\r\n\tTopics covered include but are not limited to: Hydrologic Cycle (Precipitation, Runoff, Infiltration and their Measurement, Land surface interaction); Hydrologic Analysis (Hydrograph, Wave routing, Hydrologic statistics, Frequency Analysis); Applied Hydrology (Applications in Engineering, Sciences and Agriculture, Design storms, Risk analysis, Case studies); Computational Hydrology (Numerical modeling, Hydrologic modeling and forecasting, Flow visualization, Model validation, Parameter estimation); Interdisciplinary Hydrology (Hydrometeorology, Impact of Climate Change, Precipitation data analysis, Mathematical concepts, Natural hazards); Radar Hydrology (Precipitation estimation techniques, Promise and Challenges in Radar technology, Uncertainty in radar precipitation estimates).
\r\n
\r\n\tThe contents covered in this book will serve as a valuable reference guide to students, researchers, government agencies and practicing engineers who work in hydrology and related areas. We hope that this book will open new directions in basic and applied research in hydrological science.
",isbn:"978-1-83962-330-1",printIsbn:"978-1-83962-329-5",pdfIsbn:"978-1-83962-331-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"02925c63436d12e839008c793a253310",bookSignature:"Dr. Theodore Hromadka and Dr. Prasada Rao",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9864.jpg",keywords:"Runoff, Land Surface Interaction, Hydrograph, Wave Routing, Design Storms, Risk Analysis, Numerical Modeling, Hydrologic Modeling and Forecasting, Flow Visualization, Hydrometeorology, Precipitation Data Analysis, Radar Hydrology",numberOfDownloads:293,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 8th 2020",dateEndSecondStepPublish:"September 11th 2020",dateEndThirdStepPublish:"November 10th 2020",dateEndFourthStepPublish:"January 29th 2021",dateEndFifthStepPublish:"March 30th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Principal and founder of Hromadka & Associates, professor United States Military Academy, Professor Emeritus at the California State University, and a Member of Board of Directors and an Adjunct Professor at Wessex Institute of Technology.",coeditorOneBiosketch:"Prasada Rao, Ph.D. is a professor in the Civil and Environmental Engineering Department at California State University, Fullerton. 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He has worked extensively on developing innovative, hydraulic and hydrological modelling solutions to better predict surface flow phenomena along with its impact on groundwater levels. He has also worked on developing parallel hydraulic models for large scale applications. 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1. Introduction
Site-directed mutagenesis (SDM) is undoubtedly one of the most powerful techniques in molecular biology. In this chapter, we will describe the use of SDM in the study of the human inherited metabolic disorder, Galactosemia (Type I, II, and III) and the development of novel therapies for the disease. This powerful technique not only helped confirm suspected GAL gene mutations in Galactosemia, but also played a significant role in unraveling the catalytic mechanisms of the GAL enzymes in the conserved Leloir pathway of galactose metabolism. To date, more than thirty disease-causing mutations in the human GAL genes have been characterized in great detail; and these findings have paved the way for innovative, state-of-the-art therapies, such as chaperone therapy. Recently, in order to optimize small molecule GALK inhibitors for the treatment of Type I Galactosemia, we have employed SDM to identify amino acids of the GALK enzyme that interact with its selective inhibitors. These studies exemplified the expanding roles of SDM in innovative drug design and in kinase inhibitor selectivity.
2. Background
2.1. What is galactosemia?
Galactose is a hexose that differs from glucose only by the configuration of the hydroxyl group at the carbon-4 position. Often present as an anomeric mixture of α[?]-D-galactose and β[?]-D-galactose, this monosaccharide exists abundantly in milk, dairy products and many other food types such as fruits and vegetables (Berry, Palmieri et al., 1993; Acosta and Gross, and Gross 1995; Berry et al., 1993). However, galactose can also be produced endogenously in human cells, mainly as products of glycoprotein and glycolipid turnover.(Berry et al., 1995, 2004). Once freely present inside the cells, β[?]-D-galactose is epimerized to α[?]-D-galactose through the action of a mutarotase (Beebe and Freyet al.and Frey, 1998; Thoden and Holdenet al.and Holden, 2002a). α[?]-D-galactose is then metabolized by the Leloir pathway (Leloir 1951), an evolutionarily conserved biochemical pathway which begins with the phosphorylation of galactose by the enzyme galactokinase (GALK) to form galactose-1 phosphate (gal-1P) (Cardini and Leloiret al.and Leloir, 1953). Gal-1P is subsequently, together with the substrate UDP-glucose, converted by galactose-1-phosphate uridylyltransferase (GALT) to form UDP-galactose and glucose-1 phosphate (glu-1P) (Kalckar, Braganca et al., 1953). The Leloir pathway is completed by reversibly forming UDP-glucose from UDP-galactose via UDP-galactose-4-epimerase (GALE) (Leloir 1953; Darrow and Rodstorm et al., 1968 and Rodstrom). Inherited deficiencies of GALK, GALT, and GALE activities in humans have all been observed, studied, and reviewed extensively (Bosch et al., 2002; Elsas 1993; Fridovich-Keil, Bean et al., 1993a; Bosch, Bakker et al., ). The clinical manifestations of each enzyme deficiency, however, differ markedly (Berry et al., 1995; Berry and Elsas, 2011; Fridovich-Keil, Bean et al., 1993 a; Berry, Nissim et al., 1995; Lai, Elsas et al., 2009; Berry and Elsaset al., 2011). For instance, patients with GALK deficiency (MIM 230200) (Type II Galactosemia) have the mildest clinical consequences, as they may present only with cataracts (Bosch, Bakker et al., 2002). On the other hand, GALT-deficiency (MIM 230400) (Type I or Classic Galactosemia) is potentially lethal in infancy, if undiagnosed and untreated, and is also associated with long-term, organ-specific complications (Berry, Nissim et al., 1995). GALE-deficiency (MIM 230350) (Type III Galactosemia) has been somewhat controversial with regards to clinical manifestations, as this disorder is rare; and information is mostly derived from case reports (Fridovich-Keil, Bean et al., 1993a). Until newborn screening for GALE deficiency is available, the natural history will likely remain unknown. The differences in clinical outcome between GALT and GALK deficiencies reflect the differences in tissue response to the characteristic changes in the levels of galactose metabolites as a result of the respective enzyme deficiencies.
2.2. How are the different types of galactosemia detected and diagnosed?
Newborn screening programs worldwide have greatly facilitated the early detection of Galactosemia (Kaye, Accurso et al., 2006; Levy 2010). The screening tests often involve the detection of elevated level of blood galactose and/or specific GAL enzyme in the dried blood spots on filter paper. Elevated galactose will detect GALK deficiency and GALT deficiency, but it may not detect GALE deficiency. Other states screen for GALT activity, and may therefore diagnose Type I Galactosemia. However, this screen will miss GALK and GALE deficiency. The final diagnosis is secured once the specific enzyme deficiency is confirmed by enzymatic assays or by DNA genotyping; these tests are available commercially in the USA (http://www.ncbi.nlm.nih.gov/sites/ GeneTests/, Tests #3437, #2229 and #53782).
2.3. What are the current treatments for galactosemia, and what is the outlook for patients?
The main aspect of management for all forms of Galactosemia is withdrawal of lactose/galactose from the diet as soon as the diagnosis is made, or even considered (Segal 1995). In infants, this means the replacement of breast/cow milk with soy-based formula. However, it has become clear that, despite early detection and (early) dietary intervention, there still is a significant burden of the disease, particularly for Classic Galactosemia where chronic problems persist through adulthood. The most common medical complications of Type I Galactosemia are speech dyspraxia, ataxia, premature ovarian insufficiency, and intellectual deficits, [ANY OF?](yes) which are rarely seen in other forms of galactosemia (Waggoner, Buist et al., 1990 ; Waisbren, Potter et al., 2011). GALK deficiency (Type II Galactosemia) is managed also with lactose/galactose restriction, though the complications are mainly confined to the eye (cataracts) (Bosch, Bakker et al., 2002). GALE deficiency is treated similarly, though complications of this deficiency may not be preventable with such restriction, as is GALT deficiency (Fridovich-Keil, Bean et al., 1993a).
3. Use of SDM to confirm disease-causing mutations in human GALT, GALK, and GALE genes identified clinically
3.1. The issues
Advances in federal and state newborn screening programs worldwide have resulted in the inclusion of the potentially lethal disorder, Galactosemia, in the list of diseases for which newborns are screened. Very often, once an affected newborn is identified by the biochemical assays, it is helpful to know the genotype [ALLELE] of GAL gene [mutations DELETE] involved because there appears to be a genotype-phenotype correlation for a few selected GAL gene mutations. The confirmation of the GAL genotypes [ALLELES] (reject here for the same reason) in the affected patients will provide better prognosis. Additionally, a few well-characterized GAL enzyme variants have been shown to retain significant residual enzyme activities. Consequently, patients with selected mutations might benefit from novel therapies, such as chaperone therapies.
Unfortunately many patients with Galactosemia identified to-date have novel (private) nucleotide changes in their GAL genes. For instance, the GALT gene database set up by the ARUP Laboratories (Salt Lake City, USA) has recorded over 200 nucleotide changes of the GALT gene identified in patients with Type I Galactosemia (www.arup.utah.edu/database/ GALT/GALT_welcome.php). Without clinical correlation, it is impossible to tell if any of these novel changes actually results in impaired GALT enzyme activities seen in the patients. Moreover, many patients are compound heterozygous for the GAL gene mutations. In other words, a single patient may have a unique nucleotide change in each of the two GAL alleles; and it is difficult to conclude which one is responsible for the reduction in total enzyme activity. Thus there is a real need to perform in vitro expression studies of the identified “variant” GAL genes.
3.2. Research design
Our laboratory and others have largely used similar strategies in confirming the suspected human GAL gene mutations in patients with Galactosemia (Reichardt, Levy et al., 1992; Fridovich-Keil, Quimby et al., 1995a; Lai, Willis et al., 1999; Reichardt et al., 1992;). In almost all cases, we sub-cloned the cDNA of the respective GAL gene into expression plasmid vectors, before we performed SDM of the sub-cloned fragments to obtain “mutant” cDNAs with the same sequence changes observed in patients. We then expressed the wild-type and mutated cDNAs in heterologous expression systems, such as Escherichia coli,\n\t\t\t\t\tSaccharomyces cerevisiae or even mammalian expression systems. Subsequently, we tested for differences in kinetic parameters of the GAL enzymes, such as KM and Vmax, and the expression efficiencies, such as protein and/or mRNA abundances, between mutant and control cDNAs.
3.3. The results
The primary goal for expression analysis of the suspected disease-causing mutations in the GAL genes is to show that the nucleotide changes observed are causing impaired GAL enzyme activities and could therefore be the causes for the diseases. In addition, in the course of the analysis, kinetic parameters of the variant enzymes are often determined, which are expected to help advance the structural knowledge of the GAL enzymes.
3.3.1. Type I (GALT-deficiency) galactosemia
As mentioned above, more than 200 nucleotide changes in the GALT gene have been identified so far, mostly single nucleotide substitutions. The most common human GALT mutation, Q188R, is detected in over 70% of galactosemic patients in Europe and North America. The Q188R mutation is associated with a poor clinical outcome, even with a galactose-restricted diet (Murphy, McHugh et al., 1999; Guerrero, Singh et al., 2000; Murphy et al., 1999; Webb, Singh et al., 2003). K285N is the second most common mutation found in patients in Europe, especially in the countries of central and Eastern Europe, where it can account for up to 34% of GALT alleles (Greber-Platzer, Guldberg et al., 1997; Kozak, Francova et al., 2000). In the African-American population, the S135L mutation is predominant. The corresponding enzyme leads to a relatively benign outcome, if the mutation is identified and the patient is treated with a galactose-restricted diet in the newborn period (Lai, Langley et al., 1996, 2001; Landt, Ritter et al., 1997; Lai and Elsaset al., 2001). A more common mutation, N314D, occurs in all populations mentioned above and can lead to two different phenotypes, depending on the presence or absence of a 4-bp deletion in the coding region for the carbohydrate response element. When N314D is associated with a four-nucleotide deletion in the promoter region (the Duarte type 2), homozygosity for N314D and this altered promoter region [DELETE] (reject this one as both N314D and the deletion are needed to see the enzymatic activity reduction) causes a 50% decrease of GALT activity, with a mild or even undetected phenotype (Elsas, Dembure et al., 1994). In the absence of this deletion in theed positive promoterresponse element [THIS IS CONFUSING. IS THE DELETION ABSENT (I.E., THE POSITIVE-ACTING RESPONSE ELEMENT IS PRESENT), OR IS THE DELETION THERE? I ASSUMED THE FORMER.] (the deletion is absent here), homozygosity for the missense N314D missense mutation (the Los Angeles variant), GALT activity is ) results in normal GALT in erythrocytes (Shin, Koch et al., 1998). A 5-kb deletion is found so far exclusively in Ashkenazi Jewish patients (Coffee, Hjelm et al., 2006).
Due to its frequency among GALT-deficiency galactosemic patients and its association with a poor clinical outcome, the Q188R mutation has been extensively studied. The initial study using the COS cell expression system surprisingly showed that this mutation had about 10% of normal enzymatic activity (Reichardt, Packman et al., 1991). This result was not consistent with the clinical finding that patients homozygous for Q188R have no detectable enzyme activity in their red blood cells. Another study, carried out in a yeast model that was completely devoid of GALT activity, used a PCR-mediated SDM technique and clarified that the Q188R mutation did cause loss of function of both human and yeast GALT (Fridovich-Keil and Jinks-Robertson et al.,1993b). Interestingly, this study also showed that the mutant yeast, with its loss of GALT activity, could not survive in galactose media if the Q188R missense mutation was introduced, while reconstitution of wild-type GALT resulted in normal growth (Fridovich-Keil and Jinks-Robersonand Jinks-Robertson et al., 1993b). The confounding result of the first study is likely to be explained by the presence of endogenous GALT activity in the COS cells, highlighting the importance of studying mutations in a null background system, such as the gal7-deleted yeast model used in the second study. Alternatively, one should use purified mutant proteins in the analysis of the enzymatic activities. Subsequent studies further confirmed that the Q188R mutation not only totally abolishes GALT enzyme activity, but also acts as a partial dominant-negative mutation, as the heterodimer of Q188R/wild type has only 15% of wild-type activity (Fridovich-Keil et al., 1995a; Elsevier and Fridovich-Keil,1996). Kinetic analysis showed this mutation mainly causes impaired specific activity of the heterodimer without altering the KM for both substrates. In order to further understand how mutation at this site could affect the enzyme, Lai and coworkers mutated glutamine-188 (Gln188) to arginine and asparagine, respectively, through SDM (Lai, Willis et al., 1999). More detailed kinetic measurement showed that mutating glutamine to arginine or asparagine did not affect the first step of the double-displacement action (UDP-Glu to glu-1p). In fact, Q188R-GALT even had a better Vmax as compared with the wild-type GALT. However, the Q188R mutation severely impaired the second step of the reaction. The crystal structures of E. coli GALT revealed that Gln168 (equivalent to Gln188 in human GALT) could stabilize the GALT-UMP intermediate through two hydrogen bonds formed between the amide side chain of Gln188 and the phosphoryl oxygen of the UMP moiety (Wedekind, Frey et al., 1996). Through molecular modeling studies (or “virtual SDM”), Lai and coworkers changed glutamine to arginine and asparagine, respectively, and found that the number of hydrogen bonds formed between new amino acid residues and UMP moiety decreased to one, which could have destabilized the GALT-UMP intermediate required for the second displacement reaction (Lai, Willis et al., 1999). This destabilization was well manifested in the increased Vmax in the Q188R mutant in the first displacement reaction, as the destabilization speeded up the recycling of the enzyme for the first reaction (Lai, Willis et al., 1999). To complete the double-displacement reaction, a stable GALT-UMP intermediate was required to bind gal-1P, which was better accomplished by the two hydrogen bonds from glutamine than by the single hydrogen bond from arginine or asparagine.
The S135L mutation was identified initially as a polymorphism with near normal enzymatic activity in the COS cell expression system (Reichardt, Levy et al., 1992). However, subsequent SDM studies in the yeast-expression system, defined this as a missense mutation that significantly impaired enzyme activity; but, unlike the Q188R mutation, it still had minor residual activity (Fridovich-Keil, Langley et al., 1995a). Later on, more detailed SDM and expression studies in yeast and E. coli heterologous expression systems revealed this mutation decreased the abundance of mutant protein about 2-fold compared with the wild type, as well as caused 10-fold decrease of specific activity with less than 2-fold of differences of KM values for both substrates (Wells and Fridovich-Keilet al., 1997; Lai and Elsaset al.and Elsas, 2001; Wells and Fridovich-Keil, 1997). There was no apparent difference in releasing glu-1P between the wild type and this mutant (Lai and Elsasand Elsas et al., 2001). Mutating this serine to alanine, cysteine, histidine, threonine or tyrosine by SDM confirmed that a hydroxyl group is required on the side chain of amino acid 135, since only the threonine substitution resulted in active enzyme (Lai and Elsas and Elsaset al., 2001).
The K285N mutation compromises the activity of the enzyme, as well as its abundance, in the yeast expression system (Riehman, Crews et al., 2001). As for the N314D mutation, it was regarded as the reason of reduced enzymatic activity in Duarte 2 patients; but detailed enzymatic studies facilitated by SDM revealed that the mutation itself only causes isoelectric point shifting, without affecting protein abundance, subunit dimerization or activity (Fridovich-Keil, Quimby et al., 1995b). The decrease in GALT activity observed in the Duarte type 2 patients is likely caused by the 4-bp deletion at the promoter region associated with the N314D mutation, which abolishes the binding sites of two transcription factors to the GALT gene promoter (Carney, Sanders et al., 2009). The fact that the Los Angeles variant has normal activity in the erythrocytes supports this conclusion (Carney, Sanders et al., 2009).
3.3.2. Type II (GALK-deficiency) galactosemia
More than 20 mutations associated with GALK deficiency have been reported to date. Through SDM studies, the majority of the mutations have been characterized. By expressing 10 variant GALK enzymes in GALK-less E. coli, Timson and Reece showed that five of mutant GALK enzymes (P28T, V32M, G36R, T288M and A384P), which are associated with more severe clinical phenotypes and near-zero blood galactokinase levels, are insoluble (Timson and Reeceand Reece et al., 2003). Further studies showed that these mutations disrupted the secondary structure of the enzymes, which could result in misfolding of the protein (Thoden, Timson et al., 2005). Four of the five soluble mutants (H44Y, R68C, G346S, and G349S, but not A198V) have impaired enzymatic properties, such as increased KM for one or both substrates and decreased kcat. All five are associated with low blood enzyme levels and milder symptoms. From the crystal structure of human GALK, it is clear that His44, Gly346 and Gly349 are close to the active site. Additionally, these residues reside in the signature motif III of the GHMP kinase superfamily (Bork, Sander et al., 1993; Thoden, Timson et al., 2005). Therefore, it is not surprising that any changes in these resides would alter the kinetic parameters of the enzyme. As for A198V, its kinetic parameters are essentially indistinguishable from the wild-type enzyme. Compared to other mutations, from which patients will develop cataracts with high incidence within the first few years (without treatment), the A198V enzyme causes only a moderate incidence of cataracts in later life.
Similarly, Park and colleagues characterized another four missense mutations and one insertion (G137R, R256W, R277Q, V281M and 850_851insG) by expressing the corresponding mutated genes in COS7 cells (Park, Bang et al., 2007). The steady-state expression level of R256W was lower than that of wild type. The stability of the mutant enzyme was significantly reduced, and it had no detectable activity. No protein was detected for the insertion variant. The other three mutations manifested enzymes with similar expression levels in the soluble fraction, as compared to the wild-type level. However,, but with the G137R and R277Q enzymes had approximately 10%-15% of wild-type activity, and no activity was detected for the V281M enzyme.
3.3.3. Type III (GALE-deficiency) galactosemia
GALE deficiency exists in a continuum, from generalized to peripheral via intermediate (Openo, Schulz et al., 2006). If GALE is deficient in all tissues, it is classified as generalized; and, if it is only deficient in red and white cells but normal in other tissues, it is known as peripheral deficiency. It is possible that the presence of bi-allelic amorphic mutations is incompatible with life (Sanders, Sefton et al., 2010). Infants with generalized deficiency develop disease on a lactose-containing milk diet, while infants with peripheral disease remain well, at least in the newborn period. GALE deficiency has been extensively reviewed by Fridovich-Keil and coworkers (Fridovich-Keil, Bean et al., 1993a). Genomic GALE is about 5 kb in length, with multiple alternatively spliced transcripts. Some of the reported mutations are deposited in the HGMD database (http://www.hgmd.org/). Few case series have been reported, including a Korean study, reporting 37 patients with reduced GALE activity (Park, Park et al., 2005), and two US-based studies, with one reporting 35 patients (Maceratesi, Daude et al., 1998) and the other, 10 patients (Openo, Schulz et al.,2006). Others have reported a few cases (Alano, Almashanu et al., 1998; Wohlers, Christacos et al., 1999). The V94M mutation has been reported in the homozygous state as being associated with generalized disease (Wohlers, Christacos et al., 1999). In-depth studies of the V94M mutation through SDM in the yeast system showed that this mutation severely damages the specific activity of the enzyme predominantly at the level of VM without affecting its abundance and thermal stability (Wohlers, Christacos et al., 1999; Wohlers and Fridovich-Keiland Fridovich-Keilet al., 2000). In the same study, the G90E mutation was shown to have zero enzymatic activity, rendering the mutant enzyme to high temperature and protease (Wohlers, Christacos et al., 1999). A more recent study further confirmed the impact of V94M and G90E on VM (Timson 2005). Other missense mutations have not (yet) been reported in patients, but they have been studied in vitro or in model systems. They are associated with severe enzyme deficiency; these include G90E and L183P (Quimby, Alano et al., 1997; Timson, 2005; Wohlers, Christacos et al., 1999; Timson). Missense mutations associated with peripheral disease include R169W, R239W and G302A and have been described by Park and coworkers in individuals with peripheral GALE deficiency (Park, Park et al., 2005). The K257R and G319E mutations have been described in African-Americans with peripheral deficiency (Alano Aet al., 1998 and TM). The L183P mutation encodes an enzyme that experiences severe proteolytic degradation during expression and purification. Also the authors showed that enzymes resulting from the N34S, G90E and D103G mutations exhibited increased susceptibility to digestion in limited proteolysis experiments (Timson 2005). An earlier study on L183P and N34S using SDM in a yeast model revealed that the L183P-hGALE mutant demonstrated 4% wild-type activity and 6% wild-type abundance, while N34S-hGALE demonstrated approximately 70% wild-type activity and normal abundance. However, yeast cells co-expressing both L183P-hGALE and N34S-hGALE exhibited only approximately 7% wild-type levels of activity, thereby confirming the functional impact of having both substitutions and raising the intriguing possibility that some form of dominant-negative interaction may exist between the mutant enzymes found in this patient (Quimby, Alano et al., 1997). Two other mutations, D130G and L313M, that which are associated with intermediate epimerase deficiency, manifested enzymes with near normal GALE activity, but with compromised thermal stability and protease-sensitivity (Wohlers, Christacos et al., 1999). Three other mutations associated with intermediate forms (S81R, T150M and P293L) were analyzed for their kinetic and structural properties in vitro and their effects on galactose-sensitivity of S. cerevisiae cells in the absence of Gal10p. All three mutations result in impairment of the kinetic parameters, principally the turnover number, kcat, compared to the wild-type enzyme. However, the degree of impairment was mild compared with that seen with the mutation V94M (Chhay, Vargas et al., 2008). Studies are limited by the fact the many patients are compound heterozygotes and by the observation that dominant-negative interactions may be involved in some of these cases.
4. Use of SDM in the understanding of catalytic mechanisms of the human GAL enzymes
4.1. The issue
Although the Leloir pathway is evolutionarily conserved and is indispensable for productive galactose metabolism, the catalytic mechanisms of the GAL enzymes are largely unknown.
4.2. Research design
Several groups have attempted to combine the techniques of SDM, analytical biochemistry and X-ray crystallography to advance the understanding of the catalytic mechanisms of the different GAL enzymes.
4.3. The results
4.3.1. GALK
GALK converts galactose to gal-1P by transferring γ?–phosphate group of ATP to the O1 position of galactose. It belongs to a unique kinase superfamily – the GHMP kinase family, which is named after four characteristic family members: galactokinase (GALK), homoserine kinase (HSK), mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) (Bork, Sander et al., 1993). This family of proteins was first identified by three highly conserved motifs among the four kinases mentioned above by sequence alignment and analysis. Motifs I and III are located at the N-terminal and C-terminal ends; and motif II, the most conserved, is located in the middle of the protein, with the consensus sequence of GLGSS(G/A/S) (Holden, Thoden et al., 2004).
Interestingly, two different catalytic mechanisms have been proposed for this family. A common catalytic strategy to achieve nucleophilic attack is to use a negative charged residue, such as aspartate or glutamate, to act as a Brønsted base. This catalytic base can then abstract a proton from the hydroxyl group of the substrate converting the weakly nucleophilic hydroxyl group into the more strongly nucleophilic alkoxide ion, which then attacks the electron-deficient phosphorus atom in ATP (Fig. 1A). In such systems, it is common to find positively-charged lysine or arginine residues close to the catalytic site to help stabilize the negative charges on the enzyme and the substrates. Studies on MVK suggest this enzyme follows this mechanism. The crystal structure of MVK reveals an aspartate (residue 204 in the rat enzyme) positioned to act as an active site base. There is also a lysine (residue 13 in rat MVK), which is close to both the putative catalytic aspartate residue and the hydroxyl group of the substrate (Fu, Wang et al., 2002; Yang, Shipman et al., 2002). Replacement of the lysine residue with a methionine by SDM resulted in a reduced, but non-zero, rate (Vmax was reduced approximately 60-fold) (Potter, Wojnar et al., 1997). Similar results were observed when the equivalent lysine (residue 18) was changed to methionine in yeast mevalonate diphosphate decarboxylase (Krepkiy and Miziorko and Miziorkoet al., 2004). These results are consistent with this positively-charged residue playing an assisting, but non-vital, role in catalysis. Crystal structures of GALK put it into this mechanism by revealing there are aspartate and arginine residues in the active center close to the galactose C1 hydroxyl group (Asp186 and Arg37 in the human structure, Asp183 and Arg36 in Lactococcus lactis) (Thoden and Holden and Holdenet al., 2003; Thoden, Timson et al., 2005). Similarly, changing Arg37 of human GALT to alanine resulted in a nearly inactive enzyme; and lysine resulted in compromised kcat and KM for galactose (Tang, et al., 2010).
In contrast, phosphoryl transfer in HSK has been suggested to occur by direct nucleophilic attack on the γ?-phosphate group of ATP by the δ?-hydroxyl of homoserine (Fig. 1B) (Krishna, Zhou et al., 2001). In this mechanism, the latter is stabilized by the formation of a hydrogen bond to a neighboring asparagine residue (Asn141), which is not conserved in the superfamily. Catalysis is proposed to be assisted through activation of the γ?-phosphate of ATP by the magnesium ion, which is coordinated by a conserved glutamate residue (Glu130) with the deprotonation of the δ?-hydroxyl possibly involving the γ?-phosphate (Krishna, Zhou et al., 2001).
4.3.2. GALT
GALT catalyzes the transfer of the uridine monophosphate group (UMP) from uridine diphosphate-glucose (UDP-Glu) to gal-1p to form uridine diphosphate-galactose (UDP-Gal) and glucose-1-phosphate (glu-1P) (Kalckar, Braganca et al., 1953). The reaction follows the double displacement mechanism as shown in Fig. 2 (Arabshahi, Brody et al., 1986). The most characteristic feature of the reaction is forming a covalent UMP-enzyme intermediate (Arabshahi, Brody et al., 1986). The intermediate was isolated by gel permeation chromatography in reaction mixtures containing the enzyme and radiolabeled UDP-Glu, and the radiolabeled intermediate could react with gal-1P or glu-1P to form the corresponding radiolabeled UDP sugar (Wong, Sheu et al., 1977a). This intermediate is very fragile in slightly acidic solutions but quite stable in strong basic solutions (Wong, Sheu et al., 1977a; Yang, and Freyand Frey et al., 1979), which indicates the intermediate is phosphoramides. Further degradation study of this intermediate confirmed that the nucleophile in GALT, to which the uridylyl group is bonded in the uridylyl-enzyme intermediate, is imidazole N3 of a histidine residue (Yang and Frey et al. and Frey, 1979).
Figure 1.
Catalytic mechanisms proposed for GHMP kinase. A. The enzyme catalyzes the reaction through an active base residue R1, which attracts a proton from the substrate R3, converting the weakly nucleophilic hydroxyl to an alkoxide ion, which attacks the γ?-phosphate of ATP. A positively charged residue R2, sits close to the catalytic residue and stabilizes the alkoxide ion. B. There is no active base residue in the active center, the substrate directly attacks the γ?–phosphate of ATP.
Figure 2.
Double displacement reactions of GALT. GALT binds to UDP-Glu to form a GALT-UDP-Glu intermediate. Glu-1-P is subsequently released, whereas the enzyme remains bound to UMP. Gal-1-P then reacts with the enzyme-UMP intermediate to form UDP-Gal, freeing the GALT enzyme for continued catalysis. kn and k−n denote rate constants of the forward and reverse reactions.
Substituting each of the 15 histidine residues in E. coli GALT with asparagines by SDM, proved that His164 and His166 were the only essential histidine residues in the enzyme (Field, Reznikoff et al., 1989). In order to identify which of these two residues is the catalytic residue, two more specific mutations were introduced by SDM, H164G and H166G, which resulted in loss of function of the enzyme because of the missing imidazole ring of histidine, which might be filled and salvaged by adding exogenous imidazole ring. The experimental results showed that the activity of the H166G mutant could be recovered by adding exogenous imidazole ring, while mutant H164G could not. Therefore, His166 provides the catalytic nucleophilic imidazole ring in the reaction (Kim et al., 1990).
Also, as mentioned earlier, by mutating Gln188 of human GALT (equivalent to Gln168 in E. coli GALT), the most common mutation found in Type I Galactosemia, to arginine and asparagine, respectively, we were able to determine that glutamine at position 188 stabilizes the UMP-GALT intermediate through hydrogen bonding and enables the double displacement of both glucose-1-phosphate (glu-1P) and UDP-galactose. The substitution of arginine or asparagine at position 188 reduces hydrogen bonding and destabilizes UMP-GALT. The unstable UMP-GALT allows single displacement of glu-1P with release of free GALT but impairs the subsequent binding of gal-1P and displacement of UDP-Gal (Lai,, Willis et al., 1999).
4.3.3. GALE
GALE catalyzes the inter-conversion of UDP-Glu and UDP-Gal to finish the Leloir pathway of galactose metabolism. There are four key steps for the reaction of GALE as shown in Fig. 3: (1) abstraction of the 4‘-hydroxyl hydrogen of the sugar by an enzymatic base, (2) transfer of a hydride from C4 of the sugar to the C4 of NAD+ leading to a 4‘-ketopyranose intermediate and NADH, (3) rotation of the resulting 4‘-ketopyranose intermediate in the active site, and (4) return of the hydride from NADH to the opposite face of the sugar (Maitra and Ankeland Ankel et al., 1971). When purified, this enzyme contains tightly bound NAD+, which functions as an essential coenzyme to catalyze the reaction (Darrow and and RodstormRodstrom et al., 1968). The binding of the UDP group is strong, while binding with the galactosyl, glucosyl and 4-ketohexopyranosyl moieties is weak (Kang, Nolan et al., 1975; Wong and Frey and Freyet al., 1977b). Early study on the catalytic mechanism of GALE focused on Lys153, since it is close to the NAD+, and the positively-charged ammonium group of Lys153 may perturb the electron distribution in the nicotinamide ring of NAD+ through charge repulsion upon substrate binding (Swanson and Freyand Frey et al., 1993). Replacing this residue with alanine or methionine renders the inability of the mutant proteins to be reduced by the sugar in the presence or absence of UMP. As a result, the catalytic activities of the mutants decreased by a factor over 1000. Also the purified mutant contained much less NADH as compared with wild type (Swanson and Frey and Freyet al., 1993). These results indicate that Lys153 plays an important role in the UMP-dependent reduction of GALE-NAD+. Further studies identified two more important residues, Tyr149 and Ser124, which are involved in glucose moiety binding (Thoden, Frey et al., 1996). SDM studies on the latter two residues revealed that that Tyr149 provides the driving force for general acid-base catalysis, while Ser124 plays an important role in mediating proton transfer (Liu, Thoden et al., 1997). The crystal structure of human GALE confirmed that Tyr149 (Tyr157 for human GALE) sits at the proper position to interact directly with the 4’-hydroxyl group of the sugar and attracts the proton from the hydoxy group and transfers it to NAD+ (Thoden, Wohlers et al., 2000).
Unlike what was observed for the E. coli enzyme, the human enzyme can also convert UDP-N-acetylglucosamine (UDP-GlcNAc) to UDP-N-acetylgalactosamine (UDP-GalNAc) (Kingsley et al., 1986; Piller, Hanlon et al., 1983; Kingsley, Kozarsky et al., 1986). Through structure analysis and alignment, investigators found that, when the human enzyme equivalent of Tyr299 in the E. coli protein is replaced with a cysteine residue (Cys307), the active site volume for the human protein is calculated to be approximately 15% larger than that observed for the bacterial epimerase (Thoden JB 2001). Substituting Tyr299 of E. coli GALE with a cysteine residue by SDM confers UDP-GalNAc/UDP-GlcNAc converting activity to the bacterial enzyme with minimal changes in its three-dimensional structure. Specifically, although the Y299C mutation in the bacterial enzyme resulted in a loss of epimerase activity with regard to UDP-Gal by almost 5-fold, it resulted in a gain of activity against UDP-GalNAc by more than 230-fold (Thoden, Henderson et al., 2002b).
5. Use of SDM in the development of novel treatment of Type I (classic or GALT-deficiency) galactosemia
5.1. The issues
Unlike Type II or the peripheral Type III Galactosemia, patients with Type I (GALT-deficiency) Galactosemia, also the most common type of Galactosemia, suffer a range of debilitating long-term complications, which include premature ovarian insufficiency, learning deficits, ataxia and speech dyspraxia (Lai, Elsas et al., 2009; Berry and Elsas and Elsaset al., 2011). The current galactose-restricted diet fails to prevent these complications, and the medical/ patient communities are yearning for a more effective therapy. The causes of these organ-specific complications remain unknown, but there is a strong association with the intracellular accumulation of gal-1P. But what is the source of gal-1P in these patients with Classic Galactosemia if they limit their galactose intake? Recent studies have shown that the patients on a galactose-restricted diet are never really “galactose-free. A significant amount of galactose is found in non-dairy foodstuffs, such as vegetables and fruits (Berry, Palmieri et al., 1993; Acosta and Gross and Grosset al., 1995). More importantly, galactose is produced endogenously from the natural turnover of glycolipids and glycoproteins (Berry, Nissim et al., 1995). Using isotopic labeling, Berry and coworkers demonstrated that a 50kg adult male could produce up to 2 grams of galactose per day (Berry, Nissim et al., 1995; Berry, Moate et al., 2004), 2004). Once galactose is formed intracellularly, it is converted to gal-1P by GALK and in GALT-deficient patient cells. As a result, gal-1P is concentrated more than one order of magnitude above normal, even with strict adherence to a galactose-restricted diet. Accumulation of gal-1P is regarded as a major, if not sole, factor for the chronic complications seen in patients with Classic Galactosemia, as suggested by both clinical observation and experimental results from yeast models. Patients with inherited deficiency of GALK, who do not accumulate gal-1P, do not experience the brain and ovary complications seen in GALT-deficient patients (Gitzelmann, Wells et al., 1974; Gitzelmann 1975; Stambolian, Scarpino-Myers et al., 1986). While gal7 (i.e, GALT-deficient) mutant yeast stops growing upon galactose challenge, a ga17 ga11 double mutant strain (i.e, GALT- and GALK-deficient) is no longer sensitive to galactose (Douglas and Hawthorne et al.,1964; Douglas and Hawthorne, 1964, 1966). Based on these observations, in conjunction with dietary therapy, inhibiting GALK activity with a safe small-molecule inhibitor might prevent the squeals of chronic gal-1P exposure in patients with Classic Galactosemia.
Figure 3.
Catalytic mechanism of GALE.
5.2. Research design
For the past few years, our group has conducted high-throughput screening (HTS) of small molecule compounds, which could inhibit human GALK enzyme in vitro (Tang et al., 2010; Wierenga et al., 2008). To date, we have screened over 300,000 compounds of diverse chemical structures and identified a few promising hit compounds for further characterization. One of the characterization steps involved the use of SDM to change the respective amino acids of the GALK active site in order to confirm the predicted molecular interactions between the selected inhibitors and it target, GALK, through high-precision docking programs such as GLIDE (Schrödinger). Another characterization step that is noteworthy to mention is the assay for the kinase selectivity of the selected GALK inhibitors. As alluded above, GALK belongs to a unique small molecule kinase family, the GHMP kinase family (Bork, Sander et al., 1993). While the substrates of the GHMP kinases differ widely, the ATP-binding sites of the enzymes share a significant degree of structural homology (Tang, Wierenga et al., 2010). It is, therefore, important to ensure our selected GALK inhibitors did not cross-inhibit other GHMP kinases or other kinases in general.
5.3. The results
Selectivity is always one of the most important properties for developing therapeutic kinase inhibitors because of potential side-effects from unwanted inhibition of other kinases. During the characterization phase of our hit compounds, we found six compounds that selectively inhibit GALK but not any of the other GHMP kinases. These included MVK, which shares a high degree of structural similarity with GALK (Tang, Wierenga et al., 2010). In order to understand what structural elements conferred the specificity of these compounds, we aligned the crystal structure of human GALK and human MVK and focused on the ATP-binding site. Eight amino acid residues and the L1 loop were found to be different in these two kinases. SDM was employed to mutate each residue individually or the L1 loop, and the effects of the changes on the inhibitory capabilities of the compounds were tested. Two compounds were found to be affected by the mutation S140G (Table 1) (Tang, Wierenga et al., 2010). Ser140 of GALK resides in the signature motif of the GHMP kinase family, Motif II; but this amino acid is not conserved among the GHMP kinases. GALK is the only member that has a serine at this site. This could explain the selectivity of these two compounds. Furthermore, computational molecular docking confirmed that these two compounds interacted with Ser140 through hydrogen bonds; substituting serine with glycine abolished the hydrogen bonds and totally compromised the binding of the compounds to the enzymes.
Our use of SDM in the characterization of promising GALK inhibitors not only helped identify and confirm the amino acids of GALK with which these small molecules interact, but also exemplified a more rapid and cost-effective way to study the structural interactions between small molecule modifiers and their targets. This novel approach is particularly useful when large-scale co-crystallization projects are not feasible. These studies paved the way for more in-depth investigations to identify the structural determinants required for the inhibitor selectivity of GALK and GHMP kinases.
6. Concluding remarks
Using the disease Galactosemia as an example, we showed that site-directed mutagenesis (SDM) plays a vital role in biomedical research. As in the case of Galactosemia, in which the diagnosis begins at the bedside of the affected newborns, SDM can be employed in every step of basic and translational research in an attempt to improve the prognosis and treatment of the patients. Further, not only did we show that SDM can be applied in traditional applications, such as expression analysis, we have also expanded its use in innovative drug design and the basic understanding of kinase inhibitor selectivity.
Mutations
kcat (S-1)
KM of ATP (µM)
KM of Galactose (µM)
Effects on IC50 of compound 1
Effects on IC50 of compound 4
Effects on IC50 of compound 24
T77L
4.1
218.4
1305.2
None
None
None
S79N
4.8
303.4
1227.3
None
None
None
L145Y
11.6
259.7
222.7
None
None
None
L145A
6.4
379.9
356.8
None
None
None
W106A
No protein expression
-
-
-
-
-
W106T
No protein expression
-
-
-
-
-
Y109L
43.2
70.2
963.2
None
None
None
Y109A
8.7
579.3
268.7
None
None
None
GALK Loop to MVK Loop
0.1
695.4
1857.3
None
None
None
S140G
2.1
8.2
141.9
None
Increased 10-fold
Increased 20-fold
L135P
13.3
51.1
544.9
None
None
None
R37K
0.4
6.4
623.8
None
None
None
R37A
No activity
-
-
-
-
-
WT
17.5
20.9
319
-
-
-
Table 1.
Effect of amino acid changes in human GALK on their enzymatic properties and the IC50 of selected inhibitors
Acknowledgement
We acknowledge that we could not have completed this manuscript without the outstanding contributions made by our scientific and clinical colleagues, as well as patient volunteers. Research grant support to Kent Lai includes NIH grants 5R01 HD054744-04 and 3R01 HD054744-04S1.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/42539.pdf",chapterXML:"https://mts.intechopen.com/source/xml/42539.xml",downloadPdfUrl:"/chapter/pdf-download/42539",previewPdfUrl:"/chapter/pdf-preview/42539",totalDownloads:1977,totalViews:507,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"May 12th 2011",dateReviewed:"March 15th 2012",datePrePublished:null,datePublished:"February 5th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/42539",risUrl:"/chapter/ris/42539",book:{slug:"genetic-manipulation-of-dna-and-protein-examples-from-current-research"},signatures:"M. Tang, K.J. Wierenga and K. Lai",authors:[{id:"104841",title:"Dr",name:null,middleName:null,surname:"Lai",fullName:"Lai",slug:"lai",email:"kent.lai@hsc.utah.edu",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Background",level:"1"},{id:"sec_2_2",title:"2.1. What is galactosemia?",level:"2"},{id:"sec_3_2",title:"2.2. How are the different types of galactosemia detected and diagnosed?",level:"2"},{id:"sec_4_2",title:"2.3. What are the current treatments for galactosemia, and what is the outlook for patients?",level:"2"},{id:"sec_6",title:"3. Use of SDM to confirm disease-causing mutations in human GALT, GALK, and GALE genes identified clinically",level:"1"},{id:"sec_6_2",title:"3.1. The issues",level:"2"},{id:"sec_7_2",title:"3.2. Research design",level:"2"},{id:"sec_8_2",title:"3.3. The results",level:"2"},{id:"sec_8_3",title:"3.3.1. Type I (GALT-deficiency) galactosemia",level:"3"},{id:"sec_9_3",title:"3.3.2. Type II (GALK-deficiency) galactosemia",level:"3"},{id:"sec_10_3",title:"3.3.3. Type III (GALE-deficiency) galactosemia",level:"3"},{id:"sec_13",title:"4. Use of SDM in the understanding of catalytic mechanisms of the human GAL enzymes",level:"1"},{id:"sec_13_2",title:"4.1. The issue",level:"2"},{id:"sec_14_2",title:"4.2. Research design",level:"2"},{id:"sec_15_2",title:"4.3. The results",level:"2"},{id:"sec_15_3",title:"4.3.1. GALK",level:"3"},{id:"sec_16_3",title:"4.3.2. GALT",level:"3"},{id:"sec_17_3",title:"4.3.3. GALE",level:"3"},{id:"sec_20",title:"5. Use of SDM in the development of novel treatment of Type I (classic or GALT-deficiency) galactosemia",level:"1"},{id:"sec_20_2",title:"5.1. The issues ",level:"2"},{id:"sec_21_2",title:"5.2. Research design",level:"2"},{id:"sec_22_2",title:"5.3. The results",level:"2"},{id:"sec_24",title:"6. Concluding remarks",level:"1"},{id:"sec_24_2",title:"Acknowledgement",level:"2"}],chapterReferences:[{id:"B1",body:'AcostaP. Band GrossK. C1995Hidden sources of galactose in the environment.Eur. J. Pediatr. 154(7 Suppl 2): S8792'},{id:"B2",body:'AlanoAAlmashanuSChinskyJ. MCosteasPBlitzerM. GWulfsbergE. Aand CowanT. M1998Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.J. Inherit. Metab. 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L1999Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia. Am. J. Hum. Genet. 642462470'},{id:"B84",body:'WohlersT. Mand Fridovich-keilJ. L2000Studies of the 94M-substitutedhuman UDPgalactose-4-epimerase enzyme associated with generalized epimerase-deficiency galactosaemia. J. Inherit. Metab. Dis. 23(7): 713-729.'},{id:"B85",body:'WongL. JSheuK. FLeeS. Iand FreyP. A1977aGalactose-1phosphate uridylyltransferase: isolation and properties of a uridylyl-enzyme intermediate. Biochemistry. 16510101016'},{id:"B86",body:'WongS. Sand FreyP. A1977bFluorescenceand nucleotide binding properties of Escherichia coli uridine diphosphate galactose 4-epimerase: support for a model for nonstereospedific action. Biochemistry. 162298305'},{id:"B87",body:'YangDShipmanL. WRoessnerC. AScottA. ISacchettiniJ. C2002Structure of the Methanococcus jannaschii mevalonate kinase, a member of the GHMP kinase superfamily. J. Biol. Chem. 2771194629467'},{id:"B88",body:'YangS. Land FreyP. A1979Nucleophile in the active site of Escherichia coli galactose-1-phosphate uridylyltransferase: degradation of the uridylyl-enzyme intermediate to N3-phosphohistidine. Biochemistry. 181429802984'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"M. Tang",address:null,affiliation:'
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1. Introduction
The Red Indians knew that the North American buffalo had a single pleural cavity. A single arrow to the chest was enough to collapse both lungs and expedite the death of the beast. On the other hand, the elephant is unique insofar as it is the only mammal whose pleural space is obliterated by connective tissue. This natural pleurodesis has been known for over 300 years but only recently explained [1]. Apparently, the elephant is the only mammal that can remain submerged far below the surface of the water while snorkelling. It is intriguing though that the foetal elephant has normal pleural spaces that obliterate later in gestation [2]. Humans are slightly luckier; they enjoy two pleural spaces separated by mediastinal structures; if one lung collapses, the other one sustains life. However, there are reports in the literature of some patients with pleuro-pleural congenital communications, presenting with simultaneous bilateral pneumothoraces, the so-called buffalo chest [3].
Humans collapse their lungs frequently, and the different ways we deal with this common condition match its frequency. There is bound to be differences in opinion, and the multicentre randomised controlled trials (RCT) have not come up with a solid protocol to guide management. There was no general agreement on therapy when Ruckley and McCormac of the Royal Infirmary of Edinburgh described the management of pneumothorax in 1966 [4]. There is no agreement at our present time still, despite the technological advances in our knowledge and the available randomised controlled trials. We could not agree more with Robert Cerfolio et al. on their statement that “although thoracic surgeons are the best trained physicians to manage chest tubes and pleural problems, they often do not speak the same language or recommend similar treatment algorithms even to each other” [5].
2. The physiology of respiration and pneumothorax
The pressure in the pleural space is determined by the difference between the lung elastic recoil and volume changes of the semi-rigid chest wall. The rib cage moves in three dimensions; the girdle handle movement of the ribs increases the anteroposterior and the lateral dimensions of the chest, whereas the piston-pump movement of the diaphragm leads to an increase in the vertical dimension of the chest cavity. The chest and diaphragm movements create a physiological negative pressure within the pleural space that forces the lung to change shape and volume with the respiratory cycle, resulting in inflation and deflation. Neutralising this negative pressure in the pleural space leads to lung collapse, as the elastic structure of the lung favours its collapse (recoil). Pneumothorax or air in the pleural space invariably leads to lung collapse. A thin film of fluid exists between the parietal and visceral pleurae to lubricate the sliding of these two structures, roughly 15 mls in a 70 kg adult person. The fluid is a microvascular filtrate produced by the parietal pleura and is cleared also by the parietal pleural lymphatics, a process similar to that in any other body organ.
3. Epidemiology and pathology of pneumothorax
The term “pneumothorax” was first coined by Itard (1803), but it was Laennec (1819) who described its clinical picture [6]. The term refers to “air in the pleural space”. Pneumothorax is a significant global health problem ranking high on the list of common medical conditions, especially in the emergency department. In the United Kingdom (UK), the overall person consulting rate for pneumothorax (primary and secondary combined) was 24 per 100,000 each year for men and 9.8 per 100,000 each year for women. Hospital admissions for pneumothorax as a primary diagnosis occurred at an overall incidence of 16.7 per 100,000 per year for men and 5.8 per 100,000 per year for women. Mortality rates were 1.26 per million per year for men and 0.62 per million per year for women [7].
How does air gain access to the pleural space? Well, there are several mechanisms for this to happen. Communication between atmospheric air and the pleural space can result from trauma, penetrating injuries, impalements, stabs, bullets and ammunition. Fractured ribs puncturing the lung is a common cause for traumatic pneumothorax, recorded in our accident and emergency department (58 patients between January 2007 and 2018). Pneumothorax could also occur spontaneously and unprovoked due to a puncture in the visceral pleura, allowing air to pass from the open alveoli or small bronchi directly into the pleural space. Air can gain access to the pleural space from holes or tears in the aero-digestive system, such as neck stabs to the trachea, or a bronchopleural fistula due to tuberculosis or oesophageal rupture. Iatrogenic pneumothorax is caused by interventional procedures such as central line access, bronchoscopy, oesophagoscopy, insertion of stents, etc. Air in the peritoneal cavity can gain access to the chest through holes (fenestrations) in the diaphragm. This is one of the explanations of catamenial pneumothorax [8, 9]. Pneumothorax following substance abuse and recreational drugs, especially cocaine, cannabis and marijuana, has been associated with bullous disease and pneumothorax. However, many is the time bullae are absent and the pneumothorax is associated with pneumomediastinum or pneumopericardium. In these instances, air leak does not track to the lung surface, but instead it tracks into the connective tissue separating the lung segments and heads towards the hilum. To be comprehensive one should not forget about gas producing organisms which might generate air in the pleural space without any of the above breaches.
One-way valve motion of air from the lung to pleural space is a dreaded complication. It could lead to life-threatening tension pneumothorax. In this complication, not only the ipsilateral lung collapses, but the mounting pressure on the mediastinum pushes the central structures and restricts movement of the contralateral lung. Dislocation of the heart to the contralateral side might reach a critical degree that kinks the vena cavae and severely restricts venous return to the heart. This could result in hyperacute heart failure and death [10]. Cyanosis, sweating, severe tachypnoea, tachycardia and hypotension may indicate the presence of this medical emergency. Diagnosis of tension pneumothorax is clinical, and a needle or chest drain must be inserted, before obtaining a chest X-ray.
4. Classification and treatment
Eighty percent of pneumothoraces are secondary to trauma, and 20% spontaneous without provocation. Two big categories of spontaneous pneumothorax (SP) exist, with bimodal age distribution: primary SP 15–35 years of age and secondary SP +55 years of age. Pneumothorax is distinctly rare among children less than 15 years. Wilcox et al. reported 17 cases in 12 years [11]. Primary SP occurs on a background of normal lungs, whereas secondary SP is associated with diseased lungs, such as emphysema, chronic obstructive pulmonary disease (COPD), lung fibrosis and cystic fibrosis. Secondary SP is strongly related to cigarette smoking and associated with a higher morbidity and mortality compared to primary SP. Primary pneumothorax has been associated with rupture of apical bullae or blebs (Figure 1) and has a 54.2% chance of recurring after the first episode [12]. In the UK the male-to-female ratio is 3:1 [7].
Figure 1.
Single apical bulla, a common cause of primary spontaneous pneumothorax.
The British Thoracic Society (BTS) has published an updated summary of the management of pneumothorax in 2010 [10]. Similar guidelines were published earlier by the American College of Physicians in 2001 [13] and later by the European Task Force in 2015 [14]. Breathlessness and the size of pneumothorax influence the management of SP. There is a general consensus that conservative management should be tried in the first episode, as conservative management of small pneumothoraces has been shown to be safe [10, 15]. Surgery proved that recurrence is less, and video-assisted thoracoscopic surgery (VATS) has opened the option of treating even the first-time pneumothorax on semi-urgent basis [16, 17, 18]. However, there has been no general agreement on the most effective type of surgery or that which is most accepted by patients. Ostensibly such a choice should result in the least incidence of recurrence. Axillary thoracotomy, full posterolateral thoracotomy, limited lateral muscle sparing mini-thoracotomy and triportal, biportal and needlescopic uniportal VATS have all been utilised [10, 18, 19]. A subxiphoid approach has also been tried and reported [20]. These operations have two objectives: firstly, to deal with the source of air leak (pneumostasis) by bullectomy/blebectomy, etc. and, secondly, to obliterate the pleural space leading to permanent adherence of the lung to the chest wall (pleurodesis or symphysis). In essence, we strive to emulate the elephant pleural space and prevent recurrence.
In the 1950s and 1960s, the treatment varied from extremely conservative bed rest only to early insertion of a Malecot catheter through the second intercostal space anteriorly (very painful!) and thoracotomy or bilateral thoracotomies for non-resolving cases [4]. Today’s management is nowhere near that, and minimal access surgery or VATS has taken up the management of pneumothorax to a new level [19].
Several randomised and non-randomised trials (RCT) looked into the difference between the optimal surgical techniques in SP [21]. There is no evidence to support the superiority of either VATS or open thoracotomy in the treatment of pneumothorax because the number of randomised trials is sparse and they are underpowered to detect any meaningful difference. Barker et al. published an important meta-analysis of four randomised and 25 non-randomised studies performed in 2007 comparing VATS to open thoracotomy [22]. Complex statistical tests of homogeneity and sensitivity analysis with a hypothetical model biased against open surgery were undertaken. RCT without comparative control groups were excluded. They reported a worrying fourfold increase in the recurrence of pneumothorax following VATS procedure compared to thoracotomy. Their relative risk (RR) favours open surgery; however, postoperative pain could not be assessed since most studies did not report this outcome. Neither did they report on length of hospital stay, due to severe heterogeneity in reporting. A similar previous study by Sedrakyan et al. looking only at the randomised trials did not show this difference [23]. The conclusion is that recurrence following VATS averaged 4.5%, whereas that following mini-thoracotomy was 2.3%. Waller et al. randomised 30 patients to VATS and 30 to open thoracotomy [24]. They concluded that VATS is superior to thoracotomy in the treatment of primary SP but had a higher recurrence rate in secondary SP. Ayed et al. in a randomised trial found VATS superior to thoracotomy but reported higher recurrence rates [25]. A best evidence topic by Vohra et al. reiterated on the superiority of VATS insofar as pain control, less hospital stay and better early lung functions [26]. It stopped short of recommending open thoracotomy for the treatment of this condition, quoting the Barker study. It is hard to imagine that any contemporary surgeon or clinician would recommend open thoracotomy over VATS to their patients, based on this evidence. VATS is the most favoured approach by patients. The Barker study, despite their extensive heterogeneity tests, has lumped together widely heterogeneous approaches to the previously described objectives of pneumostasis and pleurodesis. Great variations exist when it comes to what surgeons do inside the chest, a fact not factorised in the meta-analysis. In our opinion, it should not matter in any way or form how one enters the chest, whereas it matters what one does once inside the chest. Indeed, the Barker study showed that in studies that did the same pleurodesis through two different forms of access, the relative risk (RR) of recurrences in patients undergoing VATS compared with open surgery was similar [22].
With regard to pneumostasis, the practice varies widely between doing nothing (if a bulla is not found) and performing a variety of procedures. These include blind wedge of the lung apex (apicoectomy), ligation of bulla, tying, stitching, stapling, diathermy, applying silver nitrate and lasering among other methods [27, 28, 29]. Each of these variants might have a subgroup, for example, stapling with or without buttressing or covering the stapling line to reduce postoperative air leak. Should the treated bulla site (staple line) be covered with bioglue or a sealant agent? Which one? Does a pleural tent work? [30, 31, 32]. This choice could be an attractive option for ventilated patients in intensive care and for patients with severe secondary SP [33].
It is conceivable that some clinical importance is attached to the function of the pleura and the preservation of this function is advocated when a single apical bulla is all that explains the pneumothorax. In addition, pleurodesis is not without its complications. It can induce severe postoperative chest pain and increase the risk of bleeding and unscheduled return to theatre. In addition, it poses difficulties with subsequent thoracic surgery, e.g. if lung transplantation will be required later in life. Following this line of thinking, RCT have looked into the difference between bullectomy alone and bullectomy coupled with pleurodesis [34, 35, 36]. The general consensus, bar the Korean trial, is that pleurodesis with bullectomy reduces recurrence.
We then come to the second objective of pleurodesis. Several options exist, scratching, abrasion, partial or semitotal pleurectomy and pleural sclerosing agents [37]. Several chemical agents have been described: talc, tetracycline, minocycline, autologous blood, dextrose, etc. [38, 39, 40, 41]. The use of chemical pleurodesis is tied to the complication of empyema, which adds insult to injury. The bottom line is that none of these techniques or agents could give a 100% guarantee of freedom from recurrence. Heterogeneity in the methodology of RCT leads to significant differences in outcomes. Nor does the meta-analysis of Barker take into account the human factor of surgical experience and learning curves. It is not useful to lump together trainees at the beginning of their VATS learning curve together with experienced surgeons in this field. Unsupervised trainees are bound to have high recurrence rates, skewing the figures. Familiarity with small details that might avert recurrence is a function of experience. Meticulous examination of the lung surfaces is vital to unveil bullae in other lobes. Seventy percent of postoperative pneumothorax recurrences probably developed because of overlooked bullae and incomplete resection of bullae in the early period of VATS experience [42]. Equally important is to scrutinise the diaphragmatic surface for fenestrations in the child-bearing age of ladies [43]. Identification of the lung margin rosary of blebs and the knowledge of how to deal with them prevent recurrence (Figure 2). Detailed knowledge of the stapling devices, their colour code and sizes is mandatory, as well as the realisation that the intersection point of two stapling lines is the weakest link for potential air leak. How many of us perform the bubbling test (underwater testing for air leak before and after pneumostasis)? It seems logical to make sure that there is no air leak by the end of pneumostasis, to ensure the complete expansion of the lung and guarantee pleurodesis (Figure 3). Many is the time we found the source of air leak hiding within an azygos lobe (Figure 4).
Figure 2.
(a) Rosary of marginal blebs (beads), which can lead to recurrent pneumothorax. (b) Contact diathermy obliterates them and forms a scar at the margin.
Figure 3.
Bubbling test after stapling an apical bulla. More stapling was needed until the lung was watertight.
Figure 4.
Multiple apical bullae hiding within an azygos lobe.
From the above discussion, it is unreasonable to assign increased recurrence rates to the way we access the chest cavity. Access should never matter. Minimal access surgery has leapt to the forefront of access choices preferred by patients. It has proven to result in less postoperative pain, less usage of analgesics and anti-emetics, early recovery, less stay in hospital and early return to work. Therefore, it is very unlikely to advocate open thoracotomy as a first-choice procedure on the basis of the previously mentioned systematic reviews alone.
Who should and who should not insert a chest drain? There is no consensus on this matter. However, surgical abilities even of a minor order are required to safely insert a chest drain; after all this is a surgical procedure. Therefore, proctored training is mandatory before any trainee is allowed to do it alone. Should one be certified before being allowed to perform this procedure unsupervised? This is debatable. Thoracic surgeons and their trainees are the most experienced to deal with chest drains; however, the idea that surgeons should look after all chest drains in the hospital is ludicrous and logistically unachievable.
The technique of drain insertion keeps changing. The BTS guidelines in 1993 recommend using a trocar (harpoon!); however, deaths had been reported from their use, and subsequently, the BTS changed its recommendations in an updated report in 2010 [10, 44]. Harris et al. reported on current practice and adverse incidents related to chest drains at 148 acute hospitals in the UK between 2003 and 2008 [45]. Thirty-one cases of chest drain misplacement were reported with seven deaths. Misplaced drains were inserted in the liver (10), peritoneal space (6), heart (5), spleen (5), subclavian vessels (2), colon (1), oesophagus (1) and inferior vena cava (1). One of my previous mentors at the University Hospital of Wales, the late Mr. Ian Breckenridge, has previously stated that “I regard trocar systems as potentially lethal weapons, and their misuse has been responsible for the few fatalities that I have seen, when heart, lung and liver have been lacerated” [46]. Similar serious injuries and fatalities were reported elsewhere [47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57]. Trocars are now banned from the UK. It is stating the obvious that the litigation expenses accompanying these cases are exorbitantly costly to the hospital trust and the taxpayer in the UK.
Clinicians differ about the choice of drain type and size [58]. Physicians and interventional radiologist tend to choose small calibre drains (medical drains), such as pigtails, 12F or 14F, whereas surgeons tend to put larger tubes +24F (surgical drains) [10, 59, 60]. Drain kinking, blockage and accidental dislodgment are common complications of small-bore drains (Figure 5). Per contra, Riber et al. in a retrospective study concluded that surgical (wide-bore) drains significantly increase the dwell time in primary SP [61]. Although they may be effective in managing pleural infection and less painful than large drains, small-bore drains may be less effective for pleurodesis [58]. The war between chest physicians and chest surgeons around the calibre of the chest drain will continue. Chest physicians have evidence that for air drainage size does not matter and a 16F drain is as good as any. Surgeons see the dysfunctional spectrum of these drains and correct the situation by inserting larger drains.
Figure 5.
Dysfunctional medical drain (14F) removed to insert a surgical drain (28F) for pneumothorax. Twisting and overtight anchorage stitch obliterated the drain lumen.
A persistent air leak with or without re-expansion of the lung is the usual reason for consideration of the use of suction, although there is no evidence for its routine use. The optimal level of suction on the drain is controversial, and so is the optimal time of its removal [62, 63, 64, 65, 66]. Data on the actual intrapleural pressure during the use of these systems is lacking [67]. Most of the knowledge is extrapolated from studies after lung resection, and protocols for pneumothorax drain insertion are scanty. It seems that the practice is a personal preference rather than evidence driven. We tend to believe that initial suction will guarantee the full expansion of lung and improves the chances of pleurodesis.
Recent introduction of the digital drainage systems seems to offer more physiological and dynamic mobile suction, assisting in enhanced early recovery [68, 69]. Its routine use has been recommended by the National Institute for Health and Clinical Excellence (NICE) after VATS pulmonary resections [70]. For how long should we leave the drain? One day, 1 week or more? Some believe (including the author) that if the drain is not serving its purpose, it should be removed. It is our practice to remove the drain the day following the surgery, provided the digital drain registers absence of air leak and the lung is fully expanded on the chest X-ray. The backdrop of such an approach is to accept reinsertion of the drain in a minority of patients when we get it wrong. The patient is allowed home after a normal chest X-ray has followed the drain removal. Others are more conservative and of the opinion that for the pleurodesis to succeed, the drain should remain in situ 3–7 days. We tend to send patients home with a Heimlich valve (flutter bag) if air leak persists more than 3 days and follow them weekly in the outpatient clinic. There are no RCTs to compare drain dwell times, and therefore general rules apply. In the absence of air leak while suction is off, and the lung is fully expanded on the chest X-ray the drain could safely be removed, otherwise; recurrence of pneumothorax is guaranteed.
There is a general consensus that drains should never be clamped [10, 71]. However, some of us do clamp drains and send patients to the radiology department for a chest X-ray, in preparation for removing the drain despite the air leak. It must be emphasised that this management should remain selective. This “provocative” approach in removing the drain despite air leak was described before by Kirschner et al. and Cerfolio et al. [72, 73]. If the chest X-ray shows the lung stuck to the chest wall after 2 weeks of tube time, we clamp the tube and send the patient for another X-ray. If the patient is clinically well and there is no change in lung expansion, then the drain is safely removed without bothering to close the drain site, which is usually either infected or has necrotic margins that take stitches badly. A pressure dressing is all that is needed. The stuck lung does not collapse, and the drain site closes in a week or two by secondary intention. The patient has to be reassured about the hissing sound through the drain site, which stops within a week or so.
To complicate matters further, air could entrain back into the chest at the time of drain removal. This usually leads to a small residual pneumothorax, which does not expand on subsequent radiological examination. It is important to realise the difference between erroneous drain removal and recurrence of genuine air leak. The incidence of this complication is technique-dependant and proportional to the experience of the staff member allocated for this task. Instructions given to the patient at the time of removing the drain are crucial. Again RCT about removing chest drains on full inspiration, full expiration, mid inspiration or Valsalva manoeuvre found no statistical difference, and therefore no evidence-based practice could be extrapolated [73, 74]. The rate of absorption of air in the chest is roughly 1–2% of the volume of the hemithorax every 24 hours, and complete re-expansion usually takes 2–7 weeks [75]. However, this might be too late for pleurodesis. By that time the parietal pleura (in the case of pleurectomy) would have healed, and the partially collapsed lung would not stick to the chest wall. Likewise, pleurodesing agents might be diluted or washed away by the reactive effusion, resulting in treatment failure.
From the above discussion, it is safe to conclude and agree with Lim that “No single aspect of postoperative care in general thoracic surgery is subject to more variation than the management of chest drains, … yet almost all thoracic surgeons and institutions manage chest drains differently” [76].
6. Pneumothorax and pregnancy
Spontaneous pneumothorax during pregnancy is rare but not unusual [77, 78]. Notoriously pneumothorax recurs during pregnancy and poses risks to the mother and foetus during labour. In addition, exposure to radiation of the X-rays in the first trimester is tied to foetal deformities and abnormalities. There is no unified evidence-based practice to guide management in this scenario. Historically it was managed by intercostal drainage for the rest of the pregnancy duration, thoracotomy at any stage, premature induction of labour or caesarean section. The clinician must be aware that even in the first trimester, the diaphragm moves cephalad approximately 4 cm. The classical landmarks for drain insertion do not apply.
The most contemporary recommendation of management is a conservative approach. Expectant management is recommended if the mother is not dyspnoeic and there is no foetal distress and the pneumothorax on the chest X-ray is not significant (<2 cm). Symptomatic mothers could have needle aspiration or drain insertion to resolve the pneumothorax. There is no consensus as what to do with non-resolving pneumothorax, but in our centre, we tend to assess the risk in conjunction with the obstetrician’s advice and perform a VATS bullectomy and partial parietal pleurectomy. This is safe in the first trimester but should be avoided after that.
With regard to advice to the risk during labour, we adopt the one given by Lal et al. and the BTS guidelines [10, 79]. Elective-assisted delivery (forceps or ventouse extraction) at or near term is recommended, with regional (epidural) anaesthesia. Less maternal effort is required with forceps delivery, which theoretically reduces the chance of recurrence. Close cooperation between the respiratory physician, obstetrician and thoracic surgeon is essential, requiring delivery to be undertaken in a tertiary referral centre with all three specialties under one roof. If a caesarean section is unavoidable, then a spinal anaesthetic is preferable to a general anaesthetic. To avoid desaturation and tension during general anaesthesia, a prophylactic intercostal drain could be considered as a safety measure. It is advisable that the mother should undergo elective VATS procedure after convalescence due to the risk of recurrence in subsequent pregnancies.
7. Pneumothorax and air travel
Commercial air traffic is on the rise. The number of medical emergencies on-board aircraft is increasing as the age-increasing general population becomes more mobile and adventurous. Travellers with respiratory diseases are at particular risk for in-flight events. Exposure to lower atmospheric pressure in a pressurised cabin at high altitude may result in pneumothorax. Gas expansion within enclosed spaces in the human body could expand by 25–30% at the typical cruising altitude of a commercial airline flight, causing significant hypoxia. Patients at risk are those with bullae, cystic lung disease, lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis, cystic pulmonary adenomatoid malformation (CPAM) and cystic bronchiectasis [80].
The currently available guidelines are admittedly based on sparse data and include recommendations to delay air travel for 1–3 weeks after thoracic surgery or resolution of the pneumothorax [80]. No fatalities have been reported due to pneumothorax on-board aviation generally; however, true incidence of specific illnesses associated with air travel has been difficult to assess.
The diagnosis of pneumothorax can be career limiting in the US Air Force. Once an SP has been diagnosed in an individual, he/she will be grounded from further flight duties until either 9 years have elapsed without a recurrence or there has been a bilateral parietal pleurectomy [81].
Barotrauma during or after scuba diving (also on the rise) can rarely lead to pneumothorax, especially on sudden ascent not allowing time for equilibrium. The data is sparse, and there is no solid recommendation about this sport in the literature. Snorkelling sport up to a depth of 10 m does not seem to increase the risk of pneumothorax.
8. Genetics and pneumothorax
A lot of work needs to be done in the field of spontaneous pneumothorax that runs in families. Genetic profiling in patients presenting with pneumothorax might be indicated, in the hope of finding defective genes that expose conditions such as Marfan, Ehler Danlos and Birt-Hogg-Dubé syndromes [82]. These have one thing in common, defective connective tissue. Patients may or may not have pre-existing lung cysts before their pneumothoraces, which can be bilateral and recurrent. Risk stratification of other siblings needs to be calculated and predicted [83]. The importance of this subject is realised by frequent flyers, pilots, airhostesses and scuba divers. They need to know the risk and whether prophylactic procedures would be a wise thing to go for. By the same token patients who are expected to require lung transplantation at one stage in their life, such as cystic fibrosis patients, require special consideration of treatment. Pleurodesis seems to render transplantation a difficult task, but this is not a prohibitive contraindication. It might be prudent to discuss the case with a lung transplantation centre before embarking on such treatment [84].
9. Complications of pneumothorax treatment
Getting the treatment of pneumothorax right is of paramount importance. The decision of which procedure to go for might not be crucial to fit patients but might endanger the lives of compromised patients. Patients with cardiopulmonary compromise, severe COPD and emphysema might have very little cardiopulmonary reserve, so much so they tolerate lung collapse poorly. Air leak is known to be a killer after lung volume reduction surgery for severe COPD patients. Assessment for general anaesthesia is essential for compromised patients. Consideration of alternative local or spinal/extrapleural analgesia might be required.
Insertion of intercostal tubes under non-sterile conditions leads to infection and empyema with formation of a thick rind over the visceral pleura, trapping the lung in a collapsed position. Lung re-expansion is formidable in this scenario. Formal thoracotomy and lung decortication might be required to re-inflate the lung and prevent chronic empyema with a permanently infected cavity. We never push an intercostal drain few centimetres into the chest (as possibly suggested by the chest X-ray). Pushing a bit of the unsterile part of the tube inside the chest leads to empyema. It is, however, safe to shorten a drain by pulling it out and re-anchor it with a fresh stitch.
Severe surgical (subcutaneous) emphysema could complicate insertion of a chest drain. The clinician should be aware of the position of the last lateral holes of the tube, which should always be inside the bony chest (Figure 6). Until the advent of the digital systems, which tell us exactly how much air is leaking, quantifying air leak visually was a subjective bias. No leak, countable bubbles, and coalesced bubbles were the measures of air leak in the underwater seal systems. This subjective assessment leads to days of unnecessary drain dwell time. Urgency of this complication is highlighted in ventilated patients in the intensive care. Insertion of a second large intercostal drain, subcutaneous cannulae and subcutaneous small-bore drains on suction has all been tried with varying success. It should be noted that fixed wall suction in these cases might lead to tension pneumothorax and the drain must be on gravity mode without suction. Information about how to deal with surgical emphysema is very sparse, and the management of severe air leak and surgical emphysema is controversial.
Figure 6.
Lateral holes of the intercostal drain are outside the chest, a common cause for surgical emphysema.
Should the need arise for a second drain to replace a dysfunctional one due to, e.g. blockage or kinking, the second drain should not be introduced at the site of the removed first one to reduce the risk of empyema. A fresh stab wound is better in the long run.
And last but not the least is the question of pain and analgesia which should be carefully worked out before and after surgical procedures or ward bedside pleurodesis. Talc pleurodesis is known to cause severe pain that can result in cardiac arrest, and it is, therefore, prudent to pre-empt it by administration of opioid analgesia before introducing the talcum powder or slurry [85]. The question of whether postoperative non-steroidal analgesia (NSAID) is detrimental to pleurodesis is not resolved. RCT have shown a negative predictive effect of such drugs to pleurodesis and increased incidence of recurrence. Therefore, it is best to avoid them in the immediate postoperative period [86, 87].
10. The future
There is a trend for single-port VATS procedures under sedation/epidural anaesthesia [88]. The so-called tubeless surgery has a lot to commend, avoiding the risk of general anaesthesia, early recovery and discharge from hospital. However, they have the inherent caveat of suitability for selected patients. Understanding of the technique and cooperation in case of conversion to general anaesthesia is mandatory.
Advances in diagnostic techniques have increasingly allowed the identification of lung abnormalities in patients previously labelled as having a primary spontaneous pneumothorax. This allowed different managements from that of simple pneumothorax. A good example of this is demonstrated in secondary SP. The choices for lung reduction surgery and the advent of valves have revolutionised the options for this category of severe COPD [89]. Bronchial valves have been used to treat prolonged air leak, especially in ventilated patients in the intensive care, with large air leaks and inflated lungs [90, 91]. In future we might see expansion of the use of “easily removable” and temporary bronchial valves especially in the subgroup of patients who are high risk for surgical intervention.
As the cost of VATS surgery comes down, as well as capacity increases in tertiary referral hospitals, we will see more of the operative treatment for first episode of spontaneous pneumothorax, on a semi-urgent basis (1–2 days from start of episode). Better risk stratification will identify those at high risk of recurrence and put them forward for early operation.
The economic reality of reducing cost and the technological advances might team up to drive change. It is possible to see scenarios whereby pneumothorax is treated as a day case. Patients are discharged home on the same operative day, with a chest drain in situ. They would be asked to enter the reading of air flow from the digital device daily. The information is transmitted by a social media application such as WhatsApp to the hospital which instructs the patient to call in for removal of the drain. Better still, the visiting district nurse could pay the patient a visit at home to remove the drain without the need for readmission. Fiction? Perhaps not!
Currently robotic surgery is too expensive for this type of surgery, and we have not come across any meaningful publications in this regard. However, when robotic expenses come down in due course, we might see a surge in the use of the robot.
11. Conclusion
Many controversies surround the management of pneumothorax. Surgical intervention either by VATS or open procedure leads to less incidence of recurrence. The variability in reported outcomes and the paucity of published multicentre randomised controlled trials highlight the need for further studies to investigate the best options for pneumostasis and pleurodesis.
Conflict of interest
I have previously received honoraria for providing educational material, presentations and lectures for Ethicon (Johnson & Johnson), Medtronic-Covidien and Karl Storz.
\n',keywords:"pneumothorax, video-assisted thoracic surgery, thoracotomy, pleurodesis, air leak, surgical emphysema, intercostal drain, COPD",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68427.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68427.xml",downloadPdfUrl:"/chapter/pdf-download/68427",previewPdfUrl:"/chapter/pdf-preview/68427",totalDownloads:479,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 5th 2018",dateReviewed:"May 29th 2019",datePrePublished:"August 2nd 2019",datePublished:"December 11th 2019",dateFinished:null,readingETA:"0",abstract:"Surgical intervention either by video-assisted thoracoscopic surgery (VATS) or open procedure proved its worth in reducing the incidence of recurrence in pneumothorax. However, many controversies surround the management of this common medical condition. Despite advances in knowledge and technology, chest physicians and surgeons could not be more divisive about the management of pneumothorax. There are no two thoracic surgical centres and possibly no two surgeons within the same hospital that agree on the management of the different aspects of pneumothorax. The variability in reported outcomes and the paucity of published multicentre randomised controlled trials (RCT) highlight the need for further studies investigating the best options for pneumostasis and pleurodesis. This chapter aims at discussing some of these controversies and reviews the literature at its current state of evidence.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68427",risUrl:"/chapter/ris/68427",signatures:"Khalid Amer",book:{id:"7093",title:"Pneumothorax",subtitle:null,fullTitle:"Pneumothorax",slug:"pneumothorax",publishedDate:"December 11th 2019",bookSignature:"Khalid Amer",coverURL:"https://cdn.intechopen.com/books/images_new/7093.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"63412",title:"Dr.",name:"Khalid",middleName:null,surname:"Amer",slug:"khalid-amer",fullName:"Khalid Amer"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"63412",title:"Dr.",name:"Khalid",middleName:null,surname:"Amer",fullName:"Khalid Amer",slug:"khalid-amer",email:"khalid.amer@btinternet.com",position:null,institution:{name:"Southampton Hospital",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The physiology of respiration and pneumothorax",level:"1"},{id:"sec_3",title:"3. Epidemiology and pathology of pneumothorax",level:"1"},{id:"sec_4",title:"4. Classification and treatment",level:"1"},{id:"sec_5",title:"5. Controversies surrounding chest drain insertion",level:"1"},{id:"sec_6",title:"6. Pneumothorax and pregnancy",level:"1"},{id:"sec_7",title:"7. Pneumothorax and air travel",level:"1"},{id:"sec_8",title:"8. Genetics and pneumothorax",level:"1"},{id:"sec_9",title:"9. Complications of pneumothorax treatment",level:"1"},{id:"sec_10",title:"10. The future",level:"1"},{id:"sec_11",title:"11. Conclusion",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'West JB. Snorkel breathing in the elephant explains the unique anatomy of its pleura. Respiration Physiology. 2001;126(1):1-8'},{id:"B2",body:'Eales NB. 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Does pigtail catheters relieve pneumothorax? A PRISMA-compliant systematic review and meta-analysis. Medicine. 2018;97(47):89'},{id:"B60",body:'Filosso PL, Sandri A, Guerrera F, Ferraris A, Marchisio F, Bora G, et al. When size matters: Changing opinion in the management of pleural space-the rise of small-bore pleural catheters. Journal of Thoracic Disease. 2016;8(7):E503-E510'},{id:"B61",body:'Riber SS, Riber LP, Olesen WH, Licht PB. The influence of chest tube size and position in primary spontaneous pneumothorax. Journal of Thoracic Disease. 2017;9(2):327-332'},{id:"B62",body:'Sharma TN, Agrihotri SP, Jain NK, et al. Intercostal tube thoracostomy in pneumothorax: Factors influencing re-expansion of lung. The Indian Journal of Chest Diseases & Allied Sciences. 1988;30:32-35'},{id:"B63",body:'Reed MF, Lyons JM, Luchette FA, et al. Preliminary report of a prospective, randomized trial of underwater seal for spontaneous and iatrogenic pneumothorax. 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Multicenter international randomized comparison of objective and subjective outcomes between electronic and traditional chest drainage systems. The Annals of Thoracic Surgery. 2014;98(2):490-496'},{id:"B69",body:'Gilbert S, McGuire AL, Maghera S, Sundaresan SR, Seely AJ, Maziak DE, et al. Randomized trial of digital versus analog pleural drainage in patients with or without a pulmonary air leak after lung resection. The Journal of Thoracic and Cardiovascular Surgery. 2015;150:1243-1249'},{id:"B70",body:'Thopaz+ Portable Digital System for Managing Chest Drains. NICE. 2018. Available from: https://www.nice.org.uk/guidance/MTG37/chapter/1-Recommendations [Accessed: November 11, 2018]'},{id:"B71",body:'Wong PS. Management of pneumothorax. Never clamp a chest drain. British Medical Journal. 1993;307:443'},{id:"B72",body:'Kirschner PA. “Provocative clamping” and removal of chest tubes despite persistent air leak. 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Spontaneous pneumothorax complicating pregnancy: Case report and review of the literature. The Journal of Emergency Medicine. 1989;7:245-248'},{id:"B79",body:'Lal A, Anderson G, Cowen M, et al. Pneumothorax and pregnancy. Chest. 2007;132:1044-1048'},{id:"B80",body:'Hu X, Cowl CT, Baqir M, Ryu MJ. Air travel and pneumothorax. Chest. 2014;145(4):688-694'},{id:"B81",body:'Voge VM, Anthracite R. Spontaneous pneumothorax in the USAF aircrew population: A retrospective study. Aviation, Space, and Environmental Medicine. 1986;57:939-949'},{id:"B82",body:'Gupta N, Sunwoo BY, Kotloff RM. Birt-Hogg-Dubé syndrome. Clinics in Chest Medicine. 2016;37(3):475-486'},{id:"B83",body:'Viveiro C, Rocha P, Carvalho C, et al. Spontaneous pneumothorax as manifestation of Marfan syndrome. BMJ Case Reports. 2013;2013:pii: bcr2013201697'},{id:"B84",body:'Weill D. Lung transplantation: Indications and contraindications. Journal of Thoracic Disease. 2018;10(7):4574-4587'},{id:"B85",body:'Tschopp JM, Boutin C, Astoul P, Janssen JP, Grandin S, Bolliger CT, et al. Talcage by medical thoracoscopy for primary spontaneous pneumothorax is more cost-effective than drainage: A randomised study. The European Respiratory Journal. 2002;20:1003-1009'},{id:"B86",body:'Ben-Nun A, Golan N, Faibishenko I, Simansky D, Soudack M. Nonsteroidal anti-inflammatory medications: Efficient and safe treatment following video-assisted pleurodesis for spontaneous pneumothorax. World Journal of Surgery. 2011;35(11):2563-2567'},{id:"B87",body:'Lardinois D, Vogt P, Yang L, Hegyi I, Baslam M, Weder W. Non-steroidal anti-inflammatory drugs decrease the quality of pleurodesis after mechanical pleural abrasion. European Journal of Cardio-Thoracic Surgery. 2004;25(5):865-871'},{id:"B88",body:'Pompeo E, Tacconi F, Mineo D, Mineo TC. The role of awake video-assisted thoracoscopic surgery in spontaneous pneumothorax. The Journal of Thoracic and Cardiovascular Surgery. 2007;133(3):786-790'},{id:"B89",body:'Kemp SV, Herth FJF, Shah PL. Bullectomy: A waste of space or room for improvement? Respiration. 2016;92:218-219'},{id:"B90",body:'Keshishyan S, Revelo AE, Epelbaum O. Bronchoscopic management of prolonged air leak. Journal of Thoracic Disease. 2017;9(Suppl 10):S1034-S1046'},{id:"B91",body:'Wood DE, Cerfolio RJ, Gonzalez X, Springmeyer SC. Bronchoscopic management of prolonged air leak. Clinics in Chest Medicine. 2010;31(1):127-133'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Khalid Amer",address:"khalid.amer@btinternet.com",affiliation:'
The Cardiovascular and Thoracic Centre, University Hospital Southampton NHS Foundation Trust, United Kingdom
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During that time was involved in relevant research projects like “Rome Reborn†with UCLA and University of Virginia. From 2008 to 2010 he has worked on Cultural Heritage virtual reconstruction, developing optimized methodologies for reality-based and interpretative-based modeling, for example the “3D Acquisition and modeling of POMPEII Forum†with Normale di Pisa and ETH of Zurich At the same time he has defined some experimental procedures for optical active 3D systems characterization. From January, 2011 he is employed as determined researcher at INDACO Department, Politecnico of Milan. Author of several papers and Journals about 3D Imaging applied in Industrial Design, Nautical Science, Cultural Heritage and Metrology Fields.",institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"Polytechnic University of Milan",institutionURL:null,country:{name:"Italy"}}},booksEdited:[],chaptersAuthored:[{title:"Integrated Reverse Modeling Techniques for the Survey of Complex Shapes in Industrial Design",slug:"integrated-reverse-modeling-techniques-for-the-survey-of-complex-shapes-in-industrial-design",abstract:null,signatures:"Michele Russo",authors:[{id:"103153",title:"Dr.",name:"Michele",surname:"Russo",fullName:"Michele Russo",slug:"michele-russo",email:"michele.russo@polimi.it"}],book:{title:"Laser Scanner Technology",slug:"laser-scanner-technology",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"92720",title:"Prof.",name:"Shenen",surname:"Chen",slug:"shenen-chen",fullName:"Shenen Chen",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of North Carolina at Charlotte",institutionURL:null,country:{name:"United States of America"}}},{id:"93506",title:"Prof.",name:"Mercedes",surname:"Farjas",slug:"mercedes-farjas",fullName:"Mercedes Farjas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Madrid",institutionURL:null,country:{name:"Spain"}}},{id:"94700",title:"Dr.",name:"Katsuyuki",surname:"Nakamura",slug:"katsuyuki-nakamura",fullName:"Katsuyuki Nakamura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100344",title:"Prof.",name:"Nieves",surname:"Gallego Ripoll",slug:"nieves-gallego-ripoll",fullName:"Nieves Gallego Ripoll",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/100344/images/2489_n.jpg",biography:"Nieves Gallego Ripoll received the Ph.D. degree in telecommunications and electronics engineering, B.E. and M.S. degrees in telecommunication engineering from the Polytechnic University of Valencia (U.P.V.), Spain. M.B.A. degree from the E.O.I. Business School, Spain. \nShe was with Siemens Munchen, A.G. and Nokia R&D Ulm, Germany, from 2000 to 2002. He joined UPV in 2003 where she was a teaching assistant at the Department of Electronics Engineering and a researcher at the Institute for the Applications of Advanced Information and Communication Technologies (ITACA). She currently is a freelance consultant.\nShe published articles for different national and international conferences and books. \nHer professional and research interests are related to detection and classification sensors, sensor networks, laser systems, optical systems, mobile communications and eSafety systems.",institutionString:null,institution:{name:"Universitat Politècnica de València",institutionURL:null,country:{name:"Spain"}}},{id:"104298",title:"Mr.",name:"Franco",surname:"Godone",slug:"franco-godone",fullName:"Franco Godone",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}},{id:"111582",title:"Dr.",name:"Leo",surname:"Kounis",slug:"leo-kounis",fullName:"Leo Kounis",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/111582/images/system/111582.jpg",biography:"Leo D. Kounis is Head of Department of the Communication\nand Informatics Battalion of the Hellenic Ministry of Defense,\nHellenic National Defense General Staff. He obtained his BEng\n(Hons) degree in Manufacturing Systems Engineering, his MSc\nin Quality Engineering, and his PhD in Systems Reliability from\nthe University of Hertfordshire, UK. Dr. Kounis has worked as\na senior quality engineer in a number of private companies in\nGreece and has acted as part-time lecturer and scientific advisor in academia. His\nresearch interests focus in the area of quality, transportation, and sustainable energy. He has published a number of scientific papers.",institutionString:"Hellenic Ministry of Defense",institution:null},{id:"135305",title:"Dr.",name:"Julio",surname:"Zancajo",slug:"julio-zancajo",fullName:"Julio Zancajo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"135306",title:"Dr.",name:"Teresa",surname:"Mostaza",slug:"teresa-mostaza",fullName:"Teresa Mostaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"150448",title:"Dr.",name:"J. Apolinar",surname:"Muñoz-Rodriguez",slug:"j.-apolinar-munoz-rodriguez",fullName:"J. Apolinar Muñoz-Rodriguez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"313983",title:"Dr.",name:"Danilo",surname:"Godone",slug:"danilo-godone",fullName:"Danilo Godone",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53849/images/system/53849.jpg",biography:"Danilo Godone holds a PhD in 'Agriculture, Forest and Food Sciences”, doctorate’s topic was cryosphere’s phenomena monitoring by geomatic methodologies. Currently he is a PostDoc grant holder, at Geohazard Monitoring Group (CNR IRPI), studying geomatic contribution in natural hazard monitoring and analysis. His main research interests are landslide, glacier and, more generally, natural disasters. During his activities he has developed skills in GIS, also by developing customised tools by R programming, and land surveying with GPS, LiDAR and UAV technologies. He is a member of NATRISK - Research Centre on Natural Risks in Mountain and Hilly Environments, in Turin University. He acts as a freelance consultant, in the same topics, for other research bodies, training agencies and professionals, too.",institutionString:null,institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}]},generic:{page:{slug:"our-story",title:"Our story",intro:"
The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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