General and differential compositional-cum-functional physiology of bioactive components of milk from different animals.
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\r\n\tComputer graphics are not entirely an original topic, because it defines and solves problems using some already established techniques such as geometry, algebra, optics, and psychology. The geometry provides a framework for describing 2D and 3D space, while the algebraic methods are used for defining and evaluating equality related to the specific space. The science of optics enables the application of the model for the description of the behavior of light, while psychology provides models for visualization and color perception.
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\r\n\t3D computer graphics (or 3D graphics, three-dimensional computer graphics, three-dimensional graphics) is a term describing the different methods of creating and displaying three-dimensional objects by using computer graphics.
\r\n\tThe first types of graphic interpretations were put in the plane (two-dimensional 2D). Requirements for a universal interpretation led to a three-dimensional (3D) interpretation content. From these creations have arisen applied mathematics and information disciplines of graphic interpretation of content - computer graphics. It relies on the principles of Mathematics, Descriptive Geometry, Computer Science and Applied Electronics.
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\r\n\t3D computer graphics or three-dimensional computer graphics use a three-dimensional representation of geometric data (often in terms of the Cartesian coordinate system) that is stored on a computer for the purpose of doing the calculation and creating 2D images. The images that are made can be stored for later use (probably as animation) or can be displayed in real-time.
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\r\n\tObjects within the 3D computer graphics are often called 3D models. Unlike rendered (generated) images, data that are ""tied"" to the model are inside graphic files. The 3D model is a mathematical representation of a random three-dimensional object. The model can be displayed visually as a two-dimensional image through a process called 3D rendering or can be used in non-graphical computer simulations and calculations. With 3D printing, models can be presented in real physical form.
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\r\n\tComputer graphics have remained one of the most interesting areas of modern technology, and it is the area that progresses the fastest. It has become an integral part of both application software, and computer systems in general. Computer graphics is routinely applied in the design of many products, simulators for training, production of music videos and television commercials, in movies, in data analysis, in scientific studies, in medical procedures, and in many other fields.
Milk, according to USDA, is a sterile lacteal secretion from mammary glands by full milking of one or more animals and considered free of colostrum. Basically, milk is composed of significant components that may be categorized into macro and micro milk components. The former category is comprised of protein, lipids, and oligosaccharides mainly lactose, whereas the latter contains minerals and vitamins [1]. Utilization of milk from various species of animals depends upon likelihood of people and access to the dairy animals. In such situations, some of dairy animals are overlooked due to their limited population in specific regions of the world. Camel and caprine milk is specifically medicinal in nature that is limitedly utilized as staple use. The production systems are fewer than needed which is a grave situation. It is a dire need to explore bioactive components of milk from various animals and to investigate alternative resources to feed the hungry and to be benefited by pharmacological aspects.
\nThe likelihood of food consumption stresses it to be natural, free from chemical preservatives, and microbiologically safe with extended shelf life [2]. The rapid development of our society in the past few decades and the careless use of large amount of agricultural services are appearing to be a burden over human health. The hunger of the increasing population cannot be satisfied with fresh milk due to unequal production and utilization system. Previous 15 years have noticed dairy industry emerging as technology revolution in product processing [3]. But there are several harms to the soundness of milk associated with processing techniques in terms of quality and quantity losses. The current chapter encompasses bioactive components of milk from different milk-producing animals and their chances of being deteriorated by processing techniques.
\nBovine milk as whole milk and its products are serving an easy way of achieving good nutrition. Bovine milk contains the nutrients needed for growth and development of the calf and is a resource of lipids, proteins, amino acids, vitamins, and minerals. The milk is also blessed with many substances like hormones, growth factors, immunoglobulins, peptides, cytokines, polyamines, bioactive peptides, and many enzymes that play different roles in our body [4]. Milk composition has dynamic properties and its composition varies depending on lactation, diet, age, breed, energy balance, and udder health. Colostrum is very different from milk, but the most important difference is the concentration of milk protein. It will be twice in colostrum compared with milk in late lactation. Lipids in bovine milk are suspended or emulsified in the form of fat globules covered with membranes. Lipids are mainly composed of different types of fatty acids having different fraction. Milk contains about 32 g of protein per liter. Milk protein is a good source of essential amino acids. In addition, milk contains various biologically active proteins, ranging from antimicrobial drugs and ending with nutritionally enriched proteins, as well as growth factors, hormones, enzymes, antibodies, and immune-stimulants. Nitrogen in milk is distributed in casein, serum, and nonprotein nitrogen. The content of casein in milk is about 80% of milk protein. Whey protein is a globular protein that is more soluble in water than casein. The main components are β-lacto globulin, α-lactalbumin, bovine serum albumin, and immunoglobulin. Milk also contains many minerals, vitamins, and antioxidants. Antioxidants prevent the oxidation of milk and also provide protection to cells which involve in milk production and to udder also. The most important antioxidants in milk are mineral selenium and vitamins E and A [5]. However, cow milk (CM) differs from buffalo milk (BM) composition of different milk bioactive components. Buffalo milk has lower cholesterol but more calories and fat compared with cow’s milk. Cow milk has higher cholesterol level than BM, but higher fat contents are present in BM with higher calorie percentage. Buffalo milk has a higher content of fat, lactose, casein, whey proteins, and minerals than cow milk. All of the casein in buffalo milk is present in the micellar form, while in the CM, only 90–95% of the casein is in the micellar state and the rest is present in serum phase. The calcium content is higher in BM than in milk from cow, and it contains more colloidal calcium and phosphorus. The BM is richer in fat than milk from cattle, and absence of b-carotene in BM, which is present in CM, is another notable characteristic [6].
\nCamel is a blessing from God as narrated in Muslim’s Holy Quran [7]. The total population of camels in the world accounts 23.9 million. Among the countries, India has 1.9% population of camels over the total world camel population [8]. They are playing a crucial part in the lifestyle of numerous communities, especially those living in arid regions of the Middle East and the Arabian region since many centuries [9]. Total CM production is 1.3 × 106 tons [10], and the annual trade volume in the world is $ 10 billion which is expected to be increased in the near future [11]. Among various types of camels such as Bactrian camel (two humped), dromedary camel (single humped), wild Bactrian (true camels), plus llama, alpaca, guanaco, and vicuna camels [12], the dromedary camel is a resident of desert and dry land environment and accounts 94% of the total world population [13]. Camel milk being a good source of fats occupies opaque white color having salty taste due to high vitamin C content and good odor [14]. The overall constituents of camel milk account 3.4% protein, 3.5% fat, 4.4% lactose, 0.79% ash, and 87% water [15]. Mineral contents are important enriching constituents of milk which in the case of camel accounts for 0.60–1.0% [16] vis-a-vis Ca, P, Mg, Fe, Na, Zn, K, and Cu [17]. Many vitamins like A, C, D, E, and B groups are present in dromedary species of camel. High amount of vitamin C, fatty acids, and fructose and lack of beta-lactoglobulin are the most significant health promoting properties [18].
\nGoats were first domesticated by ancient peoples in the Middle East 10,000 years ago [19]. Goat farming has been increased from 751.63 million (year 2000) to 1006.79 million (year 2016) and is being ranked third after cattle and sheep in total population of animals in all over the world according to FAO [20]. However according to the Economic Survey of Pakistan, goat population has been also increased from 70.3 to 72.2 million in Pakistan [21]. The salient differential bioactive components account for total solids (13.20%), fat content (4.50%), oligosaccharides especially lactose (4.3%), protein contents (3.60%), minerals (0.80%), and vitamins [22].
\nHorses can live in many different environments and develop in different ways. The first ancestor of Hyracotherium lived about 60 million years ago. They have four toes on the front paw and three toes on their hind legs [23]. Currently, there are hundreds of breeds of equine present all over the world. However, dairy breeds are predominately found in Mongolia and USSR. Among the dairy breeds, Haflinger horses are the most important milk breed of adults weighing 500 kg, known for their milk production capacities in European countries. [24]. The lactation of mare starts almost 7 days after birth and lasts almost up to 5–8 months of foal age [25]. Due to small mammary gland, mare requires multiple milking (5–7/day) with 2–3 hour intervals [26]. However, the gross milk composition of different breeds varies with an average of fat (1.25%), protein (2.15%), lactose (6.40%), and small amount of minerals 0.4% [25].
\nUnlike caprine and bovine milk, sheep milk is rich in total solids and major milk contents that supply energy. Ovine milk is highly enriched in bioactive components such as lipids, proteins, oligosaccharides, minerals, and vitamin contents (Table 1) [27].
\nBioactive name | \nSpecies name | \nGeneral characters/functions | \nGeneral composition | \nDifferential composition (%) | \nDifferential functions | \n
---|---|---|---|---|---|
Lipids | \nBuffalo | \nAnti-cancer, antiviral, antibacterial, anti-plaque, anticaries, anti-inflammatory, anti-atherogenic, antihypertensive, prevent CHD [32, 35] | \nTriglycerides 98% (SFA, USFA, SCFA, MCFA, LCFA), CLA [5] Fat globule membrane 1–2% (diglycerides, monogly-cerides, phospholipids, sterols, FFA), peptides [5] | \nFat (8.30%) [28] >50% SFA | \nIncreases HDL and cholesterol level due to high SFA | \n
Cow | \nFat (4.88%) [28] CLA (15 mg/100 mL) [33] FG > 5 μm [33] | \n\n | |||
Caprine | \nFat (3.84%) [28] High MCFA, SCFA, and CLA (35 mg/100 mL) [22] FG < 5 μm [33] | \nReduce cholesterol and LDL, rapidly digested, anti-obesity, treatment of malabsorption patients [22] | \n|||
Ovine | \n7.1% [43] | \nAnti-atherogenic, decrease LDL cholesterol [39] | \n|||
\n | \n | \n | High caproic, caprylic, and capric acids [37] and low butyric acid [38], high oleic acid [39] FG < 3 μm [34] | \n\n | |
Camel | \n3.5% [36] | \n\n | |||
Mare | \n\n | Low triglycerides (80%) High phospholipids (5%) and FFA (9%) [25] | \n1.25% [25] FG = 2–3 μm [25] High level of MCFA, higher contents of LA and ALA [25] | \n\n | |
Proteins | \nBuffalo | \nIron carrier, lactose synthesis, retinol binding activity, immunomodulator, anticarcinogenic, antioxidant, antimicrobial, anti- inflammatory | \nCaseins 80% (αs-1, αs-2, β,k) Whey proteins 20% (α-La, β-Lg, Ig, LF, Lyz, growth factors) [40] | \n4.48% [28] | \n\n |
Cow | \n3.49% [28] | \n\n | |||
Caprine | \n3.42% Low αs1 casein, high lactoferrin [33] | \nLow αs1 casein helps easily tolerated by Childs, treatment of CMA, increased iron absorption [33] | \n|||
Ovine | \nAntihypertensive, antitumor, ACE inhibitory activity [41, 42] | \n\n | 5.7% [43] | \n\n | |
Camel | \n3.4% [15, 18] High whey proteins (high Ig, lactoferrin, lysozyme), no β-Lg, high PGRP [15, 18] | \nAnti-cancerous activity especially breast cancer, antidiabetic, treatment of autoimmune diseases [15, 18] | \n|||
Mare | \n\n | Caseins 50% (αs1, αs2, β, k), whey proteins 39% (less β-Lg, more α-La & Ig) [25] | \n2.15% [25] High β-casein (50%), low kappa casein, αs1 and αs2 (40%), also high gamma casein (10%) [29] High lactoferrin (>10 times) [30] | \nRich source of essential AA and source of nutrition, easily digestible due to high whey proteins | \n|
Carbohydrates | \nBuffalo | \nProbiotic, antioxidant, anti-inflammatory, Help in calcium | \nLactose (lactulose, lactitol, lactobionic acid, galacto) | \nLactose (4.86%) [28] | \n\n |
Cow | \n4.47% [28] | \n\n | |||
Caprine | \nTransport and absorption, beneficial bacteria growth promoter, source of fiber, treat constipation [31] | \nOligosa-ccharides (galactose, glucose, NANA) [44] | \nLactose (4.11%) [28] High amount of oligosaccharides (>10 times than cow) | \nPrebiotic | \n|
Ovine | \n4.6% [43] | \n\n | |||
Camel | \n4.4% [15, 18] High lactose | \n\n | |||
Mare | \n\n | \n | 6.40% [25] | \n\n | |
Minerals | \nBuffalo | \nStrengthening bones, avoid osteoporosis, antioxidant, antihypertensive, DNA synthesis and repair, anti-cancerous, immunomodulatory, avoid | \nHigh Ca, P, K, and Na and trace Mg, Zn, Fe, Cu, and Se [45, 46] | \n0.81% [28] | \n\n |
Cow | \n0.76% [28] | \n\n | |||
Caprine | \n0.89% [28] High selenium [45, 46] | \nComponent of complement system, formation of interleukins by T cells [45, 46] | \n|||
Ovine | \n0.9% [43] | \n\n | |||
\n | Camel | \nasthma, maintain fluid integrity [45, 46] | \n\n | 0.79% [15, 18] High chloride, low citrate, high Zn, Cu, Fe, and Mn [47] | \nHigh iron helps in oxygen transport, component of ETC [47] | \n
\n | Mare | \n\n | \n | 0.4% [25] | \n\n |
Vitamins | \nBuffalo | \nSource of nutrition, antioxidant, anti-cancerous, anti-inflammatory, protect from osteoporosis, atherosclerosis [47, 48] | \nFat soluble (A, D, E, K), water soluble (B complex) [47, 48] | \nHigh riboflavin, folic acid, B6, vitamin A | \nImmunity enhancer, treatment of CHD, prevention of megaloblastic anemia, role in morphogenesis [45, 46] | \n
Cow | \nHigh folate and vitamin B12 [45, 46] | \nHelp in synthesis of hemoglobin [45, 46] | \n|||
Caprine | \nHigh niacin, vitamin B3, vitamin A [49] | \nAnti-cancerous activity [49] | \n|||
Ovine | \n\n | \n | |||
\n | Camel | \n\n | \n | High vitamin C and niacin, low vitamin A, low vitamin E [47, 48] | \nAntidiabetic, antioxidant, wound healing [47, 48] | \n
\n | Mare | \n\n | \n | High vitamins A, D3, and K3 [25] | \n\n |
General and differential compositional-cum-functional physiology of bioactive components of milk from different animals.
SFA = saturated fatty acids; USFA = unsaturated fatty acids; SCFA = short-chain fatty acids; MCFA = medium-chain fatty acids; LCFA = long-chain fatty acids; FFA = free fatty acids; HDL = high-density lipids; LDL = low-density lipids; FG = fat globule; α-La = alpha lactalbumin; β-Lg = β-lactoglobulin; Ig = immunoglobulin; LF = lactoferrin; Lyz = lysozyme; A.A = amino acid; LA = linoleic acid; ALA = alpha linolenic acid; CLA = conjugated linoleic acid; ETC = electron transport chain; CMA = cow milk allergy; ACE = angiotensin-converting enzyme; CHD = congenital heart defect; PGRP = peptidoglycan recognition proteins; NANA = N-acetylneuraminic acid.
Rapid development of our society in the past few decades and careless use of large amount of agricultural services are appearing to be a burden over human health [3]. The hunger of the increasing population cannot be satisfied with fresh milk due to unequal production and utilization system. In the past 15 years, the dairy industry has evolved with newer techniques of production, products, and processing [3]. But there are several harms to the soundness of milk associated with processing techniques in terms of quality and quantity losses.
\nDiseases associated with the consumption of milk are common due to microbial contamination. To keep milk safe from such microbial contaminants, primarily large-scale techniques (like pasteurization) are adopted to every milk production system. For this purpose, collected milk from dairy farms is sent to a reservoir of processing units for processing, where a large amount of milk is stored [50]. Transportation of milk in such a way may cause a source of spreading viruses and bacteria. That milk is usually pasteurized and assuming that heat treatment has demolished appropriately [51]. However, some bacteria remain intact due to microbial biofilm within the distribution line and unhygienic behavior of employees [52]. While repeated or prolonged heat treatment causes protein denaturation and binding of denatured whey protein with casein micelles leads to migration of soluble calcium and phosphate to the colloidal stage and mollify of the enzymes. Research shows that the available amount of lysine, iodine, folate, and vitamins B12, C, B6, and B1 in milk decreases after pasteurization [53]. Heat treatment reduces α-la (α-lactalbumin) and PGRP (peptidoglycan recognition protein) in the case of camel milk [54]. Extreme pH, removal of bound Ca2+, addition of denaturant agents, or cleavage of disulfide bridges can denature α-lactalbumin in several ways [55]. Among vitamins, vitamin C is the most important that can be quickly destroyed when milk is heated [56].
\nTreatment at elevated temperatures reduces the quality of milk supply, as many nutrients are thermally unstable [2]. The second most parameter is aroma of dairy products, which critically affects consumer acceptance, shelf life, and other attributes. When thermal treatment is employed to reduce or destroy the microbial load and enzyme activity to ensure safety and to increase shelf life, the aroma of the milk changes and differs from that of raw milk [57]. Ultra-pasteurization (UP) and ultra-high temperature (UHT), high temperature/short time (HTST), DSI-UP, or IND-UP are widely used thermal treatments for extended shelf life of milk. These processing techniques affect color due to various reactions during thermal processing or storage. These key changes in flavor during thermal processing of milk are associated with Maillard reactions [58].
\nThe contents of flavored milk are sweeteners such as natural sugar, sucrose, fructose, glucose syrup, or a sweetener without calories depending upon the manufacturer and the consumer demand [59]. As a result of heat treatment, the basic constituents like proteins, carbohydrates, and vitamins of flavored milk undergo chemical and biochemical modifications [60]. Some of these modifications include lactulose and acid formation through lactose degradation. It promotes dehydroalanine development by side chains of amino acids through β-elimination. It is a compound that reacts readily with lysine yielding lysinoalanine and the denaturing of whey proteins [61].
\nA multistage processing technique (like skim milk development) involves wide use of heat treatment for milk preservation [62]. The formation of Maillard intermediates and glycation products during manufacture of dairy products has been studied [63]; the focus of these studies was the reduction in nutritional values, e.g., lysin [64].
\nIn the dairy industry, it is known to use a closed production system without removing or opening equipment using the CIP process. In terms of economic benefits, short cleaning procedures and long-term use of equipment in processing lines are common [65]. As a result, bacteria remain on the surface of the device and can accumulate in hard-to-reach places, such as dead ends, cracks, seals, and valves, where the complexity of cleaning and disinfection is difficult [66]. Undesirable biofilms on the surfaces of food processing have certain properties, such as increased tolerance to antimicrobial agents, increased secondary metabolites, etc. These are the potential cause of bacterial contamination [67]. In dairy industry, the presence of such biofilms leads to contamination after processing, shortens the shelf life, and promotes the transmission of diseases [68].
\nThe existence of spore-forming bacteria in milk is a critically important issue in the dairy industry. Bacterial endospores can survive in harsh environmental conditions such as high heat, low pH, desiccation, or cleaning and sanitizing chemicals [69]. Compared with vegetative cells, spores have also been found to attach more readily to stainless steel, leading to the formation of biofilms that can promote bacterial contamination within dairy processing plants. Spores present in final products can germinate and produce enzymes that decrease the quality and shelf life of dairy product; it causes the significant economic losses [70]. Additionally, some spore formers such as Bacillus cereus and Bacillus subtilis can produce toxins that are responsible for food poisoning [71]. Thermophilic geobacillus spp. and Anoxybacillus spp. are other spore formers of importance to the dairy industry, as they are commonly present in dairy powders and evaporated milk [70].
\nThe milk quality is influenced by many factors acting together and influences each other [72]. One of the most important factors is disease that adversely affects livestock systems that leads to decrease in yield, income, and survival of livelihood. The impact of livestock diseases is complicated and often exceeds the impact on the respective producers [73]. Selection of dairy animals, nutritional management, advances in milking technology, and mammary gland of the dairy animals are the other factors that are also associated with milk yield as well as its composition [74].
\nUnadulterated high-quality milk that is free of antimicrobial residues is the most appropriate choice to farmers, consumers, and milk processing companies. Such milk enables the farmers to get a fair price [75]. Antibiotics are widely used in livestock production for therapeutics, growth promoters, and prophylactics since many years [76]. Such antimicrobial drugs affect the antibiotic-sensitive bacteria that involves in many fermentation processes. So, the presence of these antimicrobial drugs may affect the dairy products. This results in damage to the sensory properties and coagulation or ripening of the dairy products [77]. If the sale of raw milk is considered “unsuitable for consumption,” due to the presence of antibiotics, transmission of milk may lead to ban by competent authorities. Costs of storage and subsequent disposal are the duties of farmers. So, farmers must incur large economic losses [78].
\nPackaging is an integrated technology that includes protection, ease of use, and communication. To protect the product, it is important to select and design the appropriate packaging materials [79]. Antimicrobial coatings are increasingly being used as a means of prolonging the shelf life of dairy products. This expansion helps consumers to reduce the amount of household waste milk [80]. The quality of the packaged milk depends on the internal properties of milk (oxidation-reduction potential, respiration rate, water activity, chemical structure, etc.) and the external factors (ambient composition, withholding temperature, relative humidity, etc.) [81]. Use of polymeric coating for maintaining the quality of milk is not possible due to many factors’ involvement like design and development. Moreover, coating contributes to thermal and gas related mechanical properties due to its unique chemical structure [82]. But, due to the high cost of this process, small industries are unable to adopt it [83].
\nDisease has a lot of impact, including a decline in productivity in livestock [84]. High infectious animal diseases, such as foot-and-mouth disease (FMD), hemorrhagic septicemia (HS), mastitis, peste des petits ruminant (PPR), and surra, cause irreparable economic losses for agricultural communities [85]. Ketosis is one of the diseases that causes lower milk production and an increased risk for developing other metabolic and infectious diseases which further affect milk properties [86]. There are many other factors especially environmental which affects production and properties of milk [87]. Mastitis is considered the most frequent health disorder in dairy farms. Decrease in milk components is one of the major origins of these economic losses both for clinical and subclinical infections [88]. These milk components are used as indicators of the metabolic status of cattle. The most relevant parameters of milk explain the balance of energy, protein, mineral, and acid-base balance and their standard concentrations and trends associated with various types of metabolic disorders. A comprehensive result of changes in the composition of milk can be used to identify early health problems. These changes in composition may help in protective cure of diseases [73].
\nDairy products are an important part of the human diet for more than 8000 years and are one of the official dietary recommendations for many countries in the world [89]. Daily intake of milk and dairy products has been identified as an important part of a balanced diet [90], because milk serves as a whole range nutrient consumed by humans (Figure 1).
\nGross milk production of different milk-producing species [21].
Recently, this technology has become widespread. The XRF method makes it possible to carry out analyses without sample separation. It helps in the quantification of minerals, trace elements, and volatiles which are difficult to determine in other analytical methods [92]. X-ray fluorescence spectroscopy (XRF) is an extension of the milk component analysis domain. Various configurations of XRF spectrometers are commercially available and are designed to provide economical and rapid analysis of milk. XRF is an excellent tool for daily analysis of the milk in dairy industries and research institutes. The results of the analysis can be used to assess nutritional value and evaluate the milk and dairy products [93].
\nIn this method, different types of milk quantity samples are used to classify several classes using reduction techniques in combination with random forest classifiers (RF). Quantitative and experimental analyses are based on locally collected milk samples from various species, including cow, buffalo, goat, and human milk samples. This classification is based on changes in the intensity of Raman peaks in a milk sample. The analysis of principal components (PCA) was used as a reduction technology in combination with RF to emphasize changes in Raman spectra that can differentiate milk samples from different species. The proposed method shows a sufficient opportunity to distinguish samples of cow milk from different species due to an average accuracy of about 94%, a specificity of about 97%, and a sensitivity of about 93% [94].
\nMastitis is mostly caused by bacterial pathogens invading the mammary gland. Typical pathogens, namely, Escherichia coli, a gram-negative bacterium usually associated with acute, clinical mastitis, and Staphylococcus aureus, a gram-positive bacterium often associated with chronic mastitis, can cause differential activation of the immune system [95]. Somatic cell count (SCC) is used as key indicator in mastitis screening programs typically applied in the frame of dairy herd improvement (DHI) testing programs [96]. Direct microscopic somatic cell count (DMSCC) is one of the approved methods by FDA (Foss, Hillerød, Denmark). Flow cytometry and Ekomilk Scan® are also used to check the somatic cell count (Figures 2 and 3) [97].
\nGeneral composition of milk from different dairy animals [91].
Comparison of the somatic cell score (SCS) using different methods.
The technique, invented in 1957 by Schalm and Noorlander, is used to detect intramammary infection caused by a major mastitis pathogen in early lactation cows [98]. They indicated that the degree of precipitation and gel formed by a mixture of the reagent and milk reflected the somatic cell count of the milk (Figure 4) [99].
\nSensitivity and specificity within first week of calving through CMT [100].
Early detection of mastitis and related pathogenic factors improves animal health status through timely and effective treatment. With the development of related technologies of proteomics, such as 2D-gel electrophoresis (2D-GE) and mass spectrometry (MS), several new proteins associated with mastitis have been identified [101]. The evolution of proteomic profiles of pathogens can help to identify the existing information on enzymes, toxins, and metabolites. However, the successful use of these new biomarkers for detection devices remains a challenge [102].
\nFat is higher in bovine specie as compared to others and it is the main source of HDL and cholesterol enhancement in blood. Protein of ovine is higher than other milk-producing animals. Protein from camel milk (lactoferrin, immunoglobulin, lysozyme) is very useful in diabetes, cancer, and autoimmune diseases. High selenium found in caprine milk fortifies immune system, while higher contents of zinc, iron, and manganese in camel milk speak of greater oxygen carrying capacity by helping ion transport exchange. Higher riboflavin, folic acid, B6, and vitamin A in buffalo milk are blessings to enhance immunity and decrease of megaloblastic anemia. Antidiabetic, antioxidant, high vitamin C and niacin, low vitamin A and E are more defined properties that refer as wound healer agent. Heat treatment protocols result in denaturation of lysine, iodine, folate, and vitamins B12, B6, B1, and C, inactivation of enzymes, and change in flavor. Skim milk production often favors increase in biofilm resistance and spread of presence of spore-forming bacteria. Adding to this are the diseases or disease conditions exacerbating compromised soundness of milk. Preclinical studies are effective approaches to avoid deterioration of milk. X-ray fluorescence analysis is effective in evaluation of nutritive values of milk and milk products without decomposition of milk. Raman spectroscopy-based analysis successfully differentiate between milk of different species with higher sensitivity and specificity. Somatic cell count and California mastitis tests are fruitful in estimation of intramammary infection. Latest techniques like proteomic protocols are explorable approaches as an effective preclinical study of milk.
\nAuthors declare no conflict of interest.
The journey of exploring acid and base starts long before, but in the last century the advancement was remarkable. In 1890, Wilhelm Ostwald electronically measured hydrogen [1]. Svante Arrhenius won the Noble prize in 1903 for the theory of ionization [2]. In 1908, Henderson and Black showed that bicarbonate and phosphate equilibrated with CO2 at normal body temperature in different solution [3]. In 1923, Bronsted first put forward the idea of acid as a substance that ionizes in solution and donate hydrogen and the base accepts the hydrogen from the solution [4]. Bronsted, Henderson and Van Slyke described acid-base balance in the early part of nineteenth century [5]. Handerson invented bicarbonate as the most important buffer system of the body, and Hasselbalch first measured the real blood pH in the early part of nineteenth century [6, 7, 8]. In 1909, S. P. S. Sorensen developed the pH scale [8]. Later Hasselbalch-Henderson developed an equation that helped in relating pH to the blood bicarbonate and PCO2 [7, 9, 10]. In the early 1980s, scientists introduced electrodes specific for each ion. Thereafter, serum electrolyte and the anion gap measurement become routine tools for assessing acidosis.
Acidosis has fatal consequences like CNS damage. Even death is not uncommon. Acidosis is characterized by a decrease in pH, and this change is rapidly corrected by the body buffer systems. Many clinical conditions develop acidosis, as well as ionic derangements and the only correction of the underlying cause can resolve it. There are equal numbers of cations and anions in the blood and among them there are some unmeasured anions. These unmeasured anions can contribute in the clinically important anion gap. In a healthy individual, there is an acceptable range of normal anion gap. But some conditions can increase or decrease this gap. Increased anion gap usually represents metabolic acidosis. Albumin and many other confounding factors influence the anion gap derangements. Accuracy in measuring anion gap is critically important for the evaluation of acidosis.
The body maintains its normal physiology by the strict balance of acid and base. The body maintains its normal arterial pH close to 7.4 at a range between 7.36–7.44, and the intracellular pH of the human body is 7.2 [11]. Normal acid-base balance is the balance between each hydrogen increase by the intake or production, and that is decreased by elimination. Acid-base balance is measured by measuring pH, CO2 and HCO3. In general, consuming animal protein add acid in the body, and consuming cereals and vegetables add alkali in the body. In oxidative metabolism, CO2 is produced in the tissue, and at a similar rate, that is eliminated by the lungs. So, pCO2 persists at about 5.33 kPa (40 mm of Hg). Different buffer systems of the body play a crucial role in removing excess H+. Metabolism of carbohydrate and fat uses O2 and produce CO2 and H2O. Normal lungs efficiently remove most of the CO2. In oxidation of amino acids, carbon dioxide and water are produced along with the liberation of nitrogen as ammonia, a toxic material in the body. In the liver, the urea cycle utilizes the ammonia, where this toxic NH3 combines with CO2, and produce urea. In the proximal tubule and other renal epithelial cells, ammonia and bicarbonate are also produced from glutamine metabolism. Some of it returns to the body fluid through the renal veins and is metabolized in the liver. And the rest of the NH3 excreted in the lumen. So, NH3 does not exist in the body fluid. Most of the NH3 is excreted in the urine, and it plays an important role in removing H+ to maintain normal acid-base balance. In the urine, NH3 binds hydrogen ion to produce NH4, and it prevents excessive acidification of urine.
Excess acid is eliminated from the body by the lungs and the kidneys. In the lungs, acid is eliminated in the form of CO2, and in the kidneys, acid is excreted as acid phosphatase and ammonium. CO2 is lipid soluble, and it crosses the cell membranes in the lungs. Most of the CO2 produced in the tissue is eliminated by alveolar ventilation. Arterial and brain chemoreceptors can sense the acid and base excess, and respiratory system responds with hyper or hypo ventilation. As a result, pH is increased or decreased by increasing and decreasing pCO2 level. The regulation between CO2 and H2CO3 level is critically maintained when the blood travels through the lung capillaries. When strong acid is added, some HCO3− become H2CO3 and blood PCO2 is increased. In acidosis, carbonic acid dissociate to CO2 and H2O. As a result, respiratory center is stimulated and it leads to hyperventilation. Hyperventilation eliminates these CO2 to maintain normal pH. In alkalosis, CO2 is retained by hypoventilation. This CO2 combines with H2O to produce H2CO3, and pH is maintained.
The kidneys excrete acids, both respiratory and nonrespiratory origin and retain HCO3− to stabilize the pH of blood. HCO3− is predominantly regulated in the kidneys. The nephron reabsorbs all filtered bicarbonate in exchange for H+. The kidneys also produce new bicarbonate to neutralize acids. Tubular cells contain carbonic anhydrase, that converts CO2 and H2O to HCO3− and H+. Newly formed HCO3− is shunted to peritubular capillaries and H+ is excreted in tubular lumen. Bicarbonate is also produced from glutamine metabolism along with ammonium. Some NH4 diffuses to body fluid and converts to urea in the liver. The rest of the them excreted in urine. The tubules are impermeable to bicarbonate, and it cannot be converted back to CO2 and H2O. So, the blood HCO3 level is increased.
In the apical membrane of the kidney tubules, sodium is reabsorbed in exchange for the hydrogen ion. Salts like sulfates, phosphates, ammonia combines the hydrogen ions and excrete it. The kidneys titrate less than half of the excreted acids and the rest is excreted as ammonium [11]. For every ammonium excreted in urine, one HCO3+− is reabsorbed. HCl and H2SO4 are produced during dietary protein metabolism reacts with NaHSO4, and produce NaCl and Na2SO4. These Na salts are excreted by the kidneys as NH4Cl, and (NH4)2SO4.
The kidneys are largely responsible for K+ excretion and most of it is reabsorbed in the proximal tubule and in the loop of Henly. In acidosis, K+ secretion is decreased and K+ absorption is increased in the collecting duct. In alkalosis, hypokalemia develops from increased K+ secretion and reduced K+ absorption in the collecting duct. H+ and K+ exchange occur in the tubules. Serum potassium level also influences the renal acid-base balance. In hyperkalemia, potassium is available in an increased amount in the filtrate, and hydrogen will be scarce for exchange with HCO3 and there will be an imbalance. In hypokalemia, less potassium will be available for H+ and K+ exchange and hydrogen will be available to exchange with bicarbonate.
Na+, K+ and NH4+ are the principle urinary cations, and the principal urinary anion is chloride. Urinary anion gap helps in estimating renal NH4+ excretion, as NH4+ is the urinary unmeasured ion. Chloride is an important anion in neutralizing positive ions, reabsorbed in the proximal convoluted tubule and secreted in urine by the collecting duct. Secreted H+ is also buffered by urinary buffer HPO4− to H2PO4, and is excreted in urine.
Acidosis results from a reduction in serum bicarbonate and cause secondary reduction of PaCO2 resulting in a low blood pH. It develops from the addition of hydrogen or removal of HCO3 from the body. PaCO2 in blood is 38 ± 2 mm of Hg and HCO3 is 24 ± 2 mmol/L. Metabolic acidosis is characterized by the blood pH <7.38 and bicarbonate <22 mmol/L [12].
Acid and base disorders are: respiratory acidosis and respiratory alkalosis, and metabolic acidosis and metabolic alkalosis [13]. In respiratory acidosis, PaCO2 is increased and it is compensated by renal H+ excretion, HCO3 retention and HCO3 generation. In respiratory alkalosis, decreased PaCO2 is compensated by renal HCO3 excretion. In metabolic acidosis, HCO3 is reduced and it is compensated by hyperventilation and PaCO2 reduction. HCO3 is increased in metabolic alkalosis, and it is compensated by increasing PaCO2 by hypoventilation [14]. Usually, respiratory disorders cause derangements of CO2 level in the blood, and change in HCO3 level is developed from metabolic disturbances.
In the blood, Alkali is present mainly in the form of sodium bicarbonate, and bicarbonate is bound to other bases. Increase in BHCO3 and decrease in H2CO3results in alkalosis, and decrease in BHCO3 and increase in H2CO3 results in acidosis [13]. The body contains many acids. They are hydrochloric acid, carbonic acid, citric acid, lactic acid, phosphoric acid and carboxylic acid. Acute metabolic acidosis is developed by the overproduction of organic acids, like lactic acid and keto acid. Chronic acidosis is caused by bicarbonate wasting and impaired urinary acidification.
Blood cells are more acidic than serum, which influences the distribution of electrolyte and water between them. These transports took place with the oxygenation and reduction of hemoglobin and shift of bases (Na+, K+) due to changes in pH. Under normal environment Na+ and K+ do not diffuse through the cell wall. Shifting of water and electrolyte through membrane results from the change in anion (HCO3− and Cl−) and H+ concentration, and that changes in cell volume. CO2, relative electrolyte concentration and weak acid concentrations are three independent variables that regulate blood pH [15].
The body has different buffer systems to maintain the normal pH of the body. Elkinton Jr. reported that multiple level of buffering linked different series of ionic exchanges which includes hydrogen, sodium, potassium, and other anions. The buffers absorb excess hydrogen and hydroxyl ions. They help in the maintenance of neutrality during redistribution of the hydrogen ion [16].
A buffer system consists of a weak acid with its conjugate base, or a weak base with its conjugate acid. Blood is a strong solution, and it has many important components that maintain the buffer systems. These include hemoglobin, bicarbonate, carbonic acid, plasma proteins, RBCs and plasma phosphate [17]. HCO3/CO2 buffer is the most important buffer system of the body, and plays a major role in regulating pH of the blood. But, the rest of the buffer systems have minimum contribution in pH regulation. In dissolved state, bicarbonate and carbon dioxide ion remains in equilibrium. Bicarbonate reduces strong acid to carbonic acid, whereas carbonic acid neutralizes strong base (Eq. (1)).
When CO2 and water is converted to HCO3 and hydrogen ions, this hydrogen ion is then buffered by hemoglobin [18].
Proteins have a buffering capacity, including hemoglobin. Protein can accept and donate H+, if there is H+ excess or it is reduced. Hemoglobin has a distinct types of buffer action. When blood passes through the capillaries, it loses oxygen and took CO2 to raise the PaCO2 and maintain the pH. Hemoglobin plays an important role in transporting both oxygen and carbon dioxide. In 1914, Douglas, Haldane and Christiansen tried to prove that the hemoglobin binds more CO2 in the reduced form than the oxygenated form [19].
The phosphate buffer system works in the internal environment of all cells. But, in the blood H2PO4− and HPO42− are found in a very low concentration. Sodium dihydrogen phosphate neutralizes strong bases and sodium monohydrogen phosphate neutralizes strong acids. The Phosphate buffer system plays an important role in the kidneys.
Two types of variables, dependent and independent, are important in acid-base balance [20]. Bicarbonate, hydroxyl ion, hydrogen ion or pH, weak acid, anion and carbon trioxide are dependent variables and they are determined by three independent variables pCO2, total weak acid and net strong ion charge [21]. Lungs, kidneys, liver and gut regulated this balance. Traditional bicarbonate/carbon-di-oxide approach, base excess approach and Stewert’s physicochemical methods are widely discussed for measuring the acid base disorders as well as to explore the physiology of body fluid.
HCO3/CO2 buffer system is the basis of this approach. Carbonic acid freely moves in the body fluid and dissociates into bicarbonate automatically when needed. Bicarbonate in the body acts as alkaline reserve. CO2, pH and HCO3 can be calculated by Hasselbalch-Henderson Equation (2) [7, 9].
This equation states that not only HCO3 and CO2, but also their ratio determines the pH. In this equation, PCO2 is the respiratory component and HCO3− is the metabolic component of the acid base imbalance. This buffer system is the largest and independent buffer system of the body and whole body acts as an open system for CO2. In traditional approach balance is determined by the influx and efflux of H+ and HCO3.
Astrup and Siggaard-Anderson introduced base excess approach, which is close to the traditional approach [22, 23]. Base excess can be calculated from bicarbonate concentration and pH of the body [4]. It can estimate the acid base status of non-respiratory origin. If base excess is too high, then it is metabolic alkalosis. If base excess is too low, then it is metabolic acidosis. When a deviation of normal blood pH is corrected by administrating base, then it is called base deficit. Which is a characteristic of metabolic acidosis. Base deficit with increase anion gap suggest the addition of acid in the body fluid. If there is a base deficit with normal anion gap, then there is bicarbonate loss from the body.
Here H+/proton is the preliminary determinant in acid base disturbances, not the CO2 [21]. The dependent variables are H+, OH−, CO32−, HA (weak acid), A−(weak anions), HCO3− and pH. The independent variables are strong ion difference (SID), total non-volatile weak acids (Atot) and PaCO2 [24]. Among them the strong ion difference has maximum effect on the hydrogen ion concentration. With that, acid base disorder can be divided into three categories: 1. respiratory (increase or decrease PaCO2), 2. SID changes (excess or deficit of strong ions or water) and 3. inorganic phosphate or albumin deficit or excess (Atot changes). In Stewart approach, a large number of variables are needed to calculate SID. Sodium, potassium, calcium and magnesium are strong positive ions, and chloride and lactate are the negative ions [25]. Bicarbonate and albumin are the balancing ion in strong ion difference. Strong ion difference (mEq/L) = [strong cations] − [strong anions]. Weak acid dissociates in body fluid (Eq. (3)).
A− Resembles weak anions, that vary with pH. Strong ion difference is filled with this weak A−, and HCO3+−, H+, OH−, CO32− are also present in minute amount, but are less important. There are many unmeasured anions accounts for ion difference. For electrical neutrality, strong ion difference and the total charge of weak ions must be equal [26]. Normal SID is dominated by sodium and chloride. But other negligible, but measurable ions are present there. Here narrowing of SID from an increase in [Na+] has alkalizing effect, whereas an increase in [Cl−] has acidifying effect. From the ionic basis metabolic acid base disturbances are about four major types [25]: (1) The water effect, and it is produced by dilutional effect on SID. Free water intake and intravenous infusion can produce it. (2) The chloride effect is caused by chloride change, and administration of normal saline is the common cause. (3) The protein effect is produced by a change in albumin concentration. (4) There are other factors, and those are influenced by unmeasured anions, that cause a wide anion gap.
In vivo, true ion gap cannot exist. There are many anions and cations in the blood. Blood cations and anions must be equal. Sodium, chloride and bicarbonate have the highest concentrations, and they are calculated for anion gap for their largest variability in different pathologic conditions. Anion gap is the difference between serum sodium ion and bicarbonate plus chloride. There are wide variations in the reported anion gap. Widely accepted anion gap is 8–12 mmol/L [15]. Anion gap is clinically important for assessing acidosis. Normal anion gap (hyperchloremic) acidosis and increased anion gap acidosis [27] are two important types of anion gap acidosis. Common serum cation levels are sodium 138.8 ± 4.56 mmol/L, potassium 4.05 ± 0.21 mmol/L, magnesium 0.98 ± 0.05 mmol/L [ 28] and calcium 2.2–2.7 mmol/L [ 29]. And normal serum anion levels are chloride 97.7 ± 3.42 mmol/L and acetate 0.23 ± 0.04 mmol/L [ 28]. The sum of cations and anions should be equal (Eq. (4)).
There are other ions which are not commonly measured, are unmeasured anions and cations [30]. Under normal conditions, albumin and phosphate accounts for this anion gap. There are many clinical conditions, where urate, lactate, ketone bodies, sulfate, salicylates, penicillin’s, citrate, pyruvate, and acetates are also responsible for increased anion gap [5]. So, anion gap [31] is Eq. (5)
Presence of unmeasured anion in blood is the anion gap and it represents metabolic acidosis [32]. When unmeasured anions like lactate and pyruvate donates proton then that proton is buffered by bicarbonate. And bicarbonate consumption increases the anion gap. The most common causes include lactic acidosis, diabetic ketoacidosis, uremia and acidosis due to drugs and toxins. Methanol, propylene glycol, ethylene glycol, salicylate, and some inborn error of metabolism are other causes of unmeasured anions [33]. Both lactate and β-hydroxybutyrate are increased in both Gram-positive septiceamia [34] and starvation [35]. Krebs cycle intermediate citrate, isocitrate, malate, α-ketogluterate, succinate and D-lactate are increased in different types of acidosis. Intestinal ischemia and short bowel syndrome cause increase in D-lactate [35]. Plasma proteins are mostly anionic comprising 75% of the unmeasured anion [36, 37, 38]. Treatment with Sodium thiosulfate that has no hydrogen can cause severe metabolic acidosis [39].
It usually indicates acidosis. Increase blood lactate, ketoacidosis, uremia (in advanced renal failure), drugs (salicylate and penicillin), ethylene glycol, methanol are contributor of high anion gap acidosis. But the increase anion gap can be due to laboratory error, hyperphosphatemia [30]. Massive rhabdomyelysis, hippurate, oxalate can also cause increased anion gap acidosis [31]. Diabetes, starvation and alcohol are the most common cause of ketoacidosis. In alcoholic ketoacidosis, primary keto acid is β-hydroxybutyrate. It can be missed in conventional assessment of ketonuria. High anion gap and normal lactate level are characteristics of alcoholic acidosis [40]. Starvation alone can cause high anion gap acidosis [41]. In the third trimester of pregnancy, short period of starvation can cause ketogenesis with a very high anion gap acidosis [42]. Septic shock, hypoxemia, hypovolemic shock, cyanide, mesenteric ischemia, CO poisoning, causes hypoxic type of L-lactic acidosis [43]. Non-hypoxic, L-lactic acidosis develops from seizure, thiamine deficiency, metformin, methanol, ethylene glycol, salicylate, propylene glycol, niacin, isoniazide, iron, propofol, toluene, paraldehyde, non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs [12]. Recurrent 5-oxoprolinuria from inborn errors of metabolism is a rare cause if high anion gap metabolic acidosis [44]. Uremia results from not only reduced ammonia secretion but also reduced filtration of sulfate and phosphate anions, and increases the anion gap [45]. Polyclonal gammopathies are also contributor of increased anion gap [46]. Serum albumin is an important contributor to the anion gap and hypoalbuminemia is a common comorbid condition. That is why, albumin correction is crucial for the anion gap calculation [36, 37]. To explore the cause of the metabolic acidosis anion gap must be corrected for albumin as well as lactate [43]. A high anion gap can be masked by a concomitant low anion gap results from hypoalbuminemia.
In anion gap calculation, sodium is the only cation that is measured. But, hypercalcemia, hyperkalemia and hypermagnesemia can produce significant decrements in anion gap. So, clinical correlation and correction of such abnormality is important. Plasma proteins comprise two third of the unmeasured anion, and hypoalbuminemia is a common cause for the low anion gap [31, 36, 37]. The reduced anion gap is usually seen in delusional states, hypernatremia, hypoalbuminemia, hypermagnesemia, hypercalcemia, bromide intoxication, hyperviscosity associated diseases etc. [47]. Sometimes it can be due to laboratory error, paraproteinemia [48, 49], or iodide [30, 50], gastrointestinal bicarbonate loss and diarrhea [31]. It has been reported that Lithium carbonate intoxication can also produce low or absent anion gap [51]. Non-sodium containing paraprotein IgG in multiple myeloma increase the unmeasured cations and reduce the anion gap [48, 52, 53]. Hypercalcemia and hypoalbuminemia in paraproteinemia also contribute to low anion gap [52].
Measuring anion gap is a routine for evaluating acidosis, and normal anion gap is sometimes misleading. As we know, the increase in anion gap is usual in metabolic acidosis. And acidosis is due to acid retention or ingestion. Normal anion gap acidosis is due to loss of HCO3− from the body. Hyperchloremic normal anion gap acidosis is characterized by acidosis with excess chloride ions [54]. Here, the low HCO3 level is a characteristic feature. Reduced negatively charged bicarbonate is compensated by the negatively charged chloride movement into the extracellular space, and normal anion gap is maintained. The causes of gastrointestinal and renal loss of bicarbonate are diarrhea, ureteral diversions, pancreatic and biliary fistulas, toluene ingestion, acetazolamide, ifosfamide, topiramite, tenofovir, renal tubular acidosis. These are the causes of normal anion gap acidosis. Rapid infusion of 0.9% normal saline can also cause hyperchloremic metabolic acidosis [55]. If the blood anion gap is normal, but there is acidosis, then the urinary anion gap Eq. (6) is calculated [12].
The urinary anion gap is negative in diarrhea, sodium infusion and proximal renal tubular acidosis. Whereas, positive urinary anion gap is found in both type 1 and type 4 renal tubular acidosis. Renal tubular acidosis is sometimes the only presenting feature of many chronic diseases and conditions associated with polyclonal gummopathies.
Metabolic acidosis results from gain of anions and loss of cations. Potassium chloride, hydrogen chloride, sodium chloride, arginine hydrochloride, calcium chloride, ammonium chloride, lysine hydrochloride can cause hyperchloremia and increase anion gap. Hyperphosphatemia increases the anion gap. But renal tubular acidosis [33], amiloride and triamterene cause a non anion gap hyperchloraemic acidosis and hyperkalemia due to impaired bicarbonate production.
Anion gap should be measured for all types of metabolic acidosis. High anion gap metabolic acidosis is a subtype of non-respiratory acidosis. Mnemonics were used for remembering the causes of high gap metabolic acidosis such as KUSMALE (Ketoacidosis, Uraemia, Salicylate poisoning, Methanol, ParAldehyde, Lactate, Ethylene glycol) and MUD PILES (Methanol, Metformin uremia, Diabetic ketoacidosis, Paraldehydes, iron, isoniazid, Lactate, ethylene glycol, Salicylates and starvation). As paraldehyde induced acidosis is extremely rare and recently three anion gap generating organic acid has been recognized. They are Short bowel syndrome producing D-lactic acid, chronic paracetamol use induced 5-oxoproline (or pyroglutamic acid) especially in malnourished woman and high dose propylene glycol (used in lorazepum, phenobarbital) infusions generate acidosis. Also, Iron and Isoniazid can cause lactic acidosis. So, GOLD MARK is a new acronym for metabolic acidosis [Glycols (ethylene and propylene), Oxyproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis] [56]. Metabolic acidosis also caused by renal bicarbonate loss in type 2 renal tubular acidosis, renal dysfunction in type 4 renal tubular acidosis, type 1 renal tubular acidosis and ingestion of ammonium chloride [31]. Acute rheumatism causes lactate induced acidosis also [57]. Symptomatic correction of acidosis will not eliminate the problem. If the clinical features suggest acidosis, then it should be assessed for anion gap as well. Following anion gap measurement accordingly history of drug, toxins and diseases need to be evaluated for managing the exact pathology thus acidosis will be properly treated.
At normal blood pH 7.4 plasma proteins are mostly anionic. It has been estimated that anion gap decreases by 2.5 mEq/L for every 10 gm/L drop of serum albumin [36, 37]. Several studies had observed that 2–2.5 times changes in albumin influences in anion gap changes [58]. Albumin contributes a greater part of the normal anion gap [46]. Phosphate and lactate contribute some anion gap as well [59]. Consideration of all of these contributors are important in explaining changes in anion gap. Calculation of anion gap is crucial in critically ill patients. Anion gap should be adjusted for Eq. (7) albumin, phosphate and lactate with the following equation [59].
IntechOpen celebrates Open Access academic research of women scientists: Call Opens on February 11, 2018 and closes on March 8th, 2018.
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\\n\\nAPPLYING FOR THE “INTECHOPEN WOMEN IN SCIENCE 2018” OPEN ACCESS BOOK COLLECTION
\\n\\nWomen scientists can apply for one book topic, either as an editor or with co-editors, for a publication of an OA book in any of the scientific categories that will be evaluated by The Women in Science Book Collection Committee, led by IntechOpen’s Editorial Board. Submitted proposals will be sent to designated members of the IntechOpen Editorial Advisory Board who will evaluate proposals based on the following parameters: the proposal’s originality, the topic’s relation to recent trends in the corresponding scientific field, and significance to the scientific community.
\\n\\nThe submissions are now closed. All applicants will be notified on the results in due time. Thank you for participating!
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\n\nAPPLYING FOR THE “INTECHOPEN WOMEN IN SCIENCE 2018” OPEN ACCESS BOOK COLLECTION
\n\nWomen scientists can apply for one book topic, either as an editor or with co-editors, for a publication of an OA book in any of the scientific categories that will be evaluated by The Women in Science Book Collection Committee, led by IntechOpen’s Editorial Board. Submitted proposals will be sent to designated members of the IntechOpen Editorial Advisory Board who will evaluate proposals based on the following parameters: the proposal’s originality, the topic’s relation to recent trends in the corresponding scientific field, and significance to the scientific community.
\n\nThe submissions are now closed. All applicants will be notified on the results in due time. Thank you for participating!
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