Monitoring tofacitinib and baricitinib treatment [128].
\r\n\tIn the maintenance and conservation of our planet's biodiversity, knowledge of current biogeographical patterns, speciation or invasion processes, flora, fauna, natural history, and ecology have outstanding importance. Many areas of biodiversity are still completely undiscovered nowadays. The ecological impacts of global climate change, urbanization, overpopulation, environmental pollution, deforestation, land cover and land-use changes also have a significant impact on biodiversity, flora, and fauna, through biogeographical patterns.
\r\n\tThe management tools, methods and processes (as applied ecological aspects) of Protected Areas and National Parks are a very important part of conservation policy. I am sure that this book will be very useful for everybody who would like to get some insight into the recent problems of biodiversity research, ecology and conservation biology also from practical or theoretical viewpoints.
Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic disease that targets primarily the synovial joint lining and causes progressive disability. Untreated, PR leads to the destruction of the joints by the erosion of cartilage and bone material. Loss of physical function is the aftermath, which is why early treatment is vital for controlling disease activity and for preventing joint damage.
\nAngiogenesis is an important process for the growth and development of all tissues, during which new blood vessels are formed from pre-existing vascularization and play a critical role in the pathogenesis of several inflammatory autoimmune diseases, such as PR. Angiogenesis is triggered by the dominance of pro-angiogenic factors over endogenous angiostatic mediators. Studies conducted over the past two decades have suggested the involvement of numerous pro-angiogenic factors such as metabolites, ions, growth factors, hypoxia-inducible factors, cytokines, chemokines, extracellular matrix metalloproteinases, and adhesion molecules, in RA pathogenesis.
\nAlso, these pro-angiogenic factors were targets for possible therapies. Thus, the research has led to the emergence of new therapies with a key role in modulating the activity of the cellular immune response and inflammation in the synovial tissue.
\nAccording to studies, patients with RA, after treatment with biological agents, showed a significant decrease compared to the initial levels of acute-phase reactants and inflammatory proteins: C-reactive protein (CRP), the red blood cells sedimentation rate (ESR), pro-inflammatory cytokines (tumor necrosis factor-alpha, TNF-α; interleukins, IL-17, IL-8, IL-18), chemokines (CXCL12), growth factors (angiopoietins, Ang-1, Ang-2; growth factor of vascular endothelium, VEGF), adhesion molecules (vascular adhesion molecule 1, VCAM-1) and matrix metalloproteinases (MMP-9 and MMP-13).
\nBiological therapy has brought many benefits for patients, by improving the prognosis, evolution, stopping or reducing destructive lesions, obtaining remission and thus increasing the quality of life and maintaining social integration.
\nBiological therapy is no longer reserved only for cases that do not respond to classical therapy, as clinical studies have shown that the number of swollen and painful joints decreases, as well as the rate of osteoarticular destructive lesions.
\nThe pathological mechanisms that drive the synovial inflammation and structural damage in RA are complex.
\nResearch in the field of RA pathogenesis has been an essential tool in the development of disease-modifying drugs, biologic therapy, and the more recent targeted therapy. There are separate domains of research that combine to offer a complete picture of the disease etiopathogenesis. These include the study of trigger agents, autoantigen-autoantibody interaction, genetic susceptibility, articular and extraarticular pathology. Major disease subtypes defined by anti-citrulline peptide antibody (ACPA) positivity provide some differences in genetic associations, immune response, disease severity and treatment effectiveness [1].
\nThe presence of ACPA is highly specific for RA [2] and occurs in response to a set of citrullinated proteins, such as fibrin, fibronectin, vimentin, type II collagen and histones [3]. Citrullination is catalyzed by peptidylarginine-deiminase (PAD), a calcium-dependent enzyme. Another post-translational process that drives the formation of autoantigen in RA is carbamylation. It is defined by the change of the amino acid lysine to homocitrulline. Smoking and chronic inflammation, both characteristic features in the context of RA pathogenesis, are thought to enhance the process of carbamylation [4].
\nA series of environmental factors, such as cigarette smoking and silica have been associated with RA development. Smoking has provided some strong evidence of the potential to generate citrullinated proteins. In a historical Danish twin cohort study, Svendsen et al. concluded that 20 years of smoking doubles the risk of RA development [5]. Environmental factors can generate an epigenetic regulation and influence specific RA immune reactions to citrullinated proteins [6]. Exposure to smoke, silica or carbon-derived nanomaterials can activate antigen-presenting cells and PADs by triggering mucosal toll-like receptors.
\nPathogenic infections associated with the onset of rheumatoid arthritis can lead to a faulty immunological tolerance towards essential self-antigens. This can subsequently cause chronic joint inflammation along with an imbalance between the various T helper subsets [7].
\nAmong the infectious agents regarded as potential triggering factors,
When highlighting the etiopathogenesis of RA, certain species of
There has not been thus far sufficient evidence to advocate for a clinical correlation between an infection with
It is known that viruses can modify the clinical picture depending on genetic background, immune responses elicited by the host and the type of virus strain involved. Certain viruses such as
There is an overall agreement that pathogenesis in RA is linked with genetic susceptibility. Studies have found more than 100 susceptibility loci in RA patients [14]. Twin studies in which heritability is reported to be ~60% provides strong evidence for this matter. It is also speculated that the interplay between environmental factors and genetics may, in fact, lay the foreground for the specific autoimmune reactions and further transition to the joint disease stage. A major genetic risk factor associated with RA concerns the human leucocyte antigen (HLA) class II region. The conserved amino acid sequence located at the antigen-binding site of the antigen-presenting molecule, encoded by the alleles of HLA-DRB1 is referred to as the shared epitope (SE) [14]. The strongest genetic associations in RA are identified in the HLA-DR1 and HLA-DR4 serotypes. Some studies do not link the HLA II locus to ACPA response directly [15, 16], rather to the progression from ACPA(+) to ACPA(+) RA, through a process of maturation via T cells which activate ACPA-producing B-cells. It is assumed that SEs play an important role in the antigen presentation process. Thus the different alleles at the SE level can influence the interaction between HLA class-II and the specific receptor of T lymphocytes (TCR) or between HLA class-II and antigen. Studies on SE phenotypes and specific HLA-DRB1 subtypes revealed that HLA-DRB1*04 has a significantly higher frequency in RA and is associated with seropositivity independent of the smoking status [17, 18].
\nACPA(+) and ACPA(−) RA patients have similar hereditability, reported at 68% and 66%, respectively. The two serotypes display differences in genetic susceptibility, including a significantly lower SE contribution in the seronegative disease of 2.4%, compared to 18% in ACPA(+) RA [19]. A major genetic risk factor outside the HLA region concerns the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene [14]. Other non-HLA susceptibility genes identified in both disease subgroups include TNFAIP3, GIN1/C5orf30, STAT4, ANKRD55/IL6ST, BLK [14]. The protective role of specific HLA-DRB1 alleles has been reported in one meta-analysis, in which HLA-DRB1*13 accounted for a lower risk of ACPA-positive RA [20]. Studies on the outcome of patients with undifferentiated arthritis determined several susceptibility loci (PTPN22, TRAF1/C5, AFF3, KIF5A, TAGAP) related to disease severity [21]. These genetic loci may provide a tipping point in the disease progression and identify as prognosis markers for the transition to an established RA [14].
\nAutoantibody secretion generated by the autoantigen release can precede the onset of fulminant joint disease by several years [22]. High-titer RF is of high diagnostic and prognostic value and is linked to erosive RA. ACPA is the most specific marker antibodies for RA and is linked, similarly to RF with erosive disease. Another autoantigen with potential pathogenetic relevance is the heterogeneous nuclear ribonucleoprotein-A2 (RA33) which is targeted by autoreactive T cells [2].
\nBoth the innate and adaptive immune systems contribute to initial antibody production and further development of sustained chronic synovitis. The fibroblast-like synoviocytes interact with cells of the innate immune system which include macrophages, monocytes, mast cells, and dendritic cells. ACPA target citrullinated proteins on the surface of macrophages and monocytes, which in turn enhances the production of pro-inflammatory mediators [3]. Activated mast cells have an essential contribution to the pro-inflammatory milieu through IL-17 A secretion [23]. The involvement of the adaptive immune response is based on the antigen activation of major histocompatibility complex (MHC) class II dependent on T cells (cell-mediated immunity), cytokine release, and stimulation of B-cell antibody production (humoral immunity).
\nThe exact relationship between reported antibodies relating to the disease and the pathogenic features observed remains a mystery due to lack of research. Limited data thus far comparing RA serotypes indicate different underlying processes that can drive parallel pathways towards similar clinical phenotypes. There is evidence of T-cell-mediated immune dysregulation in RA irrespective of autoantibody production [24]. Serotype distinctions include differences in immune cells subtypes, cytokines and chemokines [25].
\nThe synovium in patients with established RA displays an inflammatory infiltrate composed of a heterogeneous set of immune cells. Neutrophils present in the synovial fluid have an extended lifespan and feature an enhanced production of reactive oxygen species and neutrophil extracellular traps (NETosis) [25]. Synovial T cells, especially CD28-CD4+ T cells are autoreactive, produce interferon-gamma (IFN-γ) and are resistant to apoptosis [26]. Differentiated effector T cells, helper types (Th1, Th2, Th17) contribute to cytokine secretion. Antigen-specific T cells or T cells activated by the pro-inflammatory milieu of the synovia are capable of stimulating monokine production by monocytes and macrophage-like synoviocytes, especially interleukins (IL-1, IL-6) and TNF-α [26]. The T-cell dependent IL-17 cytokine has a significant pathogenic role by inducing cartilage degradation and bone erosion through stimulation of receptor activator of NF-κB ligand expression on osteoblasts. The Th17 cells population is increased both in joints and peripheral blood of patients with RA [27]. IL-23 produced by dendritic cells promotes the survival and expansion of Th17 cells. It is thought that an imbalance between IL-12 (Th17 inhibitor) and IL-23 secretion by dendritic cells contributes to RA pathogenesis [26].
\nVarious chemokines, cytokines, growth factors, and cell adhesion molecules promote neovascularization in the setting of chronic inflammation. In RA, there is an abundance of angiogenic factors, of which VEGF is of major importance. Inflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-17, IL-18, granulocyte and granulocyte-macrophage colony-stimulating factors (GM-CSF), may also induce angiogenesis through VEGF-dependent pathway [28, 29]. Affected patients have been shown to have high levels of VEGF and significantly lower levels of IL-35 [30, 31].
\nThe inflammatory cascade and synovial neoangiogenesis drive specific structural changes related to RA pathology. Synovial hypertrophy is related to abnormal proliferation of dysfunctional fibroblast-like synoviocytes (FLS), resistant to apoptosis. FLS sustain joint damage by the secretion of MMPs and tissue inhibitors of metalloproteinases. Cartilage damage is induced by the action of MMPs which cause disassembly of the type II collagen network. Also, chondrocyte apoptosis is enhanced by cytokine, mainly IL-1 and IL-17A. Inflammatory cytokines promote bone erosion through pro-osteoclastogenic effects. Also, osteoclast differentiation may be induced via immune complexes and antigen-binding of ACPA on osteoclast precursors. Bone erosions are usually located at the site where the joint capsule inserts on the periosteum [32, 33].
\nOne of the most important things to remember about RA is that it should be diagnosed as early as possible. This is of paramount importance since rheumatoid arthritis is a disease characterized by structural bone lesions that lead to bone deformity and functional disability. However, trying to make an early diagnosis of this disease can prove to be extremely difficult sometimes, and that is because there is no specific or particular symptom or sign of either early or very early RA (eRA).
\nMoreover, the 2010 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for RA, which tries to capture patients as early as possible, is to be applied ONLY to people having at least one joint with CLINICAL SYNOVITIS [34]. But, even when synovitis is present, it is not always the expression of early RA.
\nWhile early signs and symptoms of RA can be mimicked by other diseases, there are some which should be taken into consideration, such as fatigue, minimal joint pain, joint warmth, joint stiffness, limping, reduction of range of motion, fever, anemia, and depression. It is easy to see that all these are not at all specific, not even for full blown rheumatoid arthritis and even less so for early/very eRA [35].
\nThe interest of knowing how to interpret symptoms in eRA derives from multiple reasons, one of the most important being that it would be extremely useful (on a personal, as well as a societal level) to be able to predict, based on the symptoms of people, who will develop RA and who will not. Unfortunately, with the knowledge we have today, this is not yet feasible. There are still too few studies designed especially for assessing symptoms during this initial period of the disease [36].
\nNevertheless, if one tries to group the symptoms which may appear during the early stages of RA, one can delineate three categories [37]:
Non-specific symptoms: which are in fact, general (systemic) symptoms produced through the intervention of pro-inflammatory cytokines, which may, thus, intervene in any inflammatory disease, articular or not. Among them, we can outline fatigue, a general feeling of being “un-wellbeing,” anxiety, depression, non-specific myalgia or sharp/dull pain near the joints but not in the joints. Sometimes there is low-grade unexplained fever and, rather frequently, sleep disturbances which worsen the general feeling of being “un-wellbeing.” To take just one example, fatigue, which is a very common and, frequently, overlooked symptom in RA, correlates with active disease in the sense that it is more pronounced when the disease activity is higher. Its origin is not well understood; it may be the response of the organism to the presence of chronic inflammation, mediated by the action of IL-6. Poor sleep and anemia can contribute to fatigue in RA. This symptom can affect relationships, emotions, mood, productivity, creativity, the general feeling of happiness. Fatigue from RA can associate with poor appetite and weight loss [35].
All these non-specific symptoms may appear in variable proportions in people affected by eRA and their importance resides in the significance pertaining to the risk of a person presenting these symptoms, to develop established RA.
Symptoms related to the joints; may vary from mild joint stiffness (sometimes, without having the so-called characteristics of inflammatory joint stiffness) to non-explicable, non-specific joint pain, usually of short duration, with no local signs of inflammation of the joint. As one can see, these are also totally unspecific to the possibility of later developing RA; which is why their presence should prompt a very careful evaluation. On the other hand, when people complain of joint pain, diagnosing them might be easier as pain can motivate people to see a doctor.
Symptoms related to functional capacity. These symptoms interfere with one’s ability to perform daily living activities. For instance, when one is not capable of performing the opposing movement of the thumb, and hence, not able to make a fist, one will not be able to open a jar’s lid. Likewise, if the symptoms are located in the lower limbs, one might not be able to walk or wear shoes. As can be ascertained, these are elements of functional disability that one can encounter in the established RA patient, as well as in other diseases. Therefore, as these are also non-specific to the early phase of RA, they should also be evaluated with care, to reach a correct diagnosis, more so a therapeutic one.
Regardless of the category of symptoms an individual has, the interpretation of their significance is much more difficult and doctors would like to be able to have some hints as to WHAT should he investigate in order not to miss the right diagnosis, in the given window of opportunity. Investigations should be primarily directed to populations or subjects at high risk including female gender, smoking, alcohol, obesity, unhealthy dietary intake, having a family member diagnosed with RA, presence of ACPA, poor dental health, low socioeconomic status. As such, people having symptoms of the above and also one or more of the mentioned risk factors should be given the most attention in assessing their presenting health condition [38].
\nOne other method used to evaluate symptoms of eRA is to, retrospectively, question patients with established RA about their original symptoms [39], followed by making appropriate questionnaires, which are to be used prospectively, to make an early diagnosis. Such an analysis of the literature on this topic was made by Stack et al. and, reviewing 26 papers concentrating on the way patients diagnosed with RA reported their initial symptoms, they found 5 “themes” that describe patient’s initial complaints [39].
\nThe first is concerning the swelling of the joint. It was often described as being severe and was most frequently localized at the hands and feet [40, 41, 42]. It also has an impact on the ability to perform activities of daily living [43, 44]. Patients reported that it was a progressive feature [45, 46] and that it was sometimes associated with some degree of joint pain [47, 48]. These findings suggest that it might be rational to closely monitor a person complaining of recent onset sensation of joint swelling, even if the swelling itself is not apparent to the doctor.
\nThe second theme used by established RA patients to retrospectively describe their initial symptoms is one of pain and local sensibility, with multiple localizations, again, more frequently, on the hands and feet [49, 50, 51, 52] and rarely on the shoulders and hips. Two rather descriptive patterns were identified:
gradual occurrence of pain: the most often used descriptors were “episodic pain,” “gradual pain,” “easy pain,” “vague pain.” The interpretation given by patients was usually taking into account the activities performed during the day, therefore not much attention was given to the pain until it became persistent and higher in intensity [53, 54, 55];
acute onset of pain: the most often used descriptors in this circumstance, were “severe pain,” “resistant pain,” “disability provoking pain,” “unbearable pain.” Some of the patients describe the occurrence of pain like an “on-off switch” phenomenon. Most often, this pattern was rapidly followed by the occurrence of other symptoms, as well. As such, this kind of joint pain is the one that will get the patient to visit the doctor much faster [45, 46, 55].
The third theme of patients’ symptoms is joint stiffness. Quite surprisingly, this was very briefly mentioned and patients never gave a full description, neither was any emphasis put on the significance of the term [46]. In some instances, it was associated with other symptoms, such as fatigue and swelling of the joint [55].
\nThe fourth theme reported retrospectively by patients with established RA, to describe their initial symptoms, is fatigue and muscular weakness [56]. Some patients have reported this as the impossibility to “lift my food tray” [57] or to “lift my toddler” [43]. It appears that fatigue is a really important feature of the beginning of eRA [56]. Some patients even described a “flu-like” sensation of muscular weakness all over their bodies [58].
\nThe fifth and last theme that patients referred to when remembering their initial symptoms of RA is the emotional impact of prolonged suffering [55, 59, 60, 61]. It is easily conceivable that a state of sustained discomfort in which the patient does not know for how long it will last and how it may evolve will produce emotional distress. Due to this, patients reported feelings of fear, anger, anxiety, uncertainty, ambivalence. For some patients, this emotional impact was so strong that they had depression and even suicidal ideation [59]. When the emotional disturbance is significant, finding a diagnosis, even that of established RA, comes as a relief [60].
\nThese five themes revealed by Stack et al. are useful for daily clinical practice due to the fact that they can point out of the mass of patients that a physician sees every day, those that the physician should actively follow closely, in order to be able to make the right diagnosis of (preferably) eRA, if this should be the case [39].
\nSince RA is a systemic disease, potentially affecting any organ system in the body, in the proper context, some of the extraarticular manifestations of the disease, can point out the necessity to further search for a correct diagnosis. Of the numerous such manifestations, one should perhaps remember the following, as a possible manifestation of eRA: peripheral nerve entrapment (e.g. carpal tunnel syndrome), “idiopathic” pulmonary fibrosis or nodules, unexplained amyloidosis, cardiac nodules of unknown origin, cutaneous nodules (that can and should probably be biopsied when unexplained), “idiopathic” vasculitis [38].
\nAs we know, in 2014, Zhao et al. developed classification criteria for eRA, which take into account both clinical and biological aspects of the disease and perform at a variable but acceptable specificity and sensitivity [62, 63]. Nevertheless, they imply that the presence of clinically evident arthritis; and this is, sometimes, not eRA, since everybody tries to make the diagnosis as early as possible! Therefore, these criteria are useful but will miss some of the early or very early RA cases.
\nOne must not forget that we also have the EULAR recommendations on treatment of eRA [64], which state, as one of the overarching principles that “A definitive diagnosis in a patient with early arthritis should only be made after a careful history taking and clinical examination, which should also guide laboratory testing and additional procedures,” while in the recommendations it is mentioned that “Clinical examination is the method of choice for detecting arthritis” and that “if a definite diagnosis cannot be reached and the patient has early undifferentiated arthritis, risk factors for persistent and/or erosive disease, including number of swollen joints, acute phase reactants, rheumatoid factor, ACPA and imaging findings, should be considered in management decisions. Patients at risk of persistent arthritis should be started on DMARDs as early as possible (ideally, within 3 months), even if they do not fulfill classification criteria for an inflammatory rheumatological disease.” Thus, EULAR provides us with some guidance as to how to attempt to make a diagnosis as early as possible, as well as following it swiftly with the correct management [64].
\nIdentifying (especially) seronegative future established RA patients in the earliest stage of their disease is a difficult endeavor. Until now, we do not know for certain if the symptoms of a person are, by themselves, enough to efficiently stratify the risk of a person to develop established RA [65]. And this is an important unmet need in the field of RA, which precludes continuous study to lower the pressure on the healthcare system, by preventing the major, often irreversible, disabilities associated with this disease, through better early diagnostic expertise.
\nJoint pain is the universal characteristic in RA patients, but the long-standing disease has several features, easily recognizable by a trained rheumatologist, but often misdiagnosed by other specialists. The key to the recognition of the clinical and physical findings of RA is the capability to recognize the outcome of the synovial proliferation and inflammation [66]. As was already stated before, RA can affect any peripheral joints, with predilection on the small joints of the hands and feet, followed by the elbow, shoulder, ankle or knee.
\nHand and wrist involvement with secondary deformity is a typical feature of late RA [67, 68]. If in the eRA, the physical findings are not extensive, in the late disease one can identify an entire panel of changes. The late, irreversible and most prevalent changes in hands include “swan-neck” and “boutonnière” deformities, along with metacarpophalangeal joints (MCP) swelling, subluxation and “ulnar drift,” or ulnar deviation (Figure 1). Swelling of the MCP and wrists joints, together with atrophy of the intrinsic muscles of the hand, leads to the aspect of the hand like “two-humped camel’s back,” while the ulnar deviation makes it similar to the “mole’s paw.” Persistent inflammation adjacent to ulnar styloid, together with the laxity of the radioulnar ligament leads to a movement of the styloid under the examiner’s pressure, similar to the “piano key” [68].
\nImages of the small joints of the hands and feet, showing boutonnière - arrow (A and C), swan-neck – Empty arrow (B and C) and hammer toes deformities – arrowhead (D).
The boutonnière deformity presumes the flexion of the proximal interphalangeal (PIP) joint and extension of the distal interphalangeal (DIP) joint [69], whereas the swan-neck, by contrast, means hyperextension of the PIP and flexion of the DIP [68, 70]. The cause of the boutonnière deformity is the lesion of the central slip of the extensor tendon, secondary to tenosynovitis and PIP swelling, with the lateral and volar displacement and conversion of the lateral bands of the extensor tendon, into flexors of the PIP joint. In time, shortening of the tendon leads to hyperextension of the DIP joints. If the DIP swelling is disrupting the extensor tendons, the joints will be forced to remain flexed (due to the action of the only remaining tendons, the flexors). Besides, if the bulging of the PIP is volar, the lateral bands subluxate dorsally, generating hyperextension in the PIP joint and the aspect of the swan-neck deformity.
\nThe involvement of the thumb results in severe functional impairment, due to the loss of the grip between the index finger and the tip of the thumb. The most prevalent pathological aspect of the thumb in RA is one of a “flails,” followed by the boutonnière deformity, which is the same as described before, just one joint back proximally [66].
\nExtensor tenosynovitis might lead to tendon ruptures, especially at the level of the 6th compartment of extensors, while flexor tendon involvement includes besides thickening of the tendon sheet that could generate either “trigger finger” or a carpal tunnel syndrome [66].
\nIt is not uncommon that the same hand develops different deformities simultaneously leading to a major impact on hand function and subsequently on the ability to perform daily life activities [70].
\nThe elbow is often involved both early and in longstanding rheumatoid arthritis. Because of its unique role in maneuvering and positioning the hand in space, the loss of normal motion and stability, or increased pain with the use of this joint are all significant sources of impairment in patients with RA [71]. Synovitis of the elbow joint can be identified by palpation between the olecranon and the epicondyles, especially the lateral one. Olecranon bursitis is a common finding in patients with RA but should be differentiated from the one appearing in polyarticular gout. To mention, in RA it tends to be more frequently bilateral [66].
\nThe shoulder joint is a complex joint and because of its deep location it is difficult to confirm accurately the joint effusion, or the rotator cuff tears only by physical examination, therefore shoulder lesions are often under diagnosed [72]. When involved, it might generate limitation of motion in all planes, with suggestive secondary scapulothoracic movement, or “shoulder pad” sign. The pain generated by joint effusion, subacromial subdeltoid bursitis, or rotator cuff tendon tears is often referred into the deltoid muscle. The fluid inside the biceps tendon sheet is not uncommon [72].
\nKnee joint synovitis is a frequent finding in patients with RA, anterior swelling being easily detectable through clinical examination, by the “bulge sign” or the ballottement of the patella with the index finger downwards, into the fluid. The Baker cyst is a benign fluctuant swelling of the gastrocnemius-semimembranosus bursa in the popliteal fossa at the back of the knee [73], resulted after severe effusion at the level of the knee joint. Hip joint involvement is associated with pain over the greater trochanter, probably due to bursitis and pain elicited by Patrick’s test, or Flexion-Abduction-External Rotation maneuver (FABER) [74].
\nThe ankle is an important weight-bearing joint, with a lot of structures involved in RA. Synovitis is common at the level of the tibiotalar subtalar and talonavicular joints, with a high impact on the patient’s quality of life [75]. Tenosynovitis of the medial or lateral compartments is increasing the functional impairment. The forefoot comes with specific changes, including calluses under the metatarsal heads and secondary ulcerations, or joint deformities leading to the “hammertoes” aspect (Figure 1), resembling the piano hammer [66].
\nBilateral pain, tenderness, swelling and limitation of jaw movements might be the result of temporomandibular joint involvement and due to these symptoms, patients experience limitations in their daily activities, such as eating, speaking and swallowing.
\nThe involvement of the cervical spine is the most serious skeletal manifestation in patients with RA. Instabilities of the upper cervical spine can lead to headache, neck pain, paresthesias, weakness, signs of vertebrobasilar insufficiency or neurological complications such as bowel and bladder sphincter impairment [66].
\nMost frequent extraarticular features of RA are represented by the
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Recent advances in the imaging field and therapeutic possibilities are changing the outcome in RA. Still, conventional radiology (CR) represents the main imaging method for rheumatoid arthritis patients’ evaluation, in daily practice. The treat to target approach has brought into attention the new methods, ultrasonography (US) and magnetic resonance imaging (MRI), as more sensitive and specific imaging modalities. In this way, CR remains a method for identifying old and late changes, lesions that already happened, while US and MRI are the methods for identifying acute inflammatory lesions and details of small structural changes. Other methods, such as arthrography, computer tomography (CT) or scintigraphy remain suitable for complex cases and will not be subject to our paper [77].
\nConventional radiology, a cheap and widely available method shows a wide spectrum of changes at the level of the peripheral joints, including hands, wrists, feet, and ankles or even larger joints (knee, shoulder, elbow), depending on the disease duration. Thus, imaging of any joint disorder, including rheumatoid arthritis should start with this method [77].
\nPeripheral joint involvement shows typical radiographic changes in rheumatoid arthritis including soft tissue swelling related to joint effusion or synovitis, juxta-articular osteoporosis, joint space narrowing and the late disease changes, bone erosions, and ankylosis. To note, the fact that joint space narrowing (JSN) is a good indicator for hyaline cartilage loss, as the articular space is mainly composed of the two-cartilage thickness sum, normally about 2 mm [83]. A comparison with adjacent or contralateral joints might clarify narrowing. Erosions occur earliest at the level of the carpal bones, especially pisiform or triquetrum, at the level of the ulnar styloid and second metacarpophalangeal (MCP) joint, in the bare area (metacarpal head, with no cartilage) [84]. Studies showed that up to 30% of the patients do not develop erosions in the first 2 years from disease onset, but still, most of the patients do, a fact that led to the expert recommendation of repeating CR every 6–12 months in eRA and every 1–2 years in late disease [85].
\nTo quantify lesions and for a better follow-up of the disease, Sharp proposed a scoring system of erosions and JSN of hands [86]. The modified Sharp score, proposed by Van der Heijde, included feet, for a total of 16 areas evaluated for erosions and 15 for JSN in each hand and 6 areas for erosions and six for JSN in each foot [87]. Radiographic progression can redefine remission, as clinically quiet joints often progress.
\nCR of the spine might show some abnormalities, especially in the cervical segment, which is involved in more than half of the patient [85]. The most frequent finding in this area is atlantoaxial subluxation and basilar invagination [88, 89], both identified best in a lateral radiograph, with the flexed neck. For the diagnosis of atlantoaxial subluxation, one should measure the distance between the anterior arch of C1 and anterior aspect of the dens of C2. Expected values in normal subjects should not exceed 3 mm in adults and 5 mm in children. The distance higher than those cutoffs lead to a diagnosis of subluxation and the ones higher than 8 mm require surgical intervention. Basilar invagination diagnosis should be confirmed by MRI or CT [88].
\nUS was recently included by EULAR recommendations on the use of imaging, between the techniques with a potential role in RA diagnosis and management [90, 91]. The reflection of ultrasound waves by body structures generates US images of those structures in the greyscale (GS) [92]. Adding the Doppler technique to the examination, we obtain information on the blood flow inside structures. The higher the ultrasound frequency, the higher the detail on the image, but lower penetrance. In reverse, the lower the frequency, the higher penetrance, but with a low-quality image. Therefore, the use of appropriate probe frequencies is required for an optimal US evaluation. The higher frequency transducers (e.g. 10–18 MHz) are mandatory for superficial structures, such as small joints of the hands and feet and ligaments and tendons, whereas lower frequency probes (e.g. 5–12 MHz) are useful for deeper joints, such as hip, knee or shoulder [90].
\nFor most of the joints, US allows visualization of most features of rheumatoid arthritis, including joint effusion, synovial hypertrophy, bursitis, tenosynovitis or bone erosions, being more sensitive than clinical examination for depicting subclinical synovitis and other inflammatory (Figure 2), acute changes and more sensitive than CR for detection of bony structural changes, like erosions [93, 94].
\nUS images showing - synovitis of MCP joint (asterisk – synovitis, mh – metacarpal head, f – phalanx, et – extensor tendon). Original image, from the personal archive (FLORIN VREJU).
The outcome measurement in the rheumatology group (OMERACT), under the EULAR umbrella, developed definitions for all the US findings in rheumatology, which should be confirmed in two perpendicular planes. Thus, effusion is defined as abnormal hypoechoic or anechoic intraarticular material, that can be displaced and compressed, with no Doppler signal, whereas synovial hypertrophy or proliferation is defined as abnormal hypoechoic intraarticular tissue that is not displaceable and compressible but may exhibit Doppler signal [95].
\nOther inflammatory, acute, feature of RA is tenosynovitis, identified by the US as hypoechoic or anechoic thickened tissue with or without fluid within the tendon sheath, which is seen in two perpendicular planes and which may exhibit Doppler signal (Figure 3) [95].
\nUS images showing - tenosynovitis of the tibialis posterior (asterisk – tenosynovitis) in transverse, with Doppler activity (A) and longitudinal scan (B).
Since the US is more and more used in daily practice both for diagnosis and monitoring disease, a scoring system for synovitis became mandatory. The most used is the one proposed by Szkudlarek et al. [96] that scored fluid as follows: grade 0 – no effusion, grade 1 – minimal amount of fluid, grade 2 – moderate (no distension of the joint capsule) and grade 3 – extensive fluid collection (with distension of the joint capsule). The synovial hypertrophy was scored as grade 0 – none, grade 1 – minimal synovial thickening, grade 2 – synovial thickening bulging over the line linking top of bone cortical (no extension along bone diaphysis), grade 3 – synovial thickening bulging over the line, with extension to at list one of the bone diaphysis. Semiquantitative grading included grade 0 – no flow, grade 1 – single vessel signal, grade 2 – Doppler signal in less than half of the area of synovium and grade 3 – Doppler signal over more than half of the synovial area (Figure 4). Recently was developed a new combined score, Global OMERACT – EULAR Sonography Scoring (GLOESS), which considered the higher score of GS or power Doppler (PD) as the score for the joint [97].
\nUS images showing - tenosynovitis of flexor carpi ulnaris and wrist synovitis, with Doppler signal present (asterisk – tenosynovitis, fcu – flexor carpi ulnaris, # – wrist synovitis).
The most characteristic US finding in RA is bone erosion, defined as an intraarticular step-down discontinuity of the bone surface that is visible in two perpendicular planes [95]. Scoring system for erosions according to Szkudlarek et al. defined grade 0 as normal bone cortical, grade 1 as bone irregularities, but without defect in two perpendicular planes, grade 2 – the defect is seen in two perpendicular planes, grade 3 – extensive bone destruction [96]. A more accurate grading score for erosions was the one based on irregularity size: grade 0 – no erosions, grade 1 – erosion <1 mm, grade 2 – small erosion between 1 and 1.9 mm, grade 3 – moderate erosion, between 2 and 4 mm, grade 4 – dimensions higher than 4 mm [98].
\nValidity of the method and sensitivity to change were primarily demonstrated for all US findings by Terslev et al. [99, 100], thus making it an important imaging method in the management of RA, along with other studies which confirmed predicting value in the treatment response [101, 102], and the role in discriminating between clinical and imaging, real remission [93, 103, 104].
\nHowever, even if the diagnosis is enhanced and not made only by the US and even if it is highly operator dependent, ultrasonography offers a cheap and dynamic possibility for monitoring the disease activity and progression and for assessing the persistence of subclinical inflammation in RA [92, 93].
\nMagnetic resonance imaging represents a favored and favorite imaging method in inflammatory joint diseases, as it allows evaluation of all the structures involved in those pathologies, being able to depict synovitis, tenosynovitis, erosions and more than this, the bone marrow edema, a feature that remains hidden to the US. MRI sequences that can be useful in RA patients include T1-weighted (T1w), favored by short imaging times and good anatomical details, T2-weighted (T2w) and short tau inversion recovery (STIR), both good for depicting inflammation, such as bone marrow edema or synovitis [105]. Adding intravenous contrast agent, like paramagnetic gadolinium (Gd) to T1w sequences allows us to visualize detailed structural lesions and, at the same time, the tissue vascularity and perfusion, inflamed synovium being easily recognizable. It is always advisable to use two sequences in parallel, to compare high signals in the water-sensitive (WS) one (T2w or STIR) with high-resolution details in the fat sensitive one (T1w). Thus, one can identify active erosions, by a hyperintense signal in WS sequences and hypointense signals in the T1w image [105].
\nAs a conclusion, MRI allows identification of synovitis, tenosynovitis, and erosions and proves to be an important tool in the diagnosis, in the disease activity monitoring and treatment response. However, even if it brings complete information on the peripheral joints, the use of MRI in RA patients in clinical practice remains lower in comparison to US and CR, due to issues related to availability, cost, and duration of an examination. More than this, it cannot offer a dynamic assessment of structures [77].
\nAccording to guidelines, the therapeutic approach for RA patients includes an early start of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), followed by biologic DMARDs (bDMARDs) and targeted synthetic DMARDs, aimed at a low disease activity or remission.
\nRegarding csDMARDs, Methotrexate (MTX) remains the first therapeutic choice, due to its immunomodulatory and immunosuppressive action, efficacy and sustained effect; it is administered orally or subcutaneous, with doses starting from 7.5–10 mg weekly up to 20–25 mg/week, In case of MTX intolerance, leflunomide (10/20 mg/day) or sulfasalazine (2–3 g/day) should be considered as therapeutic agents [106]. Treatment monitoring requires CBC, ALT, AST and creatinine evaluation at baseline, every 2–4 weeks for the first 3 months, every 8–12 weeks for the next 3–6 months and every 12 weeks after. Screening for hepatitis B and C should be performed before initiating the treatment. An increase over three times of hepatic enzymes requires treatment interruption [106].
\nIf the therapeutic target is not achieved with csDMARD therapy, bDMARDs or tsDMARDs should represent the next approach (Figure 5) [106].
\nEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs [
Rheumatoid inflammation is initiated and maintained through immunological pathways when activated T and B cells produce cytotoxins – directly toxic to tissues – and cytokines such as TNF and interleukins (IL-1 and IL-6) – which provide further amplifies the interaction between pro-inflammatory cells [107, 108]. Biologic bDMARDs are licensed for the treatment of moderate-to-severe RA and target specific T and B-cell activation by [107, 109]:
Inhibiting TNF (with excessive production in the synovial fluid in RA) and reducing the progression of joint damage:
Adalimumab,
Certolizumab,
Etanercept,
Golimumab,
Infliximab
Binding of the CD80/86 receptor and preventing co-stimulation interaction between T cells:
Abatacept
Blocking the IL-1 receptor:
Anakinra
Blocking the IL-6 receptor and presenting a better safety profile:
Tocilizumab
Producing B-cell depletion and reducing the accumulation of bone damaging oxygen-free radicals:
Rituximab
Early use of bDMARDs can improve patient outcomes, reduce the symptoms of RA and modify the course of the disease, leading to remissions that can last several years [110].
\nBiosimilars are highly similar molecules with equivalent therapeutic effect to bDMARDs, also prescribed in RA, to reduce treatment costs because they are authorized by comparing randomized controlled trial data [109]. Biologic agents may be effective when DMARDs therapy fails to bring improvement of the physical function, but they present higher costs due to their complex manufacturing process [107, 109]. Biologic agents are genetically derived from living human or animal cells as whole monoclonal antibodies or as a specific fragment of an antibody called fusion protein [109].
\nTherefore, their protein structure predisposes patients to increased risk for infection, reactivation of latent tuberculosis, development of lupus-type reaction (mostly characterized by rashes, leukopenia, and thrombocytopenia) and vasculitis [107, 109, 111].
\nPre-existing airway disease and interstitial lung disease have shown worsening symptoms and increased mortality after administering biological RA treatment [111].
\nTherapy monitoring: all patients should perform tuberculin skin testing or interferon-gamma release assay (IGRA) blood test before commencing anti-rheumatic treatment with biologic agents. Pre-existing airway disease and interstitial lung disease have shown worsening symptoms and increased mortality after administering biological RA treatment [110]. Neurological complications similar to multiple sclerosis symptoms and demyelinating disorders have also been associated with bDMARDs treatment and regular monitoring for new skin cancer is necessary regarding all patients receiving biologic agents [111]. Patients should not receive live vaccines during treatment, except for pneumococcal, influenza and hepatitis B which are killed vaccines [107, 109, 112]. Neurological complications similar to multiple sclerosis symptoms and demyelinating disorders have also been associated with bDMARDs treatment and regular monitoring for new skin cancer is necessary regarding all patients receiving biologic agents.
\nThe bDMARDs have different pharmacokinetics properties and dosage, but similar adverse reactions and contraindications for the TNF inhibitors (TNFi). All TNFi increases cardiac mortality in RA patients with associated congestive heart failure (class III/IV and an ejection fraction of 50% or less) [107, 109]. Lymphoproliferative cancers, especially in children and adolescents, have been reported after using TNFi, therefore the US Food and Drug Administration (FDA) added a black box warning product labeling. Patients are recommended to use appropriate skin protection. TNFi does not increase the risk of congenital malformation and is classified as pregnancy category B (no documented human toxicity) [110, 113]. However, due to the intense placental transfer of Ig in the third trimester, TNFi may increase the risk of neonatal bacterial and fungal infections. The lowest risk appears in etanercept and certolizumab, which are preferred for administration [113].
\nAll in all, the following screening tests should be performed before initiating bDMARDs therapy:
Full infection history and screen, chest radiographs, tuberculin skin test, IGRA, asses risk factors for HIV, hepatitis B and C screening to exclude the presence of bacterial or viral infection;
Full blood count, urinalysis;
Check vaccination status;
Check the family/patient history of demyelinating disease or malignancy;
Review cardiac function;
Antibody profile assessment: anti-nuclear antibodies (ANA) and deoxyribonucleic acid (DNA).
\n
\n
\n
\n
Adverse reactions are mostly observed in chimeric biologic agents, such as
\n
\n
\n
Supplementary precautions should be taken in pregnancy and administration of rituximab, tocilizumab, and abatacept, due to their limited safety documentation when compared with TNFi [113].
\n\n
The multiple cytokines involved in the RA pathogenesis signal through Janus kinase/signal transduction and activator of transcription pathway (JAK-STAT). JAK represents intracellular tyrosine kinases associated with several cytokine receptors. JAK family includes JAK1, JAK2, JAK3, and TYK2 that are paired with specific receptors. Depending on the structure of their receptors, cytokines can be classified in [124]:
Type 1 receptors:
\n
\n
\n
and
Type 2 receptors include IL-10 and TNF families.
Recently, RA therapeutic research has focused on intracellular pathways and with advances in technology and disease knowledge, more targeted therapies were developed. JAKi represents an attractive therapeutic resource for patients with active moderate/severe RA, due to their oral bioavailability [124, 125].
\nCurrently, there are two JAKi approved for RA treatment, associated with MTX or as monotherapy:
\n
\n | Monitoring | \nAction | \n
---|---|---|
Lipid | \n4–8/12 weeks after treatment initiation and afterward according to hyperlipidemia guidelines | \nManagement according to hyperlipidemia guidelines | \n
Absolute neutrophil count (ANC) | \nBefore initiation and afterward according to routine patient evaluation | \nTreatment interruption if ANC is <1 × 109cells/L; may be restarted once ANC is above this value | \n
Absolute lymphocyte count (ALC) | \n\n | Treatment interruption if ANC is <0.5 × 109cells/L; may be restarted once ANC is above this value | \n
Hemoglobin (Hb) | \n\n | Treatment interruption if Hb is <8 g/dL and may be restarted once Hb is above this value | \n
Hepatic aminotransferases | \n\n | Temporary interruption if drug-induced liver injury is suspected | \n
Monitoring tofacitinib and baricitinib treatment [128].
As well as
\n
\n
The extensive research of the last two decades has concerned the diagnosis and individual prognosis of patients with RA and also the elaboration of personal treatment strategies.
\nCase management requires a continuous evaluation of the risk/benefit ratio of the therapy, so that the results are optimal and with minimal adverse effects and complications, including infections.
\nAlso, anticipating a balance between the risks of comorbidities and the benefits of treatment is a management strategy that must be taken into account.
\nThe authors declare no conflict of interest.
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\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. 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All patients should be followed up for a long period of time, regardless of the surgery method.",book:{id:"8463",slug:"pediatric-surgery-flowcharts-and-clinical-algorithms",title:"Pediatric Surgery, Flowcharts and Clinical Algorithms",fullTitle:"Pediatric Surgery, Flowcharts and Clinical Algorithms"},signatures:"Hasan Özkan Gezer",authors:[{id:"273381",title:"M.D.",name:"Hasan",middleName:"Özkan",surname:"Gezer",slug:"hasan-gezer",fullName:"Hasan Gezer"}]},{id:"44446",title:"Neonatal Pneumonia",slug:"neonatal-pneumonia",totalDownloads:14750,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"2990",slug:"neonatal-bacterial-infection",title:"Neonatal Bacterial Infection",fullTitle:"Neonatal Bacterial Infection"},signatures:"Friedrich Reiterer",authors:[{id:"152025",title:"Prof.",name:"Friedrich",middleName:null,surname:"Reiterer",slug:"friedrich-reiterer",fullName:"Friedrich Reiterer"}]},{id:"53683",title:"Pre and Postoperative Management of Pediatric Patients with Congenital Heart Diseases",slug:"pre-and-postoperative-management-of-pediatric-patients-with-congenital-heart-diseases",totalDownloads:4889,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Stabilization during preoperative cardiac surgery especially in neonates has an important role to predict outcome for pediatric congenital heart surgery. We tried to elaborate general guidelines on how to diagnose and some anticipations for emergency treatments tailored by the type of congenital heart disease in neonates. Stabilization consists of medical treatment including emergent prostaglandin institution in some types of duct dependent lesion. The role of interventional catheterization such as patent ductus arteriosus (PDA) stent, balloon pulmonary valvotomy, etc. as modalities for stabilization before surgery was also elaborated. Some general and specific guidelines based on the type of surgeries for postoperative management were also discussed.",book:{id:"5473",slug:"pediatric-and-neonatal-surgery",title:"Pediatric and Neonatal Surgery",fullTitle:"Pediatric and Neonatal Surgery"},signatures:"Eva Miranda Marwali, Beatrice Heineking and Nikolaus A. Haas",authors:[{id:"191397",title:"Dr.",name:"Eva",middleName:"Miranda",surname:"Marwali",slug:"eva-marwali",fullName:"Eva Marwali"},{id:"191414",title:"Prof.",name:"Nikolaus",middleName:null,surname:"Haas",slug:"nikolaus-haas",fullName:"Nikolaus Haas"},{id:"202373",title:"Dr.",name:"Beatrice",middleName:null,surname:"Heineking",slug:"beatrice-heineking",fullName:"Beatrice Heineking"}]},{id:"68042",title:"Neonatal Bacterial Meningitis",slug:"neonatal-bacterial-meningitis",totalDownloads:1178,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Despite improvements in neonatal intensive care, neonatal bacterial meningitis continues to be a serious disease with mortality rates varying between 10 and 15%. Additionally, long-term complications are observed among 20–50% of survivors, depending on time of diagnosis and therapy and virulence of the infecting pathogen. It is more common during the neonatal period than at any other age with the estimated incidence of 0.25 per 1000 live births. The absence of specific clinical presentation makes diagnosis of meningitis more difficult in neonates than in older children. Culture of cerebrospinal fluid is the traditional gold standard for diagnosis of bacterial meningitis, so all newborn infants with proven or suspected sepsis should undergo lumbar puncture. However, deciding when to perform lumbar puncture and interpretation of the results are challenging. Although the pathophysiology of neonatal meningitis is complex and not fully understood, researches on diagnostic and prognostic tools are ongoing. Prevention of neonatal sepsis, early recognition of infants at risk, development of novel, rapid diagnostics and adjunctive therapies, and appropriate and aggressive antimicrobial treatment to sterilize cerebrospinal fluid as soon as possible may prevent the lifelong squeal of bacterial meningitis in newborn infants.",book:{id:"7527",slug:"neonatal-medicine",title:"Neonatal Medicine",fullTitle:"Neonatal Medicine"},signatures:"Mehmet Şah İpek",authors:[{id:"267903",title:"Associate Prof.",name:"Mehmet Şah",middleName:null,surname:"İpek",slug:"mehmet-sah-ipek",fullName:"Mehmet Şah İpek"}]}],onlineFirstChaptersFilter:{topicId:"194",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:320,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:6,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:17,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"July 5th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:38,paginationItems:[{id:"82531",title:"Abnormal Iron Metabolism and Its Effect on Dentistry",doi:"10.5772/intechopen.104502",signatures:"Chinmayee Dahihandekar and Sweta Kale Pisulkar",slug:"abnormal-iron-metabolism-and-its-effect-on-dentistry",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82291",title:"The Role of Oxidative Stress in the Onset and Development of Age-Related Macular Degeneration",doi:"10.5772/intechopen.105599",signatures:"Emina Čolak, Lepša Žorić, Miloš Mirković, Jana Mirković, Ilija Dragojević, Dijana Mirić, Bojana Kisić and Ljubinka Nikolić",slug:"the-role-of-oxidative-stress-in-the-onset-and-development-of-age-related-macular-degeneration",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}},{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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