standing history, heritage, and ancient landmarks. Historic monuments on the coast are vulnerable to pollution, whether spills, solid, or plastic waste.
The Mediterranean is recognized for its natural diversity. It makes less than 1% of the world’s ocean area and 0.3% of the world’s total ocean water volume, and yet it is home to over 11% of marine species. This constitutes a high biodiversity density in terms of water volume and ocean area. NOAA’s (2010) literature provides comparative data about oceans and seas including their geometric properties (Table 1).
Table 1.
World oceans and Mediterranean data (source: ETOPO1 and NOAA, 2018).
This eco-diversity includes endemic species knowing that the Mediterranean’s moderate temperature and salinity provide a favorable breeding medium for many endangered species. Online literature and blogs tweets provide ample documentation and pictures of marine animals entangled in plastics, or thwarted from motion, or starved from plastics filling their stomachs mistaken for nutrients. All such popularized evidence is conclusive about the harmful and deadly effects of micro-plastics on marine life. There is evidence that living organisms across the Lebanese coast are threatened directly by marine litter which made the Mediterranean Sea a global priority for conservation [11].
In recent years, the issue of plastic pollution escalated and became visible to most international organizations whereby this enclosed sea, which used to top the list of tourism attraction and maritime activity, was called in 2018 the Mediterranean Plastic Trap (Figure 1). Weak or no policies, dense human activity, and polluted rivers all contribute to the problem. A glaring issue pertains to rivers carrying debris of all sorts, including plastics, from land to sea. The Nile for example takes place in the top 10 polluting rivers according to various studies in literature. As will be seen in later sections, the counterclockwise prevailing current around the Mediterranean rim carries waste from coast to coast exhibiting a highly mobile pollution. The problem is a shared problem and therefore requires a shared solution.
Contrary to popular perceptions, the Mediterranean commands significant water depths up to 5000 meters, with a bottlenecked exchange of waters with the outside world through the Gibraltar Straight—a shallow orifice on seabed about 300 m below free water surface. The Mediterranean replenishes fresh water from rivers having estuaries around its basin, keeping its salinity at about 38 parts per thousand, while the Atlantic varies from 33 to 37; North Sea 34. Any form of intrusion on its natural status, pollution by spill or litter, accidental or not, may prove irreversible and catastrophic for such an enclosed basin (Figure 2).
Figure 2.
The Mediterranean—water depth distribution.
The vulnerability of the Mediterranean to any polluting agent have been underlined by the author in previous publications including the quest and race for fossil fuel oil and gas extraction off the Lebanese coast. In recent years, extraction operations were launched in the region while Lebanon is considering the prospects of becoming an oil and natural gas producer in its waters. However, environmental concerns are directly related to operational leaks, accidental spills, or deliberate damage to storage facilities due to potential conflicts. If such environmental concerns are properly accounted for in the social cost-benefit appraisal, a regional agreement would turn towards clean renewable energy and away from offshore fossil fuel production.
Hydrodynamic data about the Mediterranean is shown in Figure 3. A differentiation is in scope between the Mediterranean and open oceans in terms of mixing and suspended matter transport processes. Water current velocity in the Mediterranean averages 0.6 m/s while it exceeds 2.5 m/s in open oceans. Knowing that the energy generated by wave motion is proportional to the square or cubic power of the water particle velocity, depending on flow regime, ocean waves can generate 17–72 times the energy generated in a closed basin like the Mediterranean. Therefore, the absorptive and abrasive capacity of the Mediterranean in decomposing or breaking down waste is much lower than the one of open oceans [12].
Figure 3.
The Mediterranean. Wave height, distribution, and surface current direction.
The fact that the Mediterranean is surrounded with sovereign countries offers opportunities of cooperation among those nations to establish a program against plastic littering. According to the United Nations Convention of the Laws of the Seas, “… States of this area have a general obligation to cooperate when facing a disagreement…” (UNCLOS, Part IX, Art. 123). A preventive approach is recommended in the long term, but a swift remedial clean-up program is necessary through the establishment of a Mediterranean cooperative for that purpose [12].
4. Case of the Lebanese coast
4.1 Plastic is the predominant pollutant on Lebanon’s shores
On Lebanese shores, in nearby seafloor and sea surface, plastic constitutes the litter component of highest proportion, making over 90% of total solid waste. This environmental problem has public health and economic consequences that need to be addressed with urgency.
During the July 2006 regional conflict, Lebanon suffered oil spills due to damage to its crude oil reservoirs in its southern territory. Such toxic matter travels on micro-plastics and exacerbates the danger of disrupting natural marine habitat. Local experience during municipal solid waste (MSW) crises shows that plastics may not constitute the largest proportion of MSW, but once it reaches the sea, it become by far the predominant component. This is due to the fact that organic MSW components disintegrate while plastics remain. UNEP/MAP (2015) studies on the Mediterranean showed that plastics make-up over 85% of floating litter, of which 45–95% lay on seafloor [1]. Categories of plastic litter in the Mediterranean were also identified and it was found that the largest percentage pertains to packaging plastic including bottles and drink containers, food boxes, bags, in addition to single-use disposable items including cotton sticks, lighters, and plastics dining utensils.
4.2 Lack of public policies related to plastic pollution: public awareness and fatigue
There have been some early efforts in establishing anti-plastic pollution policies in Lebanon, starting with policy proposals for solid waste in general [13]. Despite the passing of some laws, violations in implementation are originating from within local governments (municipalities) that undermine efforts expended by NGOs and environmental activists [14]. This problem is linked to Lebanon’s solid waste crisis which has been recurring over the last decades [15]. The landfill at Costa Brava in Beirut, Lebanon, attests to a complex combination of blurred policies, self-interest, marginalization of public rights, and violation of fundamental concepts of public goods [16]. Following the 2015 solid waste crisis and the shutdown of the Naameh landfill in May of that year, Costa Brava was opened in 2016 as a temporary fix or alternative. Public opinion followed immediately protesting against this project. Activists established a physical presence on location and assisted local communities to petition to the UNEP. The project estimated at USD 60 million went against any rational environmental assessment, or lack thereof, and violated the Barcelona Convention [17].
The issue of plastic littering in Lebanon goes beyond a traditional awareness building campaign because the local population is already well-informed about plastics litter and its negative consequences. There is an overall lethargy in Lebanon about several environmental problems and lassitude among the Lebanese regarding their livelihood, health, and safety as a result of public sector mismanagement over several decades [18]. Problems of immediate concerns—economic slump, badly defined projects with mega budgets such as misplaced water dams, among other societal problems—all compete on the “attention span” of the Lebanese citizen [12, 19, 20]. We highlight these facts for two reasons. First, an advocacy campaign on plastics amidst an economic slump is challenging. Convincing a plastics producer to fundamentally change its product line requires engagement at a corporate strategy level. Second, awareness campaigns in local communities are also challenging as they require a message crafted well beyond the unaesthetic scene of a plastic-saturated shore (Figure 4). There is a need for product innovation or process development to combat plastic litter. Reluctance within the private sector to invest in innovative techniques and actionable solutions, and a fatigued local public that has gone through tough cycles of social unrest, have contributed to getting Lebanon in an unfavorable situation in relation to plastic littering among other problems [21].
Figure 4.
Zouk Mosbeh beach cleanup, January 23, 2018, as garbage washed ashore in a storm. Source: J. Eid/AFP/Getty images, adopted by [21].
4.3 Need for evidence-based advocacy and multidisciplinary collaboration
To combat plastic littering in Lebanon, both awareness-building and advocacy are recommended in parallel. The first may be performed with the general public, educational institutions, municipalities, and other entities. The second can be implemented with the private sector, including the major local plastic manufacturers. Cases from other countries provide evidence about the role of manufacturers [22]. Organizations such as The Lonely Whale has been encouraging companies to form teams and collaborate to scale down plastics volume across the entire supply chain; from raw material orders, to processing, manufacturing, and distribution. Member companies include so far some global manufacturing giants such as General Motors, Hewlett Packard, Dell, Bureo, and Herman Miller. Similar possibilities could be explored for advocacy in Lebanon.
Plastic pollution gives rise to multi-faceted problems that require multidisciplinary collaboration. A deep understanding of the severity of the situation related to solid waste in general, and plastics in particular, requires a diligent approach that establishes a clear link between plastic pollution on one hand, and engineering, public policy, health, economic, and technical implication and potential solutions on the other hand. Advancing towards solutions must include prevention and remediation measures that should be planned for and implemented in tandem. Technical solutions must be backed by public policy design. Academic institutions, industries, and public sector entities are expected to work hand-in-hand to achieve tangible outcomes.
Recent studies showed that microplastics are eaten by fish, which are consumed by humans, causing unsafe food. This serious impact on marine life and infiltration in seafood has direct implications on public health. Numerous diseases have been reported to be on the rise in Lebanon. Various research projects at a global level established that plastics contain chemical and hazardous substances that cause a wide range of health problems including eye irritation, liver dysfunction, and cancer [23, 24]. Microplastics follow us to our kitchens and dining rooms as they were found in our food including table salt.
5. Plastics from land to sea Mediterranean subbasins and currents
Past studies of the Mediterranean subbasins showed a complex system of eddies, gyres, straights, and channels within a relatively small enclosed sea. Plastics were found in the deepest spots of oceans and are floating in the shape of islands as well, posing quantification challenges. Understanding Mediterranean bathymetry and dynamics is essential to capture how plastics are traveling from source to destination. Some of the early maps provide a simplified model of the subbasins and currents. An overall counterclockwise motion persists in the Mediterranean [25]. This motion is characterized by a south–north movement along the Lebanese coast. The 11 subbasins within the Mediterranean; numbered 1, 2a, 2b, 2c, 3 through 9, are shown in Figure 5.
Figure 5.
Mediterranean subbasins 1: Channel of Sicily, 2a: Southern Ionian, 2b: Central Ionian, 2c: Northern Ionian; 3: Adriatic; 4: Southern Cretan; 5: Western Levantine (deeper than 3000 m: The Herodotus trough); 6: Southeastern Levantine; 7: Northern Levantine; 8: Northern Cretan; 9: Aegean. Source: ifremer.fr, February 25, 2019.
A better understanding of traveling plastic trash can be developed from key concepts in fluid mechanics applied to subbasins. For instance, eddies transport debris in a circular or semi-circular motion and can be categorized into small eddies ranging up to 50 km; medium eddies from 50 to 150 km; large eddies between 150 and 250 km. The Mediterranean has the Gibraltar and Messina traits, the Otranto, Sardinia, and Sicily channels. Gyres in the Mediterranean run clockwise primarily due to the orientation of the Strait of Gibraltar, but they are elsewhere counterclockwise due to Coriolis effects.
Advances in satellite imaging technology offer a more sophisticated means to track sea water motion and facilitate the detection of existing and potential gyres of plastic waste islands. These technological advances further confirm the need for a concerted regional effort whereby several countries plan, operate, and cooperate on fighting plastic pollution in the Mediterranean. There is no evidence that the Mediterranean carries a permanent trash island but litter accumulation areas have been reported. Historical data collected in the Mediterranean Sea was used to compute the probability of debris particles to reach subbasins, in an attempt to identify possible retention areas. If retention areas are identified, the prediction of the potential location of floating trash islands becomes more manageable.
The evolution of litter based on climatological reconstructions shows a tendency of floating litter to collect in the southern portion with a long-term accumulation in the Southeastern Levantine Basin. Data analyzed by Zambianchi et al., show that drifters start from a dispersed status and end along coasts on the East Mediterranean including Lebanon as well as some North African countries for both summer and winter seasons [26].
6. Mathematical model, empirical analysis, and results
We formulated and performed a linear regression to gauge public attitudes in Lebanon by defining a dependent variable, Y, representing the need to develop regional strategies for natural resource management. The independent variables were defined as (1) the establishment of national policies specific to marine protection against pollution, (2) use of technology as remedial solutions, (3) use of engineering innovation as preventive solutions in the private sector, and (4) local enforcement. The selection of these variables was based on preliminary focus interviews and on evidence from the collection and analysis of secondary data. The variables were designed to gauge public attitudes towards regional collaboration to team up on protecting the environment. Focus interviews showed a predisposition of the community for regional collaboration because these issues affect human health beyond ecosystem protection or territorial claims. The outreach used a 1–5 Likert scale and included 750 recipients, of which 426 responded with 281 replies that covered the above variables.
Regression results showed a statistically significant and positive correlation with the first, third, and fourth variables at 5% significance level, there was no statistical significance with the second variable. In a previous analysis, we found positive correlation between the “willingness to contribute at a local community level” and remedial actions such as beach cleanup, but the present analysis addresses a regional strategy. Public attitudes show that it would be very important to start with local public policies that would be carried to regional cooperative summits during which a strategy for the whole Mediterranean would be drafted, refined and agreed upon.
In our previous analysis, we also found that respondents were skeptical about prospects of regional collaboration in the East Mediterranean whereby focus interviews at the time showed that 46% of interviewees expressed disappointment about the lack of regional collaboration in public policy design. Nevertheless, both analyses show agreement between the qualitative and quantitative results indicating that communities are eager to see policies established at a local level, and implemented regionally in collaboration with Mediterranean rim countries. Community inputs were positive about regional treaties but this prospect was described by many as wishful thinking as evidenced by many respondents in the process of qualitative data collection during focus interviews.
7. From remedial reactions to preventive strategies: innovation against plastic pollution
7.1 Remedial reactions are necessary but not sufficient
There is no doubt that remedies need to be implemented urgently such as beach cleanup, collection, sorting, recycling, and re-use. In almost all environmental problems, remedial actions evolve as a result of a damage that was already done, and therefore the author considers them as mere reactions. The case of plastic pollution and littering in a closed pond-like sea is no different. There is a large amount of research literature on plastic recycling with a call for the establishment of an industry cycle to put plastics in a “closed loop” from first-time manufacturing to re-processing to new products—but again, made of plastics in their present chemical formulation. In that context, a brief description of recyclability may shed light on the shortcomings of remedial reactions. In fact, not all plastics are easily recyclable, let alone requirements for energy and carbon footprint. Plastics come in different materials, and various levels of recyclability. All plastic containers carry at their bottom a triangular sign inscribing a number; a recycling code. The recycling code corresponds to the type of plastic used to manufacture the item. There are many types of plastics, but it is customary to summarize them in seven types that are known to carry these code numbers for recycling purposes.
Polyethylene terephthalate (PET or PETE)—PET is part of the polyester series and is typically used to manufacture bottles for water or soda. Sometimes they are used for clothing and for containers of traysthat can be heated in a microwave. PET is widely recycled as it lends itself to the process and is commonly reused.
Low-density polyethylene (LDPE) is a polymer used in many applications such as bags, gas pipes, water pipes, bottles, toys, and plastic wrap. It is not common to recycle LDPE using simple home-based programs. However, LDPE plastic bags and other containers can be reused and therefore are not classified as single-use items.
High-density polyethylene (HDPE) is a polymer used in many applications such as garbage bags, liquid soap and shampoo bottles, caps, lids, and common grocery bags. HDPE used for items other than bags can be recycled in most places. Bags can be reused or can be returned to grocery stores for collection and recycling.
Polyvinyl chloride (V or Vinyl or PVC) is used for a variety of applications but most commonly in construction, namely plumbing installations. Other applications include bathroom curtains, garden or service hoses, raincoats and waterproof boots. It is not common to recycle PVC collected from used or dismantled plumbing networks. However, PVC containers and bottles can be recycled and manufactured as exterior rainwater drainage pipes or road cones and vehicle barriers.
Polypropylene (PP) is used for outdoor furniture, medicine containers, food boxes, diapers, and rope.
Polystyrene (PS) is used to make disposable picnic items, compact disk cases and cassettes. PS could be used as foam—referred to as Styrofoam—for packaging, disposable plates, egg trays, delivery or take-out boxes. PS can be recycled but it consumes more energy than other plastics and is therefore uneconomical.1
Other plastics are marked “O” which is a group that includes various mixes of polymers. Examples of this group include (1) polylactic acid used to manufacture containers, (2) polycarbonates, used for eye glasses, DVDs, construction greenhouse panels, (3) acrylonitrile butadiene styrene or ABS, used for games, such as Legos and puzzle pieces, and (4) nylon, used for rope, wire, clothing, components in car tires.
7.2 Need for preventive strategies
In light of these facts, and given that most respondents seem to be well-versed in terms of the pros and cons of recycling, the statistical analysis showed that public attitudes clearly support the use of engineering innovation in fighting plastic pollution. Overall, there is a belief that the private sector—whether manufacturers or traders in plastic import and export—can play a fundamental role in the process. Relevant to the regression analysis, the third independent variable in the mathematical model reflects a potential engagement by major plastics manufacturers and traders. There is an urgent need to introduce innovative products such as bio-degradable substitutes to plastics, and innovative processes such as plastic-to-fuel operations. In that spirit, advocacy with local manufacturers, importers, and exporters of plastics from raw materials to finished products would set a track for preventive strategies and an anticipation of consumer behavior. Advances in product development such as bio-degradable plastic-like materials, and in manufacturing techniques as it has been the case in the USA, Japan, and Europe, must be explored for local adaptation and application in Lebanon. Engineering innovation is expected to play a major role in preventive strategies, along with the development of policies that are specific to plastic pollution.
7.3 Preventive strategies need to be regional
While research aimed at new product development support preventive strategies, other types of research grew in parallel to manage existing plastic waste, or remedial strategies. The subject of plastic pollution does not lack public attention, but it has been tackled in piecemeal solutions and in disparate geographic areas. The Regional Activity Centre for Sustainable Consumption and Production (SCP/RAC) developed a compilation of solutions that they termed as innovative and inspiring. The project was done as part of the EU-funded SwitchMed Programme.2
Out of dozens of attempts and campaigns in different countries, SCP/RAC selected the top 25 solutions that were hoped to be replicated in other geographies. Each of these solutions requires consideration as part of a potential roadmap for Lebanon. The subsequent phases of this program could elaborate a subset of these solutions and include them in an organized advocacy campaign during implementation. The proposed solutions are classified under products or processes and are identified as being private business initiatives or public sector action. For example, the EcoOcean is a new product developed through funding from the EU; the EcoOcean material. This is a trademark of EcoCortec which introduced a bio-based polymer to make bags and wrapping from polyhydroxyalkanoate (PHA). According to the company, its composition includes 77% bio-based resins with sugar cane at its base. When in contact with the marine environment or a natural terrain, EcoOcean biodegrades by anaerobic digestion. Anaerobic digestion is a technique that was introduced in the United States in the 1960s and fully implemented in California in the 1980s [27]. The intended use of this product is not to dispose of it in the ocean. However, in case it reaches the ocean, full-scale experiments conducted by the company showed that it biodegrades within a few weeks or a few months, depending on water particle dynamics. This is a critical improvement over classical plastics that remain for hundreds of years. The experiments targeted microbial action breaking the bag down to microcosms. Testing included detailed studies through microscopic examination and molecular investigation to identify microbial communities and compare them with the effects of classical plastics. It was found that some of the sea animals were feeding on this biodegradable material. As for practical use, the material was tested against moisture, heat, and tensile stress and was found usable for daily choirs. However, it is the opinion of the author of the present roadmap report that such material requires a long-term follow-up to ascertain the nature of microbial communities that would develop. Countries like Lebanon that are not as endowed in research funding and facilities as the originating countries, could be an end-user that would adopt such techniques once fully proven against any potential side-effects.
Each proposed solution, when considered on its own, seems to contribute to combating litter in the Mediterranean. Those solutions could be considered for other locations as well. However, they fall short of having a coordinated program across countries for a mobile pollutant that travels in the waters similarly to air pollutants that have a negative externality. Given the facts at hand, there is a case for coordinated public policies backed by local advocacy campaigns.
8. Movements towards policy against plastics
We turn to a few examples in the State of California, which is considered as one of the most innovative states in pro-actively developing policies against plastic pollution. The approach is done in a combination of awareness-building, advocacy, legislation, and enforcement. Consider the sign in Figure 6 posted by the US Forest Service in Los Padres National Forest that explain in a very few words how harsh it is to litter plastic bottles into the environment. This forest is renowned for its pristine status and ecosystem (Figure 7).
Figure 6.
Sign posted by the US Forest Service in los padres National Forest.
Figure 7.
Los Padres National Forest.
Additionally, the State of California currently charges the highest littering fines. Such fines are used to deter the resident or the visitor from littering (Figure 8).
Figure 8.
State of California posts the highest fines in the USA for littering.
There are many geographic similarities between California and several Mediterranean countries including Lebanon, Cyprus, Turkey, Greece, and Croatia to name a few. The old saying that in Lebanon you can drive to ski then drive back to the beach on the same day is applicable as you can go east, enjoy cooler weather and mountains covered with snow then drive back west to the shore. Lebanon and California are both active in terms of sports, outdoors, healthy cuisine, eating habits, and enjoying the beach by both locals and visitors. California residents boast about the nice weather all year round where the lifestyle is loaded with hiking, picnics, beach volleyball, wind surfing, and beach camping. Both Lebanon and California have the same latitude or distance north of the equator.
In November 2016, California voters passed Proposition 67. The proposition requested a ban on single-use plastic bags. Thousands of volunteers who provided community service by collecting plastic trash during California’s coastal cleanup day reported back that they saw a substantial decrease in plastic bag refuse. Further data collected in California showed that plastic bag litter dropped by 72% between 2010 and 2017. By November 2017, plastic bags made less than 1.5% of all litter, down from 10% in 2010. In 2017, volunteers found in Monterey County only 43 plastic bags (in number) during the clean-up campaign, compared with almost 2500 bags in 2010. In a 2010 ranking about most frequently littered items, plastic bags ranked third after cigarette butts and fast food packaging. By late 2017, they fell out of the top 10 most littered items (Phillips, 2017). The importance of natural resource management cannot be more emphasized and this is exemplified by having a dedicated position as a State Secretary for Natural Resources.
“For decades, plastic bags were one of the most common items collected during the annual California coastal cleanup, … This year, as California continues to transition to reusable bags, we are seeing a substantial decline in plastic grocery bag litter on beaches, rivers and parkways.” John Laird, California Secretary for Natural Resources
Another example is worth mentioning at the local [city] government level—also termed “municipal level” in most countries. Over 100 cities across the State of California passed their own bag bans before the statewide policy was enacted. As decentralization is discussed in Lebanon, local governments, or municipalities, can take the initiative in establishing a local city code against plastic disposal, sorting, and even management at the source.
“When I took on the problem of plastic bag pollution four years ago, California retailers were distributing more than 19 billion single-use plastic bags every year,” “Today, that number is zero. Once again California is leading the way, creating cleaner communities for all.”
Alex Padilla, California Secretary of State -.
The policy evolved in certain cities such as San Francisco to combine curbside collection and recycling booths along with plastic bag bans. This policy combines remediation with prevention.
Since the passing of anti-littering legislation in California, 40 other countries have taken action through taxing single use plastic bags, or by banning them fully or partially. In 2016, the European Union announced that by end of 2019, the consumption of plastic bags in member states would not exceed 90 bags per person per year. France implemented a full ban on lightweight plastic bags at checkout counters. Research by the Earth Policy Institute showed that one trillion single-use plastic bags are used each year, and most of them ultimately make it to the ocean through waterways. Overall, over 8 million tons of plastic per year are thrown into oceans (Earth Policy Institute, 2018). However, such policies must be studied for a potential downside as well. Upon further consideration, for a cotton bag to have a more favorable environmental footprint than a plastic bag, it needs to be reused 130 times (KQED). Nevertheless, most Mediterranean countries are in need for local and regional policies as part of a marine anti-pollution grand strategy.
9. Conclusions
Plastic pollution in the marine environment grew into a global and regional concern threatening ecosystems and human health. Private sector entities including manufacturers and traders are expected to play an essential role in the design process of public policies and actively partake in their implementation. The Mediterranean is particularly vulnerable to plastic pollution due to its enclosed geometry, its disproportionate depth in comparison with its shallow strait, and its population density around its rim. Our linear regression analysis on public attitudes in Lebanon shows that the readiness of local communities to actively fight plastic pollution is positively and significantly correlated with an appeal to establish national public policies specific to plastic littering, and a request for advocacy with the private sector. There were concerns about sorting MSW at the household level given that contractors remix and dump them in open land. Respondents support regional collaborative treaties to protect the environment, but there is a perception that chances of success for such prospects are dim. Regional policies need to be explored further with the possibilities to form joint teams of experts, and develop innovative techniques across borders.
Radical change cannot happen without engineering innovation and advocacy with the private sector. Transitioning into a plastic-free end-use requires plastics manufacturers and traders to adopt novel techniques. There is an urgent need to introduce innovative products and processes such as plastic-to-fuel operations, as part of long-term preventive strategies. Future research is recommended to further develop public policies, both locally and regionally to handle this shared problem and its negative externalities.
\n',keywords:"natural resource management, plastic pollution, Mediterranean Sea, regional environmental collaboration, policy development, private sector advocacy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70596.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70596.xml",downloadPdfUrl:"/chapter/pdf-download/70596",previewPdfUrl:"/chapter/pdf-preview/70596",totalDownloads:381,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:32,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"July 30th 2019",dateReviewed:"September 23rd 2019",datePrePublished:"August 6th 2020",datePublished:"February 17th 2021",dateFinished:"December 23rd 2019",readingETA:"0",abstract:"Natural resource management issues are at the heart of sustainability and are seldom limited to a localized community. We address marine plastic pollution which not only infests local beaches, but is found in the present research to have high mobility, a serious impact on human health, and a damaging effect on ecosystems. Plastics have reached the deepest points of our oceans and while all oceans are affected, the Mediterranean Sea is particularly vulnerable to pollution because of its high biodiversity density, its enclosed geometry, and its bathymetry. We collected primary and secondary data and drew on separate studies performed by the author. We gauged public attitudes towards plastic waste management in Lebanon and found that the public is aware of the issue and supports the formation of a Mediterranean Rim consortium to address both remedial and preventive strategies. A regression analysis is introduced where a dependent variable represents the need for regional natural resource strategies. It was found to be positively and significantly correlated with the establishment of national policies, engineering innovation as a preventive strategy, and the adoption of local implementation. Our case study in Lebanon unveiled lack of public policies for solid waste management and marine plastic litter, causing implementation challenges. We recommend that the problem of plastic pollution be tackled with cross-border cooperation among neighboring countries around the Mediterranean.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70596",risUrl:"/chapter/ris/70596",book:{id:"8985",slug:"natural-resources-management-and-biological-sciences"},signatures:"Michel Soto Chalhoub",authors:[{id:"108542",title:"Dr.",name:"Michel Soto",middleName:null,surname:"Chalhoub",fullName:"Michel Soto Chalhoub",slug:"michel-soto-chalhoub",email:"mchalhoub@live.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Plastic pollution is a regional and global problem",level:"1"},{id:"sec_3",title:"3. Vulnerability of the Mediterranean",level:"1"},{id:"sec_3_2",title:"3.1 History and biodiversity",level:"2"},{id:"sec_4_2",title:"3.2 Physical properties: waves and currents",level:"2"},{id:"sec_6",title:"4. Case of the Lebanese coast",level:"1"},{id:"sec_6_2",title:"4.1 Plastic is the predominant pollutant on Lebanon’s shores",level:"2"},{id:"sec_7_2",title:"4.2 Lack of public policies related to plastic pollution: public awareness and fatigue",level:"2"},{id:"sec_8_2",title:"4.3 Need for evidence-based advocacy and multidisciplinary collaboration",level:"2"},{id:"sec_10",title:"5. Plastics from land to sea Mediterranean subbasins and currents",level:"1"},{id:"sec_11",title:"6. Mathematical model, empirical analysis, and results",level:"1"},{id:"sec_12",title:"7. From remedial reactions to preventive strategies: innovation against plastic pollution",level:"1"},{id:"sec_12_2",title:"7.1 Remedial reactions are necessary but not sufficient",level:"2"},{id:"sec_13_2",title:"7.2 Need for preventive strategies",level:"2"},{id:"sec_14_2",title:"7.3 Preventive strategies need to be regional",level:"2"},{id:"sec_16",title:"8. Movements towards policy against plastics",level:"1"},{id:"sec_17",title:"9. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'United Nations Environment Programme (UNEP). Marine Litter Assessment in the Mediterranean—Mediterranean Action Plan (MAP). Greece: Athens; 2015'},{id:"B2",body:'Kindt JW. Marine Pollution and the Law of the Sea. Buffalo, NY: W. S. Hein; 1986'},{id:"B3",body:'Bowker M. Caught in a Plastic Trap. International Wildlife, May–June: 70; 1986'},{id:"B4",body:'Langley LS. Plastic Pollution Threatening Marine Wildlife. Charleston News and Courier, June 5: Dl col. 1. 1988'},{id:"B5",body:'U. N. General Assembly. Law of the Sea: Report of the Secretary-General, U.N. General Assembly, 45th Session, Agenda Item 43, Nov. 19, 1990 7 U.N. Doc. A/45/721; 1990'},{id:"B6",body:'Joyner CC, Frew S. Plastic pollution in the marine environment. Journal of Ocean Development and International Law. 1991;22(1):33-69. (published online, 2009, https://www.tandfonline.com/doi/ref/10.1080/00908329109545949?scroll=top)'},{id:"B7",body:'WWF—Worldwide Fund for Nature. The Mediterranean at Risk of becoming a Sea of Plastic. June 8, 2018; 2018'},{id:"B8",body:'Chalhoub MS. Solid Waste Management and Public Policy Challenges: Are Plastics Commanding the Lion’s Share? Working Paper in Engineering Practice. Louaize, Lebanon; 2017'},{id:"B9",body:'Eriksen M, Lebreton LCM, Carson HS, Thiel M, Moore CJ, Borerro JC, et al. Plastic Pollution in the World’s Oceans: More than 5 Trillion Plastic Pieces Weighing over 250,000 Tons Afloat at Sea. PLoS One. 2014;9(12):e111913. DOI: https://doi.org/10.1371/journal.pone.0111913'},{id:"B10",body:'MEDSEA—Med Sea Foundation. Clean-up Together to Clean Everyone’s House. 2019. Available from: http://www.medseafoundation.org/index.php/en/news-int-eng/132-clean-up-together-to-clean-everyone-s-house'},{id:"B11",body:'IUCN—International Union for Conservation of Nature. Endangered Species in the Mediterranean – Data; 2017'},{id:"B12",body:'Chalhoub MS. Modeling Solid Waste Conveyance into the East Mediterranean: Uncertainties and Challenges in Engineering and Public Policy, Working Paper, Louaize, 2016'},{id:"B13",body:'BBC. Lebanon is Drowning in its own Waste. 2018. Available from: http://www.bbc.com/future/story/20180328-lebanon-is-drowning-in-its-own-waste'},{id:"B14",body:'HRW—Human Rights Watch. Lebanon: No Action to Enforce New Waste Law. 2018. Available from: https://www.hrw.org/news/2018/10/18/lebanon-no-action-enforce-new-waste-law'},{id:"B15",body:'Chalhoub MS. Public policy and technology choices for municipal solid waste management a recent case in Lebanon. Journal of Environmental Science and Health, Taylor & Francis Online. 2018;4(1):1-18'},{id:"B16",body:'Daily Star. Cabinet Approves Plans to Expand Costa Brava Landfill. 2018. Available from: http://www.dailystar.com.lb/News/Lebanon-News/2018/Jan-12/433384-cabinet-approves-plan-to-expand-costa-brava-landfill.ashx'},{id:"B17",body:'EJA—Environmental Justice Atlas. Costa Brava Landfill: Lebanon. 2017. Available from: https://ejatlas.org/conflict/costa-brava-landfill-lebanon'},{id:"B18",body:'Reuters World News. Lebanon’s Public Sector Plagued by Inefficiency, Waste. 2018. Available from: https://www.reuters.com/article/us-lebanon-politics-waste/lebanons-public-sector-plagued-by-inefficiency-waste-idUSKBN1FP1SC'},{id:"B19",body:'Carnegie MEC—Carnegie Middle East center. Is Lebanon Heading towards Eonomic Bankruptcy? 2017. Available from: https://carnegie-mec.org/diwan/73280'},{id:"B20",body:'Beirut Today. Is Lebanon’s Economy on the Brink of Collapse? Beirut Today. 2019. Available from: http://beirut-today.com/2019/01/16/lebanons-economy-brink-collapse/'},{id:"B21",body:'Haugbolle S. Lebanon is Facing and Economic and Environmental Disaster, Foreign Policy. 2019. Available from: https://foreignpolicy.com/2019/02/20/lebanon-is-facing-an-environmental-and-economic-disaster-hezbollah-hariri-aoun/'},{id:"B22",body:'Forbes. Fighting Plastic Pollution from the Top. Melissa Cristina Marquez, 27 December 2017. 2018. Available from: https://www.forbes.com/sites/melissacristinamarquez/2018/12/27/fighting-plastic-pollution-from-the-top/#365a7e297616'},{id:"B23",body:'Proshad R, Kormoker T, Saiful Islam M, Asadul Haque M, Rahman M, Rahman Mithu M. Toxic effects of plastic on Human health and environment: Consequences of health risk assessment in Bengladesh. International Journal of Health. 2018;6(1):1-5'},{id:"B24",body:'Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bisphenol concentrations in human biological fluids reveals significant early prenatal exposure. Humanities Report. 2002;17:2839-2841. DOI: 10.1093/humrep/17.11.2839'},{id:"B25",body:'Nielsen JN. Hydrography of the Mediterranean and adjacent waters. Report of the Danish Oceanographic Expedition 1908-1910 to the Mediterranean and Adjacent Waters. 1912;1:77-192'},{id:"B26",body:'Zambianchi E, Trani M, Falco P. Lagrangian transport of marine litter in the Mediterranean Sea. Frontiers in Environmental Science. 2017;5(5):1-15'},{id:"B27",body:'Chalhoub MS. Anaerobic Digesters Design for Sludge Treatment in the County of Los Angeles. Report No. 005-91-02-02, Parsons Eng. Lib. Pasadena, CA: Archives/Stacks; 1991'}],footnotes:[{id:"fn1",explanation:"In the United States, several cities banned foamed PS."},{id:"fn2",explanation:"SwitchMed coordinates between the European Union, the United Nations Industrial Development Organization (UNIDO), the UN Environment and Action Plan for the Mediterranean and its Regional Activity Centre for Sustainable Consumption and Production (SCP/RAC), and the UN Environment located near Santa Barbara, California, USA."}],contributors:[{corresp:"yes",contributorFullName:"Michel Soto Chalhoub",address:"mchalhoub@live.com",affiliation:'
Department of Civil and Environmental Engineering, Notre Dame University, Zouk Mosbeh, Lebanon
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1. Introduction
The inappropriate or excessive secretion of parathyroid hormone (PTH) from one or multiple abnormal parathyroid glands typically results in hypercalcemia and the disorder of mineral metabolism called primary hyperparathyroidism (HPT) [1]. Most cases of HPT are sporadic (~95%). Among the small remaining fraction of patients with an inherited basis for HPT, most harbor germline mutation of a known parathyroid tumor susceptibility gene (listed in Table 1). In spite of their infrequency, study of the genetics of these uncommon inherited syndromes has yielded substantial insight into the etiology of both sporadic and familial parathyroid tumor development. Since the release of PTH from parathyroid cells involves close regulation by the calcium-sensing receptor (CASR), a cell surface transmembrane receptor of the G protein-coupled receptor family C [2], the germline mutation of the CASR and other genes mediating its signaling can also result in inherited syndromes characterized by hypercalcemia and circulating levels of PTH that are elevated or inappropriately normal. This chapter will summarize current knowledge of the clinical genetics and molecular pathophysiology of HPT that results from both benign and malignant parathyroid gland neoplasia.
Gene
Corresponding protein
Chromosomal location
Associated hyperparathyroid syndrome: main syndromic manifestations
Multiple endocrine neoplasia type 4 (MEN4): anterior pituitary, other involvement varies
Single to multiple glands (benign in reports to date); can be recurrent
GCM2
Glial cells missing transcription factor 2
6p24.2
Familial isolated primary hyperparathyroidism
Single to multiple glands
CASR
Calcium-sensing receptor
3q13.33-q21.1
Familial hypocalciuric hypercalcemia type 1 (FHH1) with heterozygous inactivation; neonatal severe hyperparathyroidism (NSHPT) with homozygous inactivation
FHH1: near-normal size and surgical pathology; altered serum calcium set-point for PTH release NSHPT: marked enlargement of multiple glands by polyclonal (non-neoplastic) mechanism
GNA11
G protein α11 subunit
19p13.3
Familial hypocalciuric hypercalcemia type 2 (FHH2)
ND
AP2S1
Adaptor protein-2 sigma subunit
19q13.32
Familial hypocalciuric hypercalcemia type 3 (FHH3): hypercalcemia more severe than in FHH1
NA (to date, only implicated in sporadic parathyroid tumors)
NA (to date, only implicated in sporadic parathyroid tumors)
Table 1.
Genes implicated in syndromic parathyroid neoplasia and related hypercalcemic states.
2. The evolution of calcium regulation in vertebrates
In sea water the concentration of elemental calcium is approximately 10 mM. As a result, early eukaryotes living in a marine environment had easy access to calcium. Given this abundant supply of extracellular calcium, numerous intracellular processes evolved in simple eukaryotes that depended on this divalent cation. Such calcium-dependent processes were preserved in metazoans. Thus marine chordates and early vertebrate fish depended on calcium for cellular processes such as membrane permeability, neurotransmitter release, intracellular second messenger signaling, muscular contraction, neuromuscular excitability, and the actions of multiple calcium-dependent enzymes. Calcium’s particular coordination chemistry facilitated many proteins’ ability to reversibly bind divalent calcium ions, thus enabling signaling through such binding [3].
Calcium is much scarcer on land compared to the marine environment. As lobe-finned fish, marine vertebrates believed to be the ancestors of the early amphibians, began to explore the periphery of the terrestrial environment, evolutionary pressure to develop a system of internal calcium balance mounted. A system of internal calcium homeostasis at the organismal level would ensure the continued preservation and function of numerous cellular and tissue operations that vitally depended on calcium.
Metabolically-active trabecular or cancellous bone in lobe-finned fish and associated hematopoietic bone marrow likely co-evolved [4]. These developments probably both lightened overall skeletal mass and provided a reliable internal source of calcium as a basis for calcium homeostasis. The lightening of skeletal mass was critical since lobe-finned fish and early amphibians had to come to terms with full gravitational force in their terrestrial movements, no longer buoyed by surrounding seawater in accordance with Archimedes’ principle [5]. The potential significance of the close physical apposition of hematopoietic bone marrow to spongiform bone, inferred from X-ray synchrotron microtomography of fossilized lobe-finned fish humerus [4], is suggested by the realization that osteoclasts, cells uniquely specialized to mobilize ionized calcium via resorption of bone, develop from hematopoietic stem cell precursors [6]. In contrast, osteoblasts, which lay down osteoid and mineralize bone, derive from mesenchymal stem cells which are abundant in non-hematopoietic bone marrow.
Although analogs of Gcm2, Gata3, CaSR, PTH, and other genes associated with the development and function of human parathyroid glands are expressed in the fish gills, actual parathyroid glands are first seen in amphibians [7, 8, 9]. Complete surgical excision of parathyroid gland tissue in amphibians, reptiles, birds, and mammals results in tetany and death.
3. The pathophysiology of primary hyperparathyroidism
PTH secretion from cells of the parathyroid glands is finely regulated in response to changes in the ambient ionized calcium level in order to maintain the circulating calcium concentration within a defined physiologic range. The G protein-coupled CASR is a critical regulator of PTH secretion and is located on the plasma membrane of chief cells in the parathyroid glands [10, 11]. In a classic endocrine negative feedback loop, the active form of cholecalciferol, 1,25-dihydroxyvitamin D, whose synthesis is stimulated by PTH acting on proximal renal tubular cells, inhibits PTH biosynthesis and release from parathyroid cells [12, 13, 14, 15]. The simultaneous demonstration of elevated serum calcium with an inappropriately normal or elevated PTH is a typical clinical definition of HPT [16]. The vast majority of parathyroid tumors are adenomas (i.e. benign tumors), with parathyroid cancer accounting for less than 1% of HPT in most series.
Most cases of HPT are sporadic with inherited forms of HPT representing only 2–5% of cases. As illustrated in Table 1, research into the molecular pathophysiology of this small subcategory of cases has notwithstanding yielded important understanding with respect to the genes and pathways that promote parathyroid tumorigenesis. Multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), the hyperparathyroidism-jaw tumor syndrome (HPT-JT), and familial isolated hyperparathyroidism (FIHP) are the most common inherited disorders associated with HPT [17, 18, 19, 20, 21]. Familial hypocalciuric hypercalcemia (FHH) is a related and largely benign autosomal dominant condition characterized by lifelong asymptomatic hypercalcemia. Often mis-diagnosed as HPT, in FHH the PTH-dependent hypercalcemia does not correct with partial or even subtotal parathyroidectomy [22]. The relevance of these inherited disorders to the underlying molecular pathogenetic alterations in parathyroid tumorigenesis will be discussed in more detail below.
4. Oncogenes and proto-oncogenes
Mutant genes that drive cell growth are called oncogenes and represent one potential molecular mechanism for tumor development. Oncogenes are mutationally activated versions of naturally occurring genes, called proto-oncogenes, which under normal conditions positively regulate cell division and/or cell growth [23]. Oncogenes represent gain-of-function mutants or overexpressed forms of proto-oncogenes that can induce cell growth and cell division, often in a tissue-specific fashion, resulting in tumor formation. Proto-oncogenes often encode proteins that are involved in mitogenic signal transduction. In the context of currently recognized familial cancer syndromes, germline mutational activation of proto-oncogenes is rare as an etiology compared to the inactivation of tumor suppressor genes (see below). Constitutive proliferative signaling resulting from the germline activation of most proto-oncogenes would presumably be deleterious to embryonic and fetal development.
5. The role of tumor suppressor genes in tumor development
Alfred Knudson proposed another model for tumor development based on the study of retinoblastoma disease patterns nearly 50 years ago [24]. Sporadic retinoblastoma is usually monocular. Familial retinoblastoma, though rare compared to the sporadic form, is more frequently binocular and has a much earlier age of onset. The “two-hit” hypothesis of tumor development, as proposed by Knudson, hypothesizes that two events (or “hits”) in a parental cell confer a selective growth advantage and result in that cell’s clonal expansion [25].
Newer clinical and molecular genetic insight that has emerged since his original proposal allow us to update Knudson’s concept. In many hereditary tumor syndromes, an inherited germline DNA mutation that affects one copy of a tumor suppressor gene represents the first “hit” or event and is present throughout all cells of the affected offspring. The greater likelihood of any particular cell acquiring a “second hit”, i.e. a somatic mutation in the second allele of the same tumor suppressor gene that was heretofore unaffected, accounts for the earlier age of onset and predisposition for bilateral and multifocal disease in hereditary tumor syndromes. This “second hit” in somatic DNA, that disables the remaining wild-type allele, typically results from a deletion that involves a portion or the entirety of a chromosome. In the familial tumor syndromes MEN1 and HPT-JT, inactivating mutation that involves both alleles of the MEN1 and the CDC73/HRPT2 tumor suppressor genes, respectively, can often be found in parathyroid tumor-derived DNA. In such patients, the first “hit”, namely a loss-of-function mutation of the relevant tumor suppressor gene, can frequently be demonstrated in the germline DNA.
6. Multiple endocrine neoplasia type 1 (MEN1)
MEN1 is the most common hereditary cause of primary hyperparathyroidism [26]. The syndrome of MEN1 is characterized by the predisposition to develop tumors derived from cells in the anterior pituitary, parathyroid glands, and endocrine cells present in the gut and pancreatic islets (such as gastrinomas, and pancreatic neuroendocrine tumors such as insulinomas) [27]. Tumors in several other endocrine organs and non-endocrine tumors such as lipomas, angiofibromas, and leiomyomas affecting the esophagus, uterus, and/or ureters for example, can also be associated with the syndrome [27]. HPT is the most penetrant hormonal feature of MEN1.
Familial MEN1 is characterized by autosomal dominant transmission. The predisposition to tumor development in one of the tissues characteristically involved in the MEN1 syndrome is caused by germline inactivating mutation in one copy of the MEN1 gene on chromosome 11q13 [28]. As of 2015, 576 unique germline mutations in MEN1 were reported from patients and families with MEN1 [29]. The study of DNA derived from pituitary, parathyroid, and entero-pancreatic tumors from MEN1 patients has shown that most syndromic tumors possess an acquired deletion or other inactivating mutation of the second, wild-type MEN1 allele [18, 30]. Approximately 10% of patients with MEN1 on a clinical basis are germline MEN1 mutation-negative.
Conventional DNA sequencing of tumor DNA has identified somatic MEN1 mutation in up to 35% of sporadic parathyroid adenomas [31, 32, 33, 34, 35]. In studies testing for loss-of-heterozygosity (LOH) in sporadic parathyroid adenomas, the frequency of LOH at the MEN1 locus on chromosome 11q13 ranged from 26 to 37%. Using whole exome sequencing (WES) methodology, somatic MEN1 mutation was found in some 35% of parathyroid benign tumors, comparable to results using conventional Sanger DNA sequencing [36, 37]. As mentioned above, HPT is the most penetrant feature of MEN1 and is usually the initial manifestation. As a result, true MEN1 families may sometimes be initially mis-assigned a clinical diagnosis of familial isolated hyperparathyroidism (FIHP) if only younger affected members are considered at the time that the family is ascertained (see Figure 1).
Figure 1.
The relationship among familial forms of hyperparathyroidism that may present as familial isolated hyperparathyroidism (FIHP) as a Venn diagram. The dashed circle represents the set of patients that can present with a provisional diagnosis of FIHP at the time of initial ascertainment. This includes patients with FIHP who have been evaluated for, but lack findings diagnostic of, MEN1, FHH and HPT-JT (nonsyndromic FIHP; in a solid circle). Approximately 18% of nonsyndromic FIHP kindreds harbor germline gain-of-function mutations in GCM2 (see text), whereas the remainder have currently unknown genetic etiologies. Subsets of patients with incomplete expression of MEN1, FHH and HPT-JT (the total set of patients in each syndrome represented by a solid circle) can also present with the FIHP phenotype (and thus overlap with the dashed circle). The distinction between the nonsyndromic FIHP category and the syndromic categories arbitrarily depends on the thoroughness of evaluation and the sensitivity of diagnostic tests used to detect the syndrome that can include germline gene mutational testing. MEN2A is a familial form of hyperparathyroidism that seldom if ever presents as FIHP. Within each circle representing a defined syndrome are included the genetic locus (or loci in the case of FHH; see text) of the syndromic trait and the associated gene product. The causative gene for HPT-JT encoding parafibromin is CDC73, formerly called HRPT2. The relationship among the patient sets illustrated as circles in this diagram is intended to be qualitative and neither the area of each circle nor the area of overlap between circles has any quantitative significance.
Mutation of the MEN1 gene is only rarely associated with parathyroid carcinoma. The occurrence of parathyroid carcinoma in the context of familial MEN1 is extremely uncommon. Fewer than 20 patients with HPT due to parathyroid cancer in the context of the MEN1 syndrome have been reported [38]. LOH analysis of parathyroid tumor-extracted DNA has shown that DNA loss at the location of the MEN1 gene on chromosome 11q, though frequently seen in benign parathyroid tumors, is quite uncommon in parathyroid carcinomas [39]. Recent studies that use next-generation WES of tumor-derived DNA to profile parathyroid cancers did not report any somatic mutations in MEN1 [40, 41].
7. The hyperparathyroidism-jaw tumor syndrome (HPT-JT)
HPT-JT is a familial syndrome with variable and incomplete penetrance transmitted in an autosomal dominant fashion. The key clinical features of HPT-JT include HPT, jaw tumors (fibro-osseous tumors involving the maxilla and/or mandible, formally classified as cemento-ossifying fibromas [42], and distinct from so called “brown” tumors sometimes associated with HPT), renal cysts or tumors and uterine tumors in women [43, 44, 45]. HPT is the most penetrant feature of HPT-JT and is usually the presenting manifestation. In contrast to MEN1, parathyroid cancer is frequent in HPT-JT, affecting some 20% or more of those with HPT [43, 44, 45, 46].
In the majority of HPT-JT kindreds, a germline loss-of-function mutation of the CDC73 gene (formerly called HRPT2) can be identified [19, 47]. The majority of such CDC73 mutations are predicted to inactivate gene function via frameshift or nonsense mutation, and only a minority of the mutations are missense [48]. Patients and kindreds with partial or complete deletion of the CDC73 gene in the germline have also been described [49, 50, 51, 52]. The CDC73 gene encodes a 531-residue protein named parafibromin [47]. Because germline mutation predicted to cause loss-of-function of the CDC73 gene predisposes to the neoplastic expressions of HPT-JT, parafibromin is considered to be a tumor suppressor protein. Mixed epithelial tumor of the kidney (MEST), a rare type of renal tumor (formerly classified as cystic hamartoma of the renal pelvis, leiomyomatous renal hamartoma, or adult type mesoblastic nephroma), has been associated with HPT-JT and appears to correlate with a specific CDC73 genotype, namely the Met1ILe missense mutation replacing the initiator methionine of parafibromin with isoleucine [47, 53, 54]. Somatic mutation of the CDC73 tumor suppressor gene is uncommon in sporadic parathyroid adenomas [55]. In contrast to the results of analyses in benign parathyroid tumors, mutations of CDC73 are quite frequently seen in apparently sporadic cases of parathyroid cancer [56, 57, 58]. Interestingly, recurrent somatic mutations in CDC73 have been documented by exome sequence analysis of tumor DNA from parathyroid cancers [40, 41]. Selective amplification of the mutant copy of CDC73 has been demonstrated in a subset of parathyroid carcinomas [40]. Approximately 25% of cases of seemingly sporadic parathyroid carcinoma may possess germline loss-of-function alterations in CDC73, suggesting that such patients may in fact have previously unrecognized, or formes frustes of, HPT-JT [19, 57, 58]. A minority of patients and families classified as FIHP can be shown to carry CDC73 mutation in the germline, suggesting that this inherited disorder may in some cases be phenocopied by incompletely penetrant HPT-JT (see below and Figure 1). Approximately 20% of genetically confirmed or obligate CDC73 mutation-positive family members lack HPT, fibro-osseous jaw tumors, or other manifestations of HPT-JT when their kindred is initially ascertained. Because the penetrance of the manifestations of HPT-JT increases with age among CDC73 mutation carriers, lifelong surveillance of initially asymptomatic carriers is recommended [59].
8. Multiple endocrine neoplasia type 4 (MEN4)
MEN4 is a syndrome originally described by Pellegata and coworkers in a multi-generational family with features resembling MEN1, including a proband with a growth hormone-secreting pituitary adenoma and HPT, but lacking germline MEN1 mutation [60, 61]. A germline heterozygous truncation mutation in CDKN1B was identified in the proband and several members of this kindred [60]. CDKN1B encodes the cyclin dependent-kinase inhibitor p27 (Kip1). Attention to the CDKN1B locus was a consequence of a previous genetic analysis of rats with the MenX phenotype, a recessively inherited condition caused by a frameshift mutation in Cdkn1b [60, 62]. The MenX phenotype in rats was manifest by the development of bilateral pheochromocytomas, paragangliomas, parathyroid adenomas and thyroid C cell hyperplasia [60, 62]. In the study by Pellegata et al., the proband was the only member of the MEN4/MENX kindred described who manifested HPT [60].
Following the original report by Pellegata et al. [60], several groups have investigated a possible role for CDKN1B mutation in parathyroid tumorigenesis. None of the earlier reports of MEN1 mutation-negative families harboring germline mutation in CDKN1B, and expressing MEN1-like tumors and thus classified as MEN4, had included families with more than one member with HPT proven to track with the CDKN1B mutation [60, 63, 64, 65, 66, 67, 68, 69, 70, 71], apart from the demonstration of HPT linked to CDKN1B mutation in monozygotic twins [64]. That was true until a more recent report by Frederiksen et al. describing a large Danish family in which HPT occurred in 13 members, spanning two generations, who carried a germline frameshift CDKN1B mutation [72].
Recent evidence supports the characterization of CDKN1B as a susceptibility gene for the development of primary parathyroid tumors [69, 72, 73]. This evidence validates the inclusion of germline CDKN1B mutation in the differential diagnosis of familial HPT, particularly in the evaluation of germline MEN1 mutation-negative families who yet have MEN1-like features. The strongest justification for this follows from consideration of the Danish kindred in which 13 unique family members manifest HPT linked to germline inactivating mutation of CDKN1B, described by Frederiksen and co-workers [72].
9. Familial isolated hyperparathyroidism (FIHP)
By definition, FIHP is a non-syndromic category of familial HPT describing families that contain two or more members with HPT but which lack the specific features of MEN1, MEN2A, HPT-JT or FHH (Figure 1) [74]. FIHP is genetically heterogeneous and is a diagnosis of exclusion. While at the time of initial ascertainment germline mutation of MEN1, CDC73, or CASR may account for a fraction of kindreds with the FIHP phenotype [20, 34, 75, 76, 77], the majority of FIHP families lack mutations in these established HPT-susceptibility genes (Figure 1) [20, 75, 78].
Missense variants in GCM2, a transcription factor homologous to the Drosophila “glial cells missing” (gcm) gene and required for parathyroid gland development, were recently described in the germline DNA of eight unrelated families with FIHP [21]. Previous studies showed that germline dominant-negative and loss-of-function mutations in GCM2 were associated with autosomal dominant and autosomal recessive familial isolated hypoparathyroidism, respectively [79, 80]. The two rare germline GCM2 genetic variants associated with FIHP act as gain-of-function mutations [21]. These missense mutations map to the C-terminal conserved inhibitory domain (CCID) of GCM2 and increase its transcriptional activity when measured in vitro, suggesting that GCM2 in the context of FIHP is a parathyroid proto-oncogene. It has been estimated that approximately 18% of FIHP families harbor germline activating GCM2 mutations [21], leaving ~80% of FIHP families without a currently-identified genetic etiology [74]. Other clinical investigators have identified rare germline GCM2 variants in a subset of FIHP kindreds [81]. Activating GCM2 variants mapping to the CCID region have been found among patients with sporadic parathyroid tumors in low frequency and appear to be of low penetrance [82].
10. Familial hypocalciuric hypercalcemia (FHH)
FHH is a condition of PTH-dependent hypercalcemia, often resembling HPT, that is clinically benign and genetically heterogeneous (Table 1) [22]. Following partial or subtotal parathyroidectomy, affected patients from FHH kindreds almost always remain hypercalcemic. FHH is transmitted in an autosomal dominant fashion and usually causes mild hypercalcemia with relative hypocalciuria. The hypercalcemia seen in FHH is highly penetrant across all ages, including in infants [22, 83]. The majority of cases of FHH result from heterozygous germline inactivating mutation of the CASR gene on the long arm of chromosome 3 that encodes the calcium-sensing receptor [10, 84], and is classified as type 1 FHH (FHH1). Neonatal severe hyperparathyroidism (NSHPT), a rare autosomal recessive disorder typically presenting with severe hypercalcemia occurring in the first 6 months of life, most often results from the compound heterozygous or homozygous inheritance of two loss-of-function mutant CASR alleles [85]. Rather than the cellular monoclonality that would be expected in true parathyroid tumors, molecular genetic analysis of the hyperfunctioning parathyroid glands removed from a patient with NSHPT demonstrated generalized polyclonal hyperplasia, underscoring the non-neoplastic nature of the abnormal parathyroid glands associated with CASR inactivating mutation [86].
Loss of surface expression of the CASR protein has been documented in parathyroid adenomas and may contribute to the altered calcium set point and impaired calcium-mediated negative feedback on the release of PTH typical of such adenomas. Decreased CASR mRNA expression, but not LOH at the CASR locus, has been documented in parathyroid adenomas [87]. In sporadic parathyroid tumors studied to date, somatic inactivation of the CASR gene has not been reported [88, 89].
Type 2 FHH (FHH2) resulting from germline loss-of-function mutation of GNA11, encoding the G protein α11 subunit [90, 91], and type 3 FHH (FHH3) resulting from germline inactivating mutation in AP2S1, the gene that encodes an adaptor protein involved in endocytosis mediated by clathrin [92, 93, 94, 95], have also been described. In studies of sporadic parathyroid tumors, somatic inactivating mutations of GNA11 and AP2S1 have so far not been reported.
11. Multiple endocrine neoplasia type 2A (MEN2A)
MEN2A is a familial cancer syndrome characterized by a predisposition to the development of medullary thyroid cancer (MTC), pheochromocytoma (typically benign and often bilateral), and primary HPT. In the context of MEN2A, HPT is usually mild and resembles sporadic HPT. HPT in MEN2A is almost always results from benign parathyroid disease. MEN2A is an autosomal dominant disorder that results from germline gain-of-function mutation in the RET proto-oncogene at chromosomal location 10q11. RET encodes a receptor tyrosine kinase that binds the ligand glial derived neurotrophic factor, together with a glycosylphosphatidylinositol-anchored protein co-receptor Gfra1 [96].
Germline oncogenic mutations of RET are associated with three distinct familial endocrine neoplasia syndromes, all associated with MTC: MEN2A, multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid cancer (FMTC). The disease spectrum of typical MEN2B or FMTC does not include parathyroid tumors and HPT. Genotype–phenotype correlations based on particular RET mutations are apparent and account for the distinct patterns of disease. Some 95% of MEN2A cases are due to the presence in the germline of nonsynonymous variants affecting the RET receptor’s extracellular cysteine-rich domain, namely missense mutations of RET codons 609, 611, 618, 620, or 634 [97]. In fact, germline missense alteration of RET residue cysteine-634 accounts for approximately 85% of cases of MEN2A [98].
12. Parathyroid tumorigenesis involving the CCND1 oncogene
The discovery of the CCND1 (or PRAD1, for parathyroid adenomatosis 1) oncogene resulted from the analysis of several large, non-familial, parathyroid adenomas that harbored DNA re-arrangements that involved the PTH gene locus [99, 100, 101]. A breakpoint resulting from the pericentromeric inversion of chromosome 11 DNA was identified just upstream of the CCND1/PRAD1 oncogene [101]. The inversion positioned the PTH gene regulatory region, that is normally located on the short arm of chromosome 11, just upstream of the CCND1/PRAD1 proto-oncogene located on 11q [99, 100, 101]. The product encoded by the proto-oncogene was subsequently recognized by DNA sequence analysis to be a member of the cyclin protein family [101]. The gene was therefore re-named cyclin D1 (CCND1). Overexpression of CCND1 in the parathyroid cells of transgenic mice induces cell proliferation and gives rise to the metabolic abnormalities that characterize HPT in humans [102].
While activating CCND1 missense mutations have not been observed in sporadic parathyroid tumors [103], overexpression of CCND1 has been demonstrated in 20–40% of sporadic benign parathyroid tumors and in an even larger percentage of parathyroid carcinomas [104, 105, 106, 107]. In parathyroid carcinoma, no somatic chromosomal rearrangements on chromosome 11 involving CCND1 have been reported. Neither germline activating missense mutations of CCND1 nor chromosomal translocations or rearrangements involving the CCND1 locus have been reported in any familial form of HPT.
13. Other genes involved in parathyroid tumorigenesis
Recurrent mutations in a subset of genes likely relevant to parathyroid tumorigenesis have been identified by WES analysis of DNA derived from sporadic parathyroid tumors. Eight out of 193 sporadic parathyroid tumors analyzed by WES demonstrated the Y641N missense mutation in the EZH2 gene on chromosome 7 that encodes the enhancer of zeste 2 polycomb repressive complex 2 subunit [36]. Analysis by WES of 22 parathyroid tumors derived from a Chinese patient population identified a distinct somatic missense mutation, Y646N, in EZH2 [108]. Acquired mutations of Y641 and Y646 in EZH2 were described previously in lymphoid malignancy [109, 110]. Molecular genetic profiling of 80 sporadic parathyroid neoplasms by separate investigators failed to uncover any pathogenic EZH2 mutations however, suggesting acquired EZH2 mutation may be uncommon in parathyroid tumors [111]. In the context of lymphoma, EZH2 is thought to function as a proto-oncogene [109]. To date, no transgenic mouse models restricting EZH2 mutation or overexpression to parathyroid cells have been reported.
Soong and Arnold used WES analysis of DNA extracted from 19 parathyroid adenomas and matching germline DNA to identify somatic mutations in ZFX, a putative parathyroid proto-oncogene and member of the Krüppel associated box domain-containing family of zinc finger protein transcription factors [112]. Their observations in the discovery cohort were confirmed by direct sequencing of tumor DNA from an additional validation set comprised of 111 parathyroid adenomas [112]. The mutant ZFX alleles detected in parathyroid tumors likely act as oncogenes [113]. Such somatically acquired ZFX mutations in parathyroid tumors may be uncommon, however, since an independent mutational analysis of 23 sporadic parathyroid carcinomas and 57 adenomas failed to identify any pathogenic ZFX variants [111]. The development of a transgenic mouse model and/or better characterization of the functional properties of the mutant ZFX protein may clarify the potential significance of ZFX as a parathyroid proto-oncogene.
WES analysis of 22 blood-sporadic parathyroid adenoma tumor pairs from a Chinese patient cohort identified recurrent mutations of ASXL3 [108]. ASXL3 belongs to a family of vertebrate Additional sex combs (Asx)-like proteins that may function as regulators of transcription. It remains unclear if the somatic missense ASXL3 mutations identified in the parathyroid adenomas, mutations that affected highly conserved residues, would result in gain- or loss of ASXL3 function [108]. Further studies will be required to confirm this initial observation and to clarify the mechanism by which ASXL3 mutation might drive parathyroid tumor development.
14. Conclusions
While inherited forms of HPT represent only a small fraction of cases (<5%), study of the molecular pathophysiology of these uncommon familial syndromes has yielded substantial insight into the genetic etiology of both sporadic and familial parathyroid disease and resulted in the identification of genes such as MEN1, CDC73, CASR, GNA11, AP2S1, CDKN1B, CCND1, and GCM2. It is highly likely that the mutational gain- or loss-of-function of other, yet unrecognized, genes is able to drive parathyroid neoplasia. For example, the risk in the majority of FIHP kindreds predisposing to the development of parathyroid tumors seems to result from the germline mutation of genes not presently recognized as having a role in parathyroid disease. This follows from the observation that nearly 70% of families initially considered as FIHP in multiple studies that examined for germline MEN1, CASR and CDC73/HRPT2 gene mutation, had no recognized syndromic etiology (Figure 1) [20, 75, 76, 77]. From among those FIHP kindreds who are MEN1, CASR and CDC73 mutation-negative, only about 20% are estimated to harbor germline activating mutations in the GCM2 proto-oncogene [21], which leaves nearly 80% of FIHP kindreds with a currently-undefined genetic basis for their disease (Figure 1).
The existence of currently unidentified parathyroid tumor suppressors and oncogenes is also suggested by analysis of parathyroid tumors using techniques such as comparative genomic hybridization (CGH) to identify specific chromosomal regions harboring loss or gain of DNA. Several investigators have documented recurrent loss of DNA at the 1p, 6q, 9p, and 13q chromosomal loci in parathyroid tumors, indicating the potential presence there of novel parathyroid tumor suppressor genes [114, 115, 116, 117]. The potential presence of novel oncogenes at chromosomal loci 9q, 16p, 19p, and Xq is suggested by results demonstrating specific chromosomal gain at these loci in benign or malignant parathyroid tumors [114, 116, 117, 118].
Next-generation sequencing analysis including WES of parathyroid neoplasms is an auspicious approach for the identification of novel acquired and germline gene variations that predispose to the development of HPT and parathyroid neoplasia. The apparent validation of this line of investigation by the identification of EXH2 [36], ZFX [112], and potentially ASXL3 [108], as candidate driver genes for parathyroid neoplasia was previously discussed. WES analysis of parathyroid cancer-derived DNA has similarly underscored the possible significance of recurrent somatic and germline inactivating mutations of PRUNE2 in the etiology of parathyroid malignancy [40]. The comprehensive quality and great sensitivity of WES and related next-generation sequencing methodologies should further advance our insight into the genetic basis and endocrine pathophysiology of inherited and sporadic parathyroid neoplasia in the decades ahead.
Acknowledgments
The author wishes to thank the members of the Metabolic Diseases Branch, NIDDK for many helpful discussions and suggestions. The Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (ZIA DK043012-18) supported this research. The author declares no competing financial interests.
Conflict of interest
The author declares no conflict of interest.
\n',keywords:"multiple endocrine neoplasia, MEN1, MEN2A, jaw tumor syndrome, CDC73, HRPT2, GCM2, CCND1, RET, CASR, CDKN1B, tumor suppressor, oncogene",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72573.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72573.xml",downloadPdfUrl:"/chapter/pdf-download/72573",previewPdfUrl:"/chapter/pdf-preview/72573",totalDownloads:343,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 18th 2020",dateReviewed:"May 26th 2020",datePrePublished:"July 7th 2020",datePublished:"June 30th 2021",dateFinished:"June 22nd 2020",readingETA:"0",abstract:"Regulation of serum calcium in vertebrates is maintained by the actions of the parathyroid glands working in concert with vitamin D and critical target tissues that include the renal tubules, the small intestine, and bone cells. The parathyroid glands release parathyroid hormone (PTH) into the systemic circulation as is required in order to maintain the serum calcium concentration within a narrow physiologic range. Excessive secretion of PTH from one or more abnormal parathyroid glands however results in primary hyperparathyroidism (HPT), a metabolic disease typically associated with abnormally elevated serum calcium. Although HPT is typically a sporadic disease, it can represent a manifestation of an inherited syndrome. Many sporadic parathyroid tumors result from inactivating mutations in tumor suppressor genes that were first discovered by the analysis of genomic DNA from patients with HPT as part of an inherited syndrome. Somatic and inherited alterations in DNA encoding proto-oncogenes can also cause parathyroid neoplasia. Two promising future approaches for the discovery of novel genes pertinent to parathyroid tumor development are the analysis of acquired genetic alterations in DNA isolated from parathyroid tumors and the investigation of familial HPT in kindreds lacking germline mutation in the known genes predisposing to HPT.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72573",risUrl:"/chapter/ris/72573",signatures:"William F. Simonds",book:{id:"8935",type:"book",title:"Mineral Deficiencies",subtitle:"Electrolyte Disturbances, Genes, Diet and Disease Interface",fullTitle:"Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface",slug:"mineral-deficiencies-electrolyte-disturbances-genes-diet-and-disease-interface",publishedDate:"June 30th 2021",bookSignature:"Gyula Mózsik and Gonzalo Díaz-Soto",coverURL:"https://cdn.intechopen.com/books/images_new/8935.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83881-085-6",printIsbn:"978-1-83881-081-8",pdfIsbn:"978-1-83881-086-3",isAvailableForWebshopOrdering:!0,editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"320057",title:"Dr.",name:"William F.",middleName:null,surname:"Simonds",fullName:"William F. Simonds",slug:"william-f.-simonds",email:"bills@niddk.nih.gov",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The evolution of calcium regulation in vertebrates",level:"1"},{id:"sec_3",title:"3. The pathophysiology of primary hyperparathyroidism",level:"1"},{id:"sec_4",title:"4. Oncogenes and proto-oncogenes",level:"1"},{id:"sec_5",title:"5. The role of tumor suppressor genes in tumor development",level:"1"},{id:"sec_6",title:"6. Multiple endocrine neoplasia type 1 (MEN1)",level:"1"},{id:"sec_7",title:"7. The hyperparathyroidism-jaw tumor syndrome (HPT-JT)",level:"1"},{id:"sec_8",title:"8. Multiple endocrine neoplasia type 4 (MEN4)",level:"1"},{id:"sec_9",title:"9. Familial isolated hyperparathyroidism (FIHP)",level:"1"},{id:"sec_10",title:"10. Familial hypocalciuric hypercalcemia (FHH)",level:"1"},{id:"sec_11",title:"11. Multiple endocrine neoplasia type 2A (MEN2A)",level:"1"},{id:"sec_12",title:"12. Parathyroid tumorigenesis involving the CCND1 oncogene",level:"1"},{id:"sec_13",title:"13. Other genes involved in parathyroid tumorigenesis",level:"1"},{id:"sec_14",title:"14. Conclusions",level:"1"},{id:"sec_15",title:"Acknowledgments",level:"1"},{id:"sec_18",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Bilezikian JP. Primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2018;103(11):3993-4004'},{id:"B2",body:'Brauner-Osborne H, Wellendorph P, Jensen AA. Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Current Drug Targets. 2007;8(1):169-184'},{id:"B3",body:'Carafoli E, Krebs J. Why calcium? How calcium became the best communicator. Journal of Biological Chemistry. 2016;291(40):20849-20857'},{id:"B4",body:'Sanchez S, Tafforeau P, Ahlberg PE. 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by",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10475",title:"Smart Biofeedback",subtitle:"Perspectives and Applications",isOpenForSubmission:!1,hash:"8d2bd9997707c905959eaa41e55ba8f1",slug:"smart-biofeedback-perspectives-and-applications",bookSignature:"Edward Da-Yin Liao",coverURL:"https://cdn.intechopen.com/books/images_new/10475.jpg",editedByType:"Edited by",editors:[{id:"3875",title:"Dr.",name:"Edward Da-Yin",middleName:null,surname:"Liao",slug:"edward-da-yin-liao",fullName:"Edward Da-Yin Liao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8059",title:"Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice",subtitle:null,isOpenForSubmission:!1,hash:"8cc2c649900edf37ff3374fdc96a1586",slug:"neurostimulation-and-neuromodulation-in-contemporary-therapeutic-practice",bookSignature:"Denis Larrivee and Seyed Mansoor Rayegani",coverURL:"https://cdn.intechopen.com/books/images_new/8059.jpg",editedByType:"Edited by",editors:[{id:"206412",title:"Prof.",name:"Denis",middleName:null,surname:"Larrivee",slug:"denis-larrivee",fullName:"Denis Larrivee"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8851",title:"Advances in Neural Signal Processing",subtitle:null,isOpenForSubmission:!1,hash:"a44ac118b233b29a3d5b57d61680ec38",slug:"advances-in-neural-signal-processing",bookSignature:"Ramana Vinjamuri",coverURL:"https://cdn.intechopen.com/books/images_new/8851.jpg",editedByType:"Edited by",editors:[{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",slug:"ramana-vinjamuri",fullName:"Ramana Vinjamuri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8751",title:"Somatosensory and Motor Research",subtitle:null,isOpenForSubmission:!1,hash:"86191c18f06e524e0f97a5534fdb2b4c",slug:"somatosensory-and-motor-research",bookSignature:"Toshiaki Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/8751.jpg",editedByType:"Edited by",editors:[{id:"70872",title:"Prof.",name:"Toshiaki",middleName:null,surname:"Suzuki",slug:"toshiaki-suzuki",fullName:"Toshiaki Suzuki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9347",title:"Neuroimaging",subtitle:"Neurobiology, Multimodal and Network Applications",isOpenForSubmission:!1,hash:"a3479e76c6ac538aac76409c9efb7e41",slug:"neuroimaging-neurobiology-multimodal-and-network-applications",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9347.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8938",title:"Inhibitory Control Training",subtitle:"A Multidisciplinary Approach",isOpenForSubmission:!1,hash:"bd82354f3bba4af5421337cd42052f86",slug:"inhibitory-control-training-a-multidisciplinary-approach",bookSignature:"Sara Palermo and Massimo Bartoli",coverURL:"https://cdn.intechopen.com/books/images_new/8938.jpg",editedByType:"Edited by",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6998",title:"Synucleins",subtitle:"Biochemistry and Role in Diseases",isOpenForSubmission:!1,hash:"2b4b802fec508928ce8ab9deebd1375f",slug:"synucleins-biochemistry-and-role-in-diseases",bookSignature:"Andrei Surguchov",coverURL:"https://cdn.intechopen.com/books/images_new/6998.jpg",editedByType:"Edited by",editors:[{id:"266540",title:"Dr.",name:"Andrei",middleName:null,surname:"Surguchov",slug:"andrei-surguchov",fullName:"Andrei Surguchov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:65,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"46296",doi:"10.5772/57398",title:"Physiological Role of Amyloid Beta in Neural Cells: The Cellular Trophic Activity",slug:"physiological-role-of-amyloid-beta-in-neural-cells-the-cellular-trophic-activity",totalDownloads:5886,totalCrossrefCites:18,totalDimensionsCites:31,abstract:null,book:{id:"3846",slug:"neurochemistry",title:"Neurochemistry",fullTitle:"Neurochemistry"},signatures:"M. del C. Cárdenas-Aguayo, M. del C. Silva-Lucero, M. Cortes-Ortiz,\nB. Jiménez-Ramos, L. Gómez-Virgilio, G. Ramírez-Rodríguez, E. Vera-\nArroyo, R. Fiorentino-Pérez, U. García, J. Luna-Muñoz and M.A.\nMeraz-Ríos",authors:[{id:"42225",title:"Dr.",name:"Jose",middleName:null,surname:"Luna-Muñoz",slug:"jose-luna-munoz",fullName:"Jose Luna-Muñoz"},{id:"114746",title:"Dr.",name:"Marco",middleName:null,surname:"Meraz-Ríos",slug:"marco-meraz-rios",fullName:"Marco Meraz-Ríos"},{id:"169616",title:"Dr.",name:"Maria del Carmen",middleName:null,surname:"Cardenas-Aguayo",slug:"maria-del-carmen-cardenas-aguayo",fullName:"Maria del Carmen Cardenas-Aguayo"},{id:"169857",title:"Dr.",name:"Maria del Carmen",middleName:null,surname:"Silva-Lucero",slug:"maria-del-carmen-silva-lucero",fullName:"Maria del Carmen Silva-Lucero"},{id:"169858",title:"Dr.",name:"Maribel",middleName:null,surname:"Cortes-Ortiz",slug:"maribel-cortes-ortiz",fullName:"Maribel Cortes-Ortiz"},{id:"169859",title:"Dr.",name:"Berenice",middleName:null,surname:"Jimenez-Ramos",slug:"berenice-jimenez-ramos",fullName:"Berenice Jimenez-Ramos"},{id:"169860",title:"Dr.",name:"Laura",middleName:null,surname:"Gomez-Virgilio",slug:"laura-gomez-virgilio",fullName:"Laura Gomez-Virgilio"},{id:"169861",title:"Dr.",name:"Gerardo",middleName:null,surname:"Ramirez-Rodriguez",slug:"gerardo-ramirez-rodriguez",fullName:"Gerardo Ramirez-Rodriguez"},{id:"169862",title:"Dr.",name:"Eduardo",middleName:null,surname:"Vera-Arroyo",slug:"eduardo-vera-arroyo",fullName:"Eduardo Vera-Arroyo"},{id:"169863",title:"Dr.",name:"Rosana Sofia",middleName:null,surname:"Fiorentino-Perez",slug:"rosana-sofia-fiorentino-perez",fullName:"Rosana Sofia Fiorentino-Perez"},{id:"169864",title:"Dr.",name:"Ubaldo",middleName:null,surname:"Garcia",slug:"ubaldo-garcia",fullName:"Ubaldo Garcia"}]},{id:"58070",doi:"10.5772/intechopen.72427",title:"MRI Medical Image Denoising by Fundamental Filters",slug:"mri-medical-image-denoising-by-fundamental-filters",totalDownloads:2564,totalCrossrefCites:17,totalDimensionsCites:30,abstract:"Nowadays Medical imaging technique Magnetic Resonance Imaging (MRI) plays an important role in medical setting to form high standard images contained in the human brain. MRI is commonly used once treating brain, prostate cancers, ankle and foot. The Magnetic Resonance Imaging (MRI) images are usually liable to suffer from noises such as Gaussian noise, salt and pepper noise and speckle noise. So getting of brain image with accuracy is very extremely task. An accurate brain image is very necessary for further diagnosis process. During this chapter, a median filter algorithm will be modified. Gaussian noise and Salt and pepper noise will be added to MRI image. A proposed Median filter (MF), Adaptive Median filter (AMF) and Adaptive Wiener filter (AWF) will be implemented. The filters will be used to remove the additive noises present in the MRI images. The noise density will be added gradually to MRI image to compare performance of the filters evaluation. The performance of these filters will be compared exploitation the applied mathematics parameter Peak Signal-to-Noise Ratio (PSNR).",book:{id:"6144",slug:"high-resolution-neuroimaging-basic-physical-principles-and-clinical-applications",title:"High-Resolution Neuroimaging",fullTitle:"High-Resolution Neuroimaging - Basic Physical Principles and Clinical Applications"},signatures:"Hanafy M. Ali",authors:[{id:"213318",title:"Dr.",name:"Hanafy",middleName:"M.",surname:"Ali",slug:"hanafy-ali",fullName:"Hanafy Ali"}]},{id:"41589",doi:"10.5772/50323",title:"The Role of the Amygdala in Anxiety Disorders",slug:"the-role-of-the-amygdala-in-anxiety-disorders",totalDownloads:9671,totalCrossrefCites:4,totalDimensionsCites:28,abstract:null,book:{id:"2599",slug:"the-amygdala-a-discrete-multitasking-manager",title:"The Amygdala",fullTitle:"The Amygdala - A Discrete Multitasking Manager"},signatures:"Gina L. Forster, Andrew M. Novick, Jamie L. Scholl and Michael J. Watt",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"146553",title:"BSc.",name:"Andrew",middleName:null,surname:"Novick",slug:"andrew-novick",fullName:"Andrew Novick"},{id:"146554",title:"MSc.",name:"Jamie",middleName:null,surname:"Scholl",slug:"jamie-scholl",fullName:"Jamie Scholl"},{id:"146555",title:"Dr.",name:"Michael",middleName:null,surname:"Watt",slug:"michael-watt",fullName:"Michael Watt"}]},{id:"26258",doi:"10.5772/28300",title:"Excitotoxicity and Oxidative Stress in Acute Ischemic Stroke",slug:"excitotoxicity-and-oxidative-stress-in-acute-ischemic-stroke",totalDownloads:7157,totalCrossrefCites:6,totalDimensionsCites:25,abstract:null,book:{id:"931",slug:"acute-ischemic-stroke",title:"Acute Ischemic Stroke",fullTitle:"Acute Ischemic Stroke"},signatures:"Ramón Rama Bretón and Julio César García Rodríguez",authors:[{id:"73430",title:"Prof.",name:"Ramon",middleName:null,surname:"Rama",slug:"ramon-rama",fullName:"Ramon Rama"},{id:"124643",title:"Prof.",name:"Julio Cesar",middleName:null,surname:"García",slug:"julio-cesar-garcia",fullName:"Julio Cesar García"}]},{id:"62072",doi:"10.5772/intechopen.78695",title:"Brain-Computer Interface and Motor Imagery Training: The Role of Visual Feedback and Embodiment",slug:"brain-computer-interface-and-motor-imagery-training-the-role-of-visual-feedback-and-embodiment",totalDownloads:1439,totalCrossrefCites:13,totalDimensionsCites:23,abstract:"Controlling a brain-computer interface (BCI) is a difficult task that requires extensive training. Particularly in the case of motor imagery BCIs, users may need several training sessions before they learn how to generate desired brain activity and reach an acceptable performance. A typical training protocol for such BCIs includes execution of a motor imagery task by the user, followed by presentation of an extending bar or a moving object on a computer screen. In this chapter, we discuss the importance of a visual feedback that resembles human actions, the effect of human factors such as confidence and motivation, and the role of embodiment in the learning process of a motor imagery task. Our results from a series of experiments in which users BCI-operated a humanlike android robot confirm that realistic visual feedback can induce a sense of embodiment, which promotes a significant learning of the motor imagery task in a short amount of time. We review the impact of humanlike visual feedback in optimized modulation of brain activity by the BCI users.",book:{id:"6610",slug:"evolving-bci-therapy-engaging-brain-state-dynamics",title:"Evolving BCI Therapy",fullTitle:"Evolving BCI Therapy - Engaging Brain State Dynamics"},signatures:"Maryam Alimardani, Shuichi Nishio and Hiroshi Ishiguro",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"},{id:"231131",title:"Dr.",name:"Maryam",middleName:null,surname:"Alimardani",slug:"maryam-alimardani",fullName:"Maryam Alimardani"},{id:"231134",title:"Dr.",name:"Shuichi",middleName:null,surname:"Nishio",slug:"shuichi-nishio",fullName:"Shuichi Nishio"}]}],mostDownloadedChaptersLast30Days:[{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:192666,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. Vaccaro",authors:[{id:"91165",title:"Prof.",name:"Vafa",middleName:null,surname:"Rahimi-Movaghar",slug:"vafa-rahimi-movaghar",fullName:"Vafa Rahimi-Movaghar"}]},{id:"63258",title:"Anatomy and Function of the Hypothalamus",slug:"anatomy-and-function-of-the-hypothalamus",totalDownloads:4558,totalCrossrefCites:6,totalDimensionsCites:12,abstract:"The hypothalamus is a small but important area of the brain formed by various nucleus and nervous fibers. Through its neuronal connections, it is involved in many complex functions of the organism such as vegetative system control, homeostasis of the organism, thermoregulation, and also in adjusting the emotional behavior. The hypothalamus is involved in different daily activities like eating or drinking, in the control of the body’s temperature and energy maintenance, and in the process of memorizing. It also modulates the endocrine system through its connections with the pituitary gland. Precise anatomical description along with a correct characterization of the component structures is essential for understanding its functions.",book:{id:"6331",slug:"hypothalamus-in-health-and-diseases",title:"Hypothalamus in Health and Diseases",fullTitle:"Hypothalamus in Health and Diseases"},signatures:"Miana Gabriela Pop, Carmen Crivii and Iulian Opincariu",authors:null},{id:"57103",title:"GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets",slug:"gaba-and-glutamate-their-transmitter-role-in-the-cns-and-pancreatic-islets",totalDownloads:3478,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"Glutamate and gamma-aminobutyric acid (GABA) are the major neurotransmitters in the mammalian brain. Inhibitory GABA and excitatory glutamate work together to control many processes, including the brain’s overall level of excitation. The contributions of GABA and glutamate in extra-neuronal signaling are by far less widely recognized. In this chapter, we first discuss the role of both neurotransmitters during development, emphasizing the importance of the shift from excitatory to inhibitory GABAergic neurotransmission. The second part summarizes the biosynthesis and role of GABA and glutamate in neurotransmission in the mature brain, and major neurological disorders associated with glutamate and GABA receptors and GABA release mechanisms. The final part focuses on extra-neuronal glutamatergic and GABAergic signaling in pancreatic islets of Langerhans, and possible associations with type 1 diabetes mellitus.",book:{id:"6237",slug:"gaba-and-glutamate-new-developments-in-neurotransmission-research",title:"GABA And Glutamate",fullTitle:"GABA And Glutamate - New Developments In Neurotransmission Research"},signatures:"Christiane S. Hampe, Hiroshi Mitoma and Mario Manto",authors:[{id:"210220",title:"Prof.",name:"Christiane",middleName:null,surname:"Hampe",slug:"christiane-hampe",fullName:"Christiane Hampe"},{id:"210485",title:"Prof.",name:"Mario",middleName:null,surname:"Manto",slug:"mario-manto",fullName:"Mario Manto"},{id:"210486",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Mitoma",slug:"hiroshi-mitoma",fullName:"Hiroshi Mitoma"}]},{id:"35802",title:"Cross-Cultural/Linguistic Differences in the Prevalence of Developmental Dyslexia and the Hypothesis of Granularity and Transparency",slug:"cross-cultural-linguistic-differences-in-the-prevalence-of-developmental-dyslexia-and-the-hypothesis",totalDownloads:3601,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"673",slug:"dyslexia-a-comprehensive-and-international-approach",title:"Dyslexia",fullTitle:"Dyslexia - A Comprehensive and International Approach"},signatures:"Taeko N. Wydell",authors:[{id:"87489",title:"Prof.",name:"Taeko",middleName:"N.",surname:"Wydell",slug:"taeko-wydell",fullName:"Taeko Wydell"}]},{id:"58597",title:"Testosterone and Erectile Function: A Review of Evidence from Basic Research",slug:"testosterone-and-erectile-function-a-review-of-evidence-from-basic-research",totalDownloads:1331,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Androgens are essential for male physical activity and normal erectile function. Hence, age-related testosterone deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for erectile dysfunction (ED). This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function. Testosterone affects several organs and is especially active on the erectile tissue. The mechanism of testosterone deficiency effects on erectile function and the results of testosterone replacement therapy (TRT) have been well studied. Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.",book:{id:"5994",slug:"sex-hormones-in-neurodegenerative-processes-and-diseases",title:"Sex Hormones in Neurodegenerative Processes and Diseases",fullTitle:"Sex Hormones in Neurodegenerative Processes and Diseases"},signatures:"Tomoya Kataoka and Kazunori Kimura",authors:[{id:"219042",title:"Ph.D.",name:"Tomoya",middleName:null,surname:"Kataoka",slug:"tomoya-kataoka",fullName:"Tomoya Kataoka"},{id:"229066",title:"Prof.",name:"Kazunori",middleName:null,surname:"Kimura",slug:"kazunori-kimura",fullName:"Kazunori Kimura"}]}],onlineFirstChaptersFilter:{topicId:"18",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81646",title:"Cortical Plasticity under Ketamine: From Synapse to Map",slug:"cortical-plasticity-under-ketamine-from-synapse-to-map",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104787",abstract:"Sensory systems need to process signals in a highly dynamic way to efficiently respond to variations in the animal’s environment. For instance, several studies showed that the visual system is subject to neuroplasticity since the neurons’ firing changes according to stimulus properties. This dynamic information processing might be supported by a network reorganization. Since antidepressants influence neurotransmission, they can be used to explore synaptic plasticity sustaining cortical map reorganization. To this goal, we investigated in the primary visual cortex (V1 of mouse and cat), the impact of ketamine on neuroplasticity through changes in neuronal orientation selectivity and the functional connectivity between V1 cells, using cross correlation analyses. We found that ketamine affects cortical orientation selectivity and alters the functional connectivity within an assembly. These data clearly highlight the role of the antidepressant drugs in inducing or modeling short-term plasticity in V1 which suggests that cortical processing is optimized and adapted to the properties of the stimulus.",book:{id:"11374",title:"Sensory Nervous System - Computational Neuroimaging Investigations of Topographical Organization in Human Sensory Cortex",coverURL:"https://cdn.intechopen.com/books/images_new/11374.jpg"},signatures:"Ouelhazi Afef, Rudy Lussiez and Molotchnikoff Stephane"},{id:"81582",title:"The Role of Cognitive Reserve in Executive Functioning and Its Relationship to Cognitive Decline and Dementia",slug:"the-role-of-cognitive-reserve-in-executive-functioning-and-its-relationship-to-cognitive-decline-and",totalDownloads:23,totalDimensionsCites:0,doi:"10.5772/intechopen.104646",abstract:"In this chapter, we explore how cognitive reserve is implicated in coping with the negative consequences of brain pathology and age-related cognitive decline. Individual differences in cognitive performance are based on different brain mechanisms (neural reserve and neural compensation), and reflect, among others, the effect of education, occupational attainment, leisure activities, and social involvement. These cognitive reserve proxies have been extensively associated with efficient executive functioning. We discuss and focus particularly on the compensation mechanisms related to the frontal lobe and its protective role, in maintaining cognitive performance in old age or even mitigating the clinical expression of dementia.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Gabriela Álvares-Pereira, Carolina Maruta and Maria Vânia Silva-Nunes"},{id:"81488",title:"Aggression and Sexual Behavior: Overlapping or Distinct Roles of 5-HT1A and 5-HT1B Receptors",slug:"aggression-and-sexual-behavior-overlapping-or-distinct-roles-of-5-ht1a-and-5-ht1b-receptors",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.104872",abstract:"Distinct brain mechanisms for male aggressive and sexual behavior are present in mammalian species, including man. However, recent evidence suggests a strong connection and even overlap in the central nervous system (CNS) circuitry involved in aggressive and sexual behavior. The serotonergic system in the CNS is strongly involved in male aggressive and sexual behavior. In particular, 5-HT1A and 5-HT1B receptors seem to play a critical role in the modulation of these behaviors. The present chapter focuses on the effects of 5-HT1A- and 5-HT1B-receptor ligands in male rodent aggression and sexual behavior. Results indicate that 5-HT1B-heteroreceptors play a critical role in the modulation of male offensive behavior, although a definite role of 5-HT1A-auto- or heteroreceptors cannot be ruled out. 5-HT1A receptors are clearly involved in male sexual behavior, although it has to be yet unraveled whether 5-HT1A-auto- or heteroreceptors are important. Although several key nodes in the complex circuitry of aggression and sexual behavior are known, in particular in the medial hypothalamus, a clear link or connection to these critical structures and the serotonergic key receptors is yet to be determined. This information is urgently needed to detect and develop new selective anti-aggressive (serenic) and pro-sexual drugs for human applications.",book:{id:"10195",title:"Serotonin and the CNS - New Developments in Pharmacology and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg"},signatures:"Berend Olivier and Jocelien D.A. Olivier"},{id:"81093",title:"Prehospital and Emergency Room Airway Management in Traumatic Brain Injury",slug:"prehospital-and-emergency-room-airway-management-in-traumatic-brain-injury",totalDownloads:49,totalDimensionsCites:0,doi:"10.5772/intechopen.104173",abstract:"Airway management in trauma is critical and may impact patient outcomes. Particularly in traumatic brain injury (TBI), depressed level of consciousness may be associated with compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. This chapter will address the indications and optimal method of securing the airway, prehospital and in the ER, in patients with traumatic brain injury.",book:{id:"11367",title:"Traumatic Brain Injury",coverURL:"https://cdn.intechopen.com/books/images_new/11367.jpg"},signatures:"Dominik A. Jakob, Jean-Cyrille Pitteloud and Demetrios Demetriades"},{id:"81011",title:"Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition as a Background for Future Clinical Applications",slug:"amino-acids-as-neurotransmitters-the-balance-between-excitation-and-inhibition-as-a-background-for-f",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.103760",abstract:"For more than 30 years, amino acids have been well-known (and essential) participants in neurotransmission. They act as both neuromediators and metabolites in nervous tissue. Glycine and glutamic acid (glutamate) are prominent examples. These amino acids are agonists of inhibitory and excitatory membrane receptors, respectively. Moreover, they play essential roles in metabolic pathways and energy transformation in neurons and astrocytes. Despite their obvious effects on the brain, their potential role in therapeutic methods remains uncertain in clinical practice. In the current chapter, a comparison of the crosstalk between these two systems, which are responsible for excitation and inhibition in neurons, is presented. The interactions are discussed at the metabolic, receptor, and transport levels. Reaction-diffusion and a convectional flow into the interstitial fluid create a balanced distribution of glycine and glutamate. Indeed, the neurons’ final physiological state is a result of a balance between the excitatory and inhibitory influences. However, changes to the glycine and/or glutamate pools under pathological conditions can alter the state of nervous tissue. Thus, new therapies for various diseases may be developed on the basis of amino acid medication.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Yaroslav R. Nartsissov"},{id:"80821",title:"Neuroimmunology and Neurological Manifestations of COVID-19",slug:"neuroimmunology-and-neurological-manifestations-of-covid-19",totalDownloads:41,totalDimensionsCites:0,doi:"10.5772/intechopen.103026",abstract:"Infection with SARS-CoV-2 is causing coronavirus disease in 2019 (COVID-19). Besides respiratory symptoms due to an attack on the broncho-alveolar system, COVID-19, among others, can be accompanied by neurological symptoms because of the affection of the nervous system. These can be caused by intrusion by SARS-CoV-2 of the central nervous system (CNS) and peripheral nervous system (PNS) and direct infection of local cells. In addition, neurological deterioration mediated by molecular mimicry to virus antigens or bystander activation in the context of immunological anti-virus defense can lead to tissue damage in the CNS and PNS. In addition, cytokine storm caused by SARS-CoV-2 infection in COVID-19 can lead to nervous system related symptoms. Endotheliitis of CNS vessels can lead to vessel occlusion and stroke. COVID-19 can also result in cerebral hemorrhage and sinus thrombosis possibly related to changes in clotting behavior. Vaccination is most important to prevent COVID-19 in the nervous system. There are symptomatic or/and curative therapeutic approaches to combat COVID-19 related nervous system damage that are partly still under study.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Robert Weissert"}],onlineFirstChaptersTotal:17},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"May 23rd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. 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