On the Road to Recovery: Do I/D Polymorphisms in the ACE Gene have a Part to Play?_Crimson Publishers

On the Road to Recovery: Do I/D Polymorphisms in the ACE Gene have a Part to Play? by Jan Adamczyk in Research & Investigations in Sports Medicine_Open Access Journal of Sports Medicine

Abstract

The serum angiotensin converting enzyme (ACE) level in individuals with a DD genotype is two-fold higher than those with an II genotype. The DD genotype is correlated with a higher risk of cardiovascular diseases, lower adaptability to hypoxic conditions, as well as lower cardio-respiratory capacity. The aim of the study was to examine the role of I/D polymorphisms in the ACE gene in surgical patients vs. healthy, active individuals. Two groups were investigated in the study: 91 surgical patients and 39 physically active controls. The level of adaptation to physical stress, compensating processes, and sense of well-being of participants were determined with subjective and objective inferential methods. Additionally, the represented ACE gene polymorphism was evaluated using molecular analyses.

The role of the DD vs. II genotype is unclear in healthy, active individuals. Whilst in patients who regularly participated in sport accrued shorter hospital stay time (P = 0.04). The type of surgery performed significantly affects patients’ time to convalescence (P = 0.03). Patients’ time in hospital after oncological surgeries is longer, regardless of whether chemotherapy was received or not. Based on the collected data, it was not possible to indicate a common genotype predisposing resistance to physical stress in both examined groups, with no statistically significant correlation between the ID polymorphism of ACE gene in either group. However, the noted tendencies may suggest a role of allele I and II genotypes in patient convalescence and as such, necessitates further investigation.

Keywords: Genotype; Maximal intensity effort; Climbers; Surgical patients

Introduction

Since 1923, maximal oxygen uptake (V̇O_2max) has referred to the oxygen uptake attained during maximal intensity exercise that could not be increased despite further exercise workload increments, thereby defining the limits of the cardio respiratory system. Surgical intervention requires the human body to undergo high physical stress, including hypoxia, which influences tissue regeneration after surgery as a consequence of an oxygen delivery versus consumption mismatch that occurs when cell proliferation exceeds neoangiogenesis [1]. Hypoxia inhibits, or even prohibits, continuing physical and intellectual activity during and post-surgical interventions, contributing to the prolongation of tissue recovery and patient’s general convalescence. Interestingly, in Rossetti et al. [2], physically active individuals, with greater sea-level fitness levels, reported less strenuous effort during simulated and actual physical activities, had better mood levels (less fatigue), and chose a higher step rate during perceptually regulated exercise, and did not suffer from any worsened arterial oxygen desaturation. Comparatively, surgical patients with acceptable levels of endurance performance are shown to recover, relatively better, are discharged home earlier, and return to their daily activities sooner than patients with low levels [3].

The capacity to perform endurance exercise and, consequently, physical resistance is asserted to be genetically conditioned [4]. Genetic factors have an essential influence over components of the athletic performance such as elite athlete status [5], some of motor skills [6], endurance [7], maximal oxygen uptake [8-10], increased risk of injurence [11], resistance to pain [12] or determinants of aggression in sport [13] and other phenotypes.

Among 200 single nucleotide polymorphisms (SNP) associated with physical performance, the angiotensin-converting enzyme (ACE) gene is one of most frequently investigated [14]. The ACE converts angiotensin I to angiotensin II. This entails blood vessels narrowing in diameter, and results in increased blood pressure. Functionally, the most significant is intron 16 of the human ACE gene (location: 17q23.3) where a 287 bp Alu sequence insertion fragment (I allele) and deletion fragment (D allele) were recognized [15]. Significant differences between genotypes II and DD were observed in terms of blood pressure. The ACE gene is the most intensively examined gene in view of athletic performance, especially endurance performance, particularly given the importance of blood pressure during prolonged and intense exercise [16]. Allele I is overrepresented among active individuals who practice endurance sports [17].

Whether healthy and active, or suffering through ill-health, the interest among both populations for recovery, fitness and adaptation is of paramount importance [18]. The serum ACE level in individuals with a DD genotype is two-fold higher than those with an II genotype and is correlated with a higher risk of cardiovascular diseases, lower adaptability to hypoxic conditions, as well as lower cardio-respiratory capacity, it was therefore postulated that the existence of the II, DD or ID polymorphism may be associated with outcome and recovery in both populations. The aim of the study was to examine the role of I/D polymorphisms in the ACE gene

Methods

The study sample comprised surgical patients and physically active controls (described below) andwas conducted in accordance with the Declaration of Helsinki. The physically active group consisted of 39 male and female volunteers, ranging from professional climbers (ascended over 7000m) and recreational athletes, all of which met national physical activity guidelines. The group of patients underwent gastrointestinal surgeries and comprised 91 men and women of varied health status, aged 28 to 84 years. They were subdivided into 36 non-oncological surgery patients subjected to “medium” surgical procedures (cholecystectomy, stoma reversal, thyroid resection), and to “big” surgical procedures (colectomy, digestive tract reconstruction, adrenalectomy); and 55 oncological patients subjected to digestive tract tumor surgeries, who spent more time in hospital, and whose surgical procedures were more advanced and extensive. Additionally, 29 patients also underwent chemotherapy.

The study consisted of two parts: molecular analysis, and analysis of participants’ health status and well-being, pre and post-surgery and physical activity, respectively. All participants gave their full written and informed consent to take part in the study. Participants’ health status, fatigue level, and existing medical conditions and symptoms were evaluated using self-report questionnaires, whilst patients’ course of post-operative recovery was analyzed in detail. The buccal cells were donated by participants with the use of sterile foam-tipped applicators (Puritan, USA). DNA was extracted using a GenElute Mammalian Genomic DNA Miniprep Kit (Sigma, Germany) according to the manufacturer’s protocol. The samples were genotyped in duplicate. PCR amplification of the polymorphic region of the ACE gene containing either an insertion (I) or deletion (D) fragment was performed using a T100™ Thermal Cycler (Bio-Rad, Germany) instrument. One pair of primers (forward: CTG GAG ACC ACT CCC ATC CTT TCT, and reverse: GAT GTG GCC ATC ACA TTC GTC AGA) was used to determine the ACE genotype, yielding amplification products of approximately 490bp (for allele I) and 190bp (for allele D). PCR mixture and thermal-time profile were coequal as described by Cięszczyk et al. [17]. The amplified DNA fragments were visualized by using 1.5% agarose gels stained with ethidium bromide.

All statistical calculations were made with the use of the SAS® ver. 9.3 software package (2013). The significance of experimental factors was determined with a multifactorial analysis of covariance according to the following linear models: for mountaineers y_ijkm = s_i + a_j +m_k + g_l + e_ijklm, where: y_ijkm- value of the analyzed trait, s_i - fixed effect of sex (i = 1,2), a_j- fixed effect of age (j = 1,2), m_k- fixed effect of mountaineer class (k = 1,2), g_l- fixed effect of genotype/polymorphism (l = 1,2,3), e_ijklm - random error; and for patients y_ijkmno = s_i + a_j + z_k + c_l + p_m + g_n+ e_ijklmno, where: y_ijkmnop - value of the analyzed trait, s_i - fixed effect of sex (i = 1,2), a_j- fixed effect of age (j = 1,2), z_k - fixed effect of surgery type (k = 1,2), c_l - fixed effect of chemotherapy treatment, p_m - fixed effect of sport class (m = 1,2,3,4,5), g_l- fixed effect of genotype/polymorphism (l = 1, 2, 3), e_ijklm - random error. Post-hoc Tukey test’s for multiple comparisons were used to compare means for the items.

Results

The investigated polymorphism conformed to the Hardy-Weinberg equilibrium. A distribution of the genotypes and alleles in physically active individuals and patients is shown in Table 1. The ACE gene polymorphism was not shown to significantly affect well-being pre or post physical activity (Table 2). However, in the case of individuals with genotype II, well-being did not deteriorate post physical activity, while the tendency for well-being to decline was the highest for genotype DD. Neither class (amateur/professional) nor age (under or over 35 years) significantly affected well-being pre or post physical activity (Table 3).

Table 1:Distribution of genotypes and alleles in healthy individuals and patients.

Table 2:Comparative analysis between polymorphisms and participants’ well-being.

Table 3:Comparative analysis of well-being, and patients’ convalescence.

The ID genotype in the ACE had no significant effect on the patients’ time spent in hospital (P>0.05; Table 2). However, time to convalescence following a surgical procedure was the shortest in patients with genotype II, and the longest in patients with genotype DD. Furthermore, patients with genotype DD did not endure surgeries as well as those with genotype II, and their well-being deteriorated to a greater extent post-surgery compared with well-being pre-surgery. The type of surgery had a significant impact on convalescence (Table 4). Time spent in hospital after oncological surgeries was shown to be longer than after non-oncological surgeries, irrespective of whether chemotherapy was administered. Patients’ age did not significantly affect time spent in hospital or well-being (Table 3). However, older patients required more time for convalescence and home discharge, and their well-being also deteriorated to a greater extent post- surgery. It was also observed that the greater frequency with which patients practiced sports, the shorter their hospital admittance (Table 5). Furthermore, physically active patients had a better well-being post-surgery than patients doing no sports.

Table 4:Comparative analysis of patients’ convalescence time, well-being, administration of chemotherapy, and surgery type.

Table 5:Comparative analysis of patients’ convalescence time, well-being, and sport participation level.

Discussion

The main finding of this study is that patients who are more physically active and practice sports regularly, stay for a shorter time in hospital, post-surgery (p = 0.04). Secondly, Occurrence of allele I remained invariant between participants with high or low levels of well-being. It is asserted that certain genetic factors may influence physical performance [11]. The D/I polymorphism of the ACE gene has been extensively studied for its association with diseases and physical performance. The ACE gene, by affecting the regulation of the heart and circulatory system function, is unequivocally important for the performance of endurance exercises at high intensity [19].

Professional or high-level sporting performance is, often, associated with a high V̇O_2max, and is often positively correlated with the presence of allele I in the ACE gene [20]. Moreover, individuals with genotype II in the ACE gene were found to experience low blood pressure, which positively affects their endurance performance during prolonged and intense exercise [15]. The efficacious function of the cardiopulmonary system is necessary for both healthy individuals and post-surgery recovery [3].

Our study did not find a statistically significant relationship between the presence of allele I in the ACE gene and physical fitness and well-being post physical activity or surgical intervention, respectively. Similarly, Oelz et al. [21] also noted no effects of the polymorphism on their participants’ performance; whilst Rankinen et al. [4] noted a significant association of V̇O_2max with genotype DD, but not with genotype II [5]. Elevated ACE was noted in deletion homozygotes in the cardiac muscle and the circulatory system in elite athletes [22]. This is related to a higher level of conversion of angiotensin I into angiotensin II, which in turn contributes to the growth of cardiomyocytes and fibroblasts. An increase in the strength of skeletal muscles and the cardiac muscle (increased mass of the left ventricle) has been demonstrated in individuals with DD and DI genotypes in the ACE gene than in individuals with genotype II in response to physical exercise during military training [16]. Other authors also observed that allele D was associated with greater strength, muscle volumes, a higher percentage of fast-twitch muscle fibers [23]. This was confirmed by a study of short-distance swimmers in whom allele D was present more often than in a sedentary control group [24].

The adaptation of the circulatory system to high altitudes involves decreased maximal cardiac output and stroke volume. Maximal aerobic capacity is essentially determined by the matching of convective and diffusion oxygen transport systems, which can be modulated by specific pulmonary vasodilating interventions [25]. Allele D of the ACE gene was also shown to deleteriously affect heart rate, blood pressure, and arterial oxygen saturation [25]. Charu et al. [26] noted that the D/D and D/I genotypes occurred often in individuals susceptible to high altitude pulmonary edema (HAPE), and in turn, allele I was present in individuals resistant to HAPE. In a study of residents living at elevations of above 3400m, the occurrence of allele I was found to be significantly higher in inhabitants of high-altitude rather than low-altitude environments. These results indicate that the overrepresentation of the ACE gene may be a factor playing a fundamental role in high-altitude adaptation [27]. Notwithstanding, the DD polymorphism is associated with higher oxygen uptake, periventricular leukomalacia, or intraventricular hemorrhage [28].

An Insertion polymorphism can be also associated with a higher risk of coronary heart disease and left ventricular hypertrophy [29], whilst the presence of allele I also seems to prevent pathologies in the body by reducing the prevalence of the so-called metabolic syndrome, i.e. a clustering of risk factors associated with developing cardiovascular disease. Signs of metabolic syndrome include insulin resistance and hypertension, which decrease following the use of ACE inhibitors. Further, the DD polymorphism was shown to occur more often in women with arterial hypertension and with recognized metabolic syndrome [30].

Adaptability was confirmed where the mean muscle fiber cross-sectional area was significantly smaller and the number of capillaries per unit cross-sectional area was significantly greater in individuals with I/I genotype, which enables more efficient oxygen transport and nutrition of muscles [21]; thereby enabling more effective use of energy substrates, and adaptation of glucose catabolism enzymes [30]. Efficacious transport of nutrients and oxygen to the muscle in individuals with the I/I genotype during prolonged physical exercise may not only be exclusively associated with the efficiency of oxygen supply to skeletal muscles via the circulatory system; allele I of the ACE gene likely determines to a greater degree the induction of post-exercise responses leading to a quick attainment of homeostasis [31]. The increased effectiveness of these biochemical processes at the cellular level rationalizes the storage of other energy substrates in the body, in particular glycogen stores [16]. A study of resistance to local exercise by I/I genotype individuals highlighted that participants performed more weightlifting repetitions (using elbow flexors) [16]; indicating a positive effect of local changes on individuals with genotype I/I, not just merely on their endurance performance levels attained as a function of their more efficient cardiovascular system [24]. It has been asserted that allele I may have a positive influence on aerobic endurance, most likely manifest through local muscle performance, opposed to the central circulatory system [24]. Whilst Oelz et al. [21] noted that the presence of genotype I/I in the ACE gene may not only be relevant to the functioning of cardiovascular system, but also for aerobic and respiratory factors.

Apart from ACE, other components of the renin-angiotensin system (AGT, AGTR1, CYPR11B) have been investigated [31]. The RAS component hormones found in many human body organs, e.g. heart, kidneys, brain, and body fat, are significant for control of gene expression and cell growth. Their activation may contribute to high blood pressure, obesity, diabetes, and dyslipidemia [30], i.e. medical conditions necessitating prolonged hospitalization. It was also indicated that, in individuals resistant to physical stress, allele I co-occurs exclusively with the ET-1 genotype [26]. Furthermore, a positive correlation has been highlighted between the ACE D polymorphism and AGT 235M [25], whilst a correlation between ACE (A240T) with high-altitude pulmonary edema [32], as well as with I/D polymorphism, have been noted [33]. Due to equivocal nature of empirical studies to date, it would be highly desirable to carry out further research into genotypes of professional and amateur athletes, and, in particular, surgical patients to investigate the mechanisms of exercise/surgical tolerance, recovery, and responses to high physical stress and hypoxia.

Limitations

Although during the course of this study we performed detailed molecular and qualitative analyses, there are further data that could be collected in future studies to supplement existing measures, such as oxygen saturation or uptake, heart function, and blood pressure. This would permit a greater understanding of the physiological responses to both surgery and healthy individuals, notwithstanding issues of feasibility; this was not the primary aim of the study. A further limitation of this study was the use of self-report modalities to ascertain physical activity level and well-being, nevertheless, both constructs are routinely collected using such methods in clinical practice and epidemiological research. The authors would, however, recommend that objective measure of physical activity [34] being scrutinized in greater detail in future studies [35].

Based on the collected data, it was not possible to indicate a common genotype predisposing resistance to surgery or physical activity, with no statistically significant correlation between the ID polymorphism of ACE gene in either group. However, in the patient group, physical activity was conducive to shorter time to convalescence, and should be considered by clinicians and other key stakeholders in the management of such patients.

References

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The Silent Voice of Those Who are no Longer: Transgenerational Transmission of Information from the Perspective of the Informational Model of Consciousness_Crimson Publishers

The Silent Voice of Those Who are no Longer: Transgenerational Transmission of Information from the Perspective of the Informational Model of Consciousness by Florin Gaiseanu in Gerontology & Geriatrics Studies_gerontology and geriatrics journals

Abstract

The “nature or nurture” problem concerning the debate on the innate features with respect to the acquired ones is approached in terms of information, from the perspective of the Informational Model of Consciousness. This model reveals seven distinct informational systems reflected in consciousness as informational centers, i.e. memory (Iknow-Ik), decisional info-operational center (Iwant-Iw), emotions (Ilove-Il), metabolic operations (Iam-Ia), genetic transmission (Icreate-Ic), genetic info-generation (Icreated-Icd) and the anti-entropic center (Ibelieve-Ib). Ib is a life-assisting beneficial center, because it is opposed to the entropic action of matter, eliminating or reducing the uncertainty characteristic to unknown possibilities to certainty, and inducing in this way the trust and confidence in own actions. The pro and contra arguments of the “nature or nurture” are shortly presented, noting the large range of divergent opinions and concepts on the approached problem. It is shown that the information concept acting both as informal and matter-related information, specifically referred to the embodiment/ disembodiment mechanisms for the transmission of information during the epigenetic processes, can coherently approach and explain the transgenerational transmission of the traits acquired during the life span of the predecessors. The concepts of tendency, affinity, propensity, predisposition, aptitude, vocation and talent, specific for inheritable properties described by ICD are discussed, pointing out the large pallet and variety of such concepts describing the evidences detected by external observers on the inherited behaviors, and that of self-perceived by the implicated individual, as a silent voice of whose are no longer. The external manifestation of such inherited features and traits depends on practice, because the characteristic operation of the nervous system and of epigenetic processes is based on repetition and/or intensive practice, but these are permanently guided by the silent voice of those who are no longer, with various signal intensities.

Introduction

Since a long time, probably since always, people did not wonder that the newborn and the future child resembled the mother, the father, the grandparents or even great-grandfather or great-grandmother, both as a physiognomy or behavioral style and preoccupations, because this seems to be a natural common situation. However, the science, starting with philosophy and continuing with branches such as psychology and psychiatry, the humanities and social sciences, as well as the behavioral and cognitive sciences, are still wondering since about 50 years, which is the appropriate answer to the “nature or nurture” problem. That means-in inheritability terms-what is determinant for the new generation: the inherited or the acquired properties during the span life? In other words, if the characteristics of a person in a certain field of activity, usually in music, in art in general, in mathematics or other sciences, in athletic or other performance fields requiring a distinct level of intelligence and/or dexterity, are the result of predispositions, innate aptitudes, of talent, or rather of the technical skills and of the exercise practiced with abnegation and tenacity [1]. For this purpose, the testing methods and especially the approaching mode of this problem were brought into discussion, both from a conceptual or interpretation point of view, and the balance between the two fundamental alternatives was discussed, but surprisingly, under the form of “all or nothing”, which means, one excludes the other [1].

Could be this the right answer to such a fundamental question, defying sometimes even the evidences? We do not have yet enough research tools and knowledge to elucidate this “problem”, intervening this time from the perspective of the modern sciences of information, of neurosciences and of genetics? As expected, a series of interventions to this surprising result, trying to restore, from various points of view, the balance lost in such an exclusionist conclusion, have outlined the followings aspects:

(i) It is not suitable to reduce the „nature – nurture” problem to only two extreme alternatives, this asking for instance to apply a asymptotic comparative analysis within so-called testing-the-limits method [2], or other elaborated models [3];

(ii) The identification and testing of the fundamental specific parameters of the human “processor”, like working memory capacity, learning rates, and forgetting rates should be taken into account [4];

(iii) It is wrong to exclude the motivation and self-confidence in the personal training, because these comes from an intimate discovery of special sensitivity, and even worse, to reduce this problem to a ban-imposed egalitarianism ideology, justified by a false interpretation of the equality of opportunities [5];

(iv) It is absurd to ignore the heritability of musical talent, evoking only the “environmentalism” factor [6];

(v) The perseverance, the hard but gradual work and the industriousness cannot be underestimated [7]; to explain suitably the relation between innate talent and high levels of ability, it is necessary to consider the differences in structure between most everyday abilities and expert performance [8];

(vi) Practice and other factors are important contributors to outstanding performance, but not enough to explain great creative works [9];

(vii) Experience is no improvement over talent [10];

(viii) General intelligence is central to many forms of talent [11];

(ix) Talent scouts, not practice scouts: talents are real [12];

(x) Creativity is an important factor over the practice [13];

(xi) The inborn talent yes, does exist [14].

Taking into account the large range of disperse and not coherent opinions on this topic, in order to try to clarify some fundamental aspects concerning it, in this paper it is discussed the transgenerational transmission of information and the innate predispositions from the perspective of the recently elaborated Informational Model of Consciousness [15-18], which explains the nature and structure of consciousness [17,19-21], its properties [22-24] and the neuro relations with the body [24-26], allowing to develop useful applications [27-29].

The Informational Model of Consciousness: Basic Structure and Transmission of Information

In the left side of (Figure 1) it is shown schematically the structure of consciousness, based on the concept of information. To understand this concept in its various forms, we have to point out that information could be interpreted as an informal property, like that received from the mass media or surrounding sources by our own senses (sight, hearing, smell, taste, touch), or intrinsic matter-related information, intervening into the intimate microscopic structure of matter [16,18]. A much more quantity of information is integrated into the living structures, in the human body, where practically all the constituting components-the living cells-communicate with themselves and with the others in a continuous and intimate manner [15]. For this reason, we may define the human body as an informed matter structure. Therefore, consciousness could be regarded as the representation/reflection in the mind of the functionality of specific informational systems which refer to:

Figure 1:Schematic representation of the components of the Informational Model of Consciousness, their connections with the corresponding body execution elements and the transgenerational transmission of information.

i. Accumulation of information (memory), marked suggestively in Figure 1 as the informational center I know (I k);

ii. Operation with information and decision, marked as the center I want (I w);

iii. Emotional activities, defined as I love (Il), love being the most representative of them;

iv. Metabolic activities for body maintenance, connected to nourishment matter, marked as the informational center I am (Ia), indicating the self-status, power and health;

v. The living/genetic creation assuring the reproduction, reflected in consciousness as the informational center Icreate (Ic);

vi. Info-genetic generation, transmitting the genetic characteristics from the parents (informed matter A and B in Figure 1) to the new body (informed matter C), and represented by the informational center suggestively called I created (I cd);

vii. Info-connection activities, consisting especially in the control of the certainty/uncertainty balance, which reinforces the confidence, trust and equilibrium, the power to choose and believe, therefore defined as the informational center Ibelive (Ib).

Each of informational system relates to specific areas of the brain and with the specific execution system by means of the neuro cord and neuro derivations to the body organs [26], schematically represented in Figure 1 left side. The center Ib and its connections explain the near-death phenomena (ex-corporal view, “tunnel” crossing, peace and light feeling, virtual meeting with the members of family who are no longer) during the clinical arrest of the heart and cease of the brain activity [22], the special properties of the mind like premonition, clairvoyance, telepathy and psychokinetic phenomena [19,23], religious and mystic experience [15,21], and even the possibility of an after-life existence of consciousness as an independent entity [24]. During the day by day activities, the main role of this center is to function as a life “navigation lighthouse” and “helm”, assuring the right/believed way to the life objectives and mobilizes, maintains and focuses the internal forces to the fulfilling of these objectives. In informational terms, this center represents an anti-entropic pole of information, because I believe signifies the selection from an uncertainty range of informational possibilities (which expresses actually the entropy of such an informational field) a certain information, which induces in consciousness and body security, trust and confidence, helping in this way the living prerogatives. Therefore, this center could be also regarded as an anti-entropic pole of the organism, assisting and supporting the living processes.

The memory (Ik) accumulates not only the life experience, as informational and emotional remembrances [17], but also the decision criteria, according to the mentality, especially acquired and consolidated during the childhood [20]. During the life span, this accumulation allows to attain the wisdom in the advanced age, when new criteria are added from the analysis of the various events of the life experience, from the selection between “Good” and “Bad” induced results. The life itself is a base of continuous learning for adaptation.

The adaptation process is managed by the operational/ decisional center of information Iw. Although the entire information is memorized as a life experience by Ik, only Iw may select and activate only the necessary information which serves as a basis of informational analysis and decisional process. The qualities of this center could be associated with the intelligence, speed of reaction/ operation and the correctness of the solution. However, this center operates based on decision criteria, most of them acquired in the familial ambient, enriched with that acquired during the life experience, including the professional and social one [20]. Besides the quantity and quality of the acquired and stoked information (Ik), emotions (Il), familial and social relations (Ic), inherited affinities (Icd), certitude/belief (Ibelieve) and the personal power state (Ia) contribute also to the final decision, so this will depends actually on signals received from the all other centers. The main result of the decision center Iw is the Attitude, which is the informational output of the conscious component of the informational system of the human body, necessary for immediate and/or medium-term adaptation to the environmental requirements.

Emotions, activated and managed by Il, could play an important role in decision. Emotions represents information stoked also in memory (Ik), but these are reactions of the body to the primary information, received or activated by Iw from the data library Ik. The emotions could be activated automatically, as a defense reaction, so are triggered very quickly by the alarm system of the brain (amygdala) or could be the result of some slower chemicaltype processes [30]. We defined such emotions based on chemical agents as emo-states and could be triggered consciously by the memorized or acquired information [15]. From this point of view, while the activities of Ik, Iw are conscious, the activity of Il is rather combined between conscious and unconscious one. The practice for a long time of the same type of emotions could create an emodependence on such induced states, with favorable consequences or not, so the activity of Il should be closely observed and suitably controlled [20].

As emotions can be therefore still controlled by conscious mind, the activities of Ik, Iw and Il represent the so-called operative informational system, which basically determines the reaction to information and is expressed by Attitude (Figure 1, upper right side). The center Ia reflects the status of the autonomic and automatic metabolic processes, because of the body connection to the external necessary matter (foods, air, water). Besides the common signals detected by the internal sensors and transmitted to the brain referring to the nourishment needs, like hungry and thirsty, this center vigils also the general situation of the body itself, the health, power and appropriate energy. By means of the autonomic execution systems managed by the programmed informational center of the brain, the absorbed matter is converted into the useful nutrients for the cells, assuring energy and substitution or reproduction materials for the body. The self-appreciation and selfesteem are close components of the characteristic range of qualities of this center.

The center lc is closely linked to the relations with the partner of life, with the members of own formed family and with the society. The high objective of life is to create offspring and to form and educate the new generation, assuring in this way the species continuity and survival. The information is transmitted as a genetic output (Figure 1, right side), which is a codified (“imprinted)” form of living informed matter, participating together with the complementary genetic information of the partner to the creation of the new member of the family. The relative relations between generations are very close, as could be expressed in popular terms by consanguinity. Such term is a result of ancient multigenerational observations, claiming that the constituent common genetic information is a basic support of common physical and psychical features. The information baggage genetically transmitted, and the information transmitted by education especially within the first years of life, when the nervous system of the child is under intensive structuration, is fundamental for the formation of mentality of the new individual.

Mentality includes a set of guiding rules and automatic chain-thinking prototypes inherited from parents and acquired by education, which states the fixing points and criteria of informational processing for own decision making. The capacity of conscious acquirement and processing of information is limited, so many of our typical behavioral manifestations are integrated into the automatic informational system, as less thinking-effort consuming [27]. The parent attitude on the children comportment is therefore of great importance during this stage and not only. Within the confrontation with the life problems, the silent voice of the parents and their advising recommendations accompanies everywhere and whenever the future adolescent and adult, even toward the ancient age. This close relation is reflected within the informational activity of the center Icd of the new generation (C in Figure 1, right downside). Within Icd are manifested the inherited properties of the new nascent child and future adult. The genetic information is transmitted by the genetic system and is manifested both in the similarity of the body and psychological features. During the life span this center manages also the typical characteristics of the age, from infancy to convenience.

As conscious cannot have access and interventions in the activities of the informational systems supporting the centers Ia, Ic and Icd, which are based, as it commented above on intimate molecular processes, the sum of these systems forms the unconscious component of the informational system of the human body (marked in obscure color in the right side of the Figure 1). The info output of the unconscious system is represented by the genetic transmission of information. The information in this case is supported by genetic matter, so according to the Informational Model of Consciousness, the transfer of information is done as a matter-related information.

The Silent Voice of Those Who Are no Longer: Transgenerational Transmission of Information

We name aptitude a series of manifested easiness with which somebody can think or make something specific. This is noted by the person himself or herself, and by the others. Such a behavior it is not qualified as a “hard” or difficult task. That is because the silent voice of the inherited properties is manifesting on this way. The affinity for a certain type of activity, expressed by the easy acceptance and ability to reproduce it without efforts is also due to the inherited features. On an increasing amplitude scale of the inherited qualities could be placed the tendency, affinity, propensity, predisposition, aptitude, vocation and talent. The silent voice of those who are no longer is manifested in various tones, registries and intensities; natural grace, innate gift, ability, skill, aptness, flair, knack, brilliance, belong to such a category.

The large range of existing words and concepts attributed to the inheritance qualities reflects the fine, graduated tuning scale of such qualities and the large recognition of the info-transference phenomenon from the predecessors to the offspring. If we want to refer to the info-material support of such inherited transference and to the related mechanisms, we should look no further than the early 90’s, when the new branch of genetics science, known now as epigenetics, started to flourish. Within the Informational Model of Consciousness, it was recently shown that the specific epigenetics mechanisms, allowing the intimate transference of information inside and between cells can be interpreted in terms of information science, by a process of embodiment/disembodiment of information [15]. Epigenetics studies the mechanisms which determines the acquisition of information at cellular level, induced by the environmental cues and stress. By stress we have to understand the factors situated outside of the commonly accepted range in the natural living ambient, and could be referred to whether, foods, or any other factor which can intervene to change the individual or group behavior, submitted under such circumstances to an adaptation process, but without change the genetic configuration.

One effect of this epigenetic process could be the transmission of the acquired traits to the next generation or generations, if this stress continues to persist (Figure 1). Such factors like drug or alcohol addiction were demonstrated to have influence on the next generation, specifically on the female (mother) line [31]. Epigenetics processes are also implicated in memory formation [32]. In a recent study it was shown that parents’ stressful experiences can influence an offspring’s vulnerability to many pathological conditions, including psychopathologies, and their effects may even endure for several generations. In this recent study it was confirmed that the main types of such epigenetic dynamic processes could be direct, when the changes occur during the lifespan of an individual due to a direct exposure to the environment experience, or indirect, both when it concerns changes that occur inside of the womb due to events during gestation and changes that affect the individual’s predecessors (parents, grandparents, etc.), due to events that occur even long before conception and that are somehow (e.g., through gametes, the intrauterine environment setting) transmitted across generations [33].

The intimate epigenetic process consists in three main steps as follows. During the first step, the signal which originates the interaction of the perceived information with the body itself is the “epigenator”, which can be molecules of the cell, “informed” by an info-embodiment process [15,27] and this signal triggers a cascade of cell molecular signal response, if the epigenetic is sufficiently persistent. Therefore, a repetitive and/or intensive signal is an imprescriptible condition that the epigenetic process should be initiated. In terms of epigenetics, the cell response signal is the “initiator”, which acts on the chromosomes, composed by DNA (deoxyribonucleic acid 30-40%), RNA (ribonucleic acid 1-10%), and histones (50-60%), which are some proteins anchoring the DNA helix structure. The proportion of these components varies not only for different species and for various tissues of the same organism, but even in the same cell, depending on the various stages of the cell cycle [15]. Finally, the epigenetic “maintainer” signal conserves the stable embodied information which will be transmitted to the daughter cells. In terms of the Informational Model of Consciousness, the insistent repetition of an information from the environment is a key factor for the epigenetic processes, allowing the transgenerational transmission of the traits. The repetition and/or intensive exposure to the epigenetic signal allows the initial informational signal to be transferred from the short-term memory to the long-term memory and from here to the memory of the skills, a complex and complete set of info-abilities automatically triggered [27], as it is for instance the playing an instrument or driving a bike [15].

The practice is therefore an important component of the performance, because by its natural form of working, the brain asks repetitive steps for a stable info-integration into the cells. However, what are the “epigenetics” and info-”initiators” of such a process? Who calls a child or young person to dedicate his time, energy and internal forces to a certain type of activity? This is the silent voice of those who are no longer (Figure 1, right lower side-transmitted epigenetic traits). As external observer, we call the manifestation of this voice affinity, propensity, predisposition, aptitude, vocation or talent. As personal self-own observers, we follow the calling of this voice, which indicates us that a certain activity is easy and pleasant to be done, stimulating the creativity, dedication and perseverance in practice and/or in a deep and profound study. This depends of course on the intensity of this voice, which means the intensity which the transgenerational signal was epigenetically transmitted by Icd. If this signal is weak and fragile, as often could happen at the children, whose power of Ia, Il and Ib is still low, it is necessary of course a stimulating impulse and encouragement from the side of parents, educators or instructors. If this signal is sufficiently high to be self-detected, the personal center Ib has a sufficient force to maintain the “navigation helm” on the right direction, assuring the confidence, trust and tenacity for the fulfilling of the final objective: the talent full manifestation.

Conclusion

It was shown that the old controversy on “nature or nurture” problem referring specifically to the inherited properties of the human like predispositions and talent with respect to the acquired ones by practice, can be approached in terms of transgenerational transmission of information, from the perspective of the Informational Model of Consciousness. This model reveals the existence of seven informational centers with specific activities, each of them with distinct tasks but interacting and collaborating each other’s for suitable adaptation to the environmental cues and stressors. The center Ik is the memory, Iw the operational decision, Il the emotion center, Ia self-status center reflecting the state of the metabolism operations, Ic the genetic transmission, Icd the info - genetic generator and Ib the anti-entropic center, assisting the life prerogatives, because it reduces to certainty the large range of uncertainty possibilities. As the Informational Model of Consciousness is able to describe in terms of information the intimate cellular transmission by mechanisms of embodiment/ disembodiment of information, it was shown that the epigenetic processes acts as convertors of the received information from the environment into the matter-related epigenetic information, transmissible by Ic to the offspring as genetic output.

The center Icd reflects the inherited physiological and psychological properties, particularly the affinity, propensity, predisposition, aptitude, vocation and talent. The large spectrum of the observed and defined inherited qualities shows the fine degree of variety and of signal intensity with which the silent voice of those who are no longer, the family predecessors, may express their acquired traits to the present generation. This signal is manifested to the own person and to the external observers. The practice is an important requirement that the talent become an evidence for the external observers, because the acquirement of stable information both by nervous system and epigenetic processes is based on repetitive and intensive training. However, the various self-observed internal signals coming from the precedent generations marking predispositions and affinities are easily detected, indicating that certain activities are facile and pleasant to be done. Just these signals are the predispositions, aptitudes, affinities and the entire range of the inherited tendency qualities. If the voice of those who are no longer is low at the children, then encouragement and stimulation impulses from the side of parents, teachers and instructors should be expressed. If these voices are sufficiently high, then the child or the young person himself or herself will meet the force (Ia), mental capacity (Ik, Iw) and tenacity (Iw), attachment feeling (Il), trust and confidence (Ib) to follow the voice calling (Icd) to attain the performance lciated by the external observers as talent.

Acknowledgment

As a continuity of life and information, the author dedicates this work to his son Adrian Gaiseanu and his family, together with special appreciations for his dedicated work and results. To his daughter Ana with special appreciations and to all members of family who appreciate and love him. In the memory of his eminent and exemplar parents, the distinguished (Magna cum Laude) Professor Emanoil Gaiseanu and distinguished (Emeritus) Professor Florica Gaiseanu and of all Members of Family who were part of his life: his brother Professor Constantin Gaiseanu, Fam. Popescu, Plopeanu, Potlogeanu, whose silent voices are still intimately listened.

References

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3. Bronfenbrenner U, Ceci S (1998) Could the answer be talent? Behavioral and Brain Sciences 21(3): 409-410.
4. Charness N (1998) Explaining exceptional performance: Constituent abilities and touchstone phenomena. Behavioral and Brain Sciences 21(3): 410-411.
5. Csikszentmihalyi M (1998) Fruitless polarities. Behavioral and Brain Sciences 21(3): 411.
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8. Ericsson KA (1998) Basic capacities can be modified or circumvented by deliberate practice: A rejection of talent accounts of expert performance. Behavioral and Brain Sciences 21(3): 413-414.
9. Feldman D, Katzir T (1998) Natural talents: An argument for the extremes. Behavioral and Brain Sciences 21(3): 414.
10. Heller K, Ziegler A (1998) Experience is no improvement over talent. Behavioral and Brain Sciences 21(3): 417-418.
11. Humphreys L (1998) General intelligence is central to many forms of talent. Behavioral and Brain Sciences 21(3): 418.
12. Rutter M (1998) Talent scouts, not practice scouts: Talents are real. Behavioral and Brain Sciences 21(3): 421-422.
13. Weisberg R (1998) Creativity and practice. Behavioral and Brain Sciences 21(3): 429-430.
14. Freeman J (1998) Inborn talent exists. Behavioral and Brain Sciences 21(3): 415.
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16. Gaiseanu F (2018) Information: from philosophic to physics concepts for informational modeling of consciousness. Philosophy Study 8(8): 368-382.
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Radial Shock Waves in the Treatment of Pseudoarthrosis_Crimson Publishers

Radial Shock Waves in the Treatment of Pseudoarthrosis by Paulo Kertzman in Orthopedic Research Online Journal_orthopedic research and reviews journal

Abstract

In this work we will analyze an innovative method using radial shock waves for the treatment of pseudarthrosis in superficial bones, avoiding surgical treatment that is usual for these cases. Treatment with shock waves promotes consolidation by stimulating osteoblasts and tissue regeneration factors, without the need for further surgery, reducing risks for patients. Forty consecutive cases were treated between June 2016 and December 2018. All patients had received indication for surgical treatment to correct the consolidation failure and therefore no control group or use of placebo treatment was made so as not to harm patients. Twenty-two men and 18 women were treated, ranging from 18 to 83 years with an average of 30.2 years. The mean time between the beginning of treatment with radial Shock Waves and the last treatment of the fracture was 8.8 months ranging from 6 to 38 months. In each session, 3000 radial waves were applied, the first 500 with 2 pressure bar for analgesia and 2500 waves with 4 bar for effective treatment. The site of the application of radial shock waves was determined by radiographs. Treatment was performed in an outpatient clinic without the need for hospitalization or anesthesia. Patients were reevaluated with radiographs after treatment in the periods of 2.4 and 6 months. The criterion for evaluation was radiographs evidencing.

Introduction

In this paper, we performed an innovative method, little described in the literature, using the radial shock waves for the treatment of pseudoarthrosis in superficial bones. Despite the current concepts in the surgical treatment of fractures with minimally invasive techniques and better fixation, about three to fifteen percent of cases involve to failed consolidation, being considered a pseudarthrosis after six months of the initial trauma without signs consolidation on the last 3 months [1]. The treatment usually recommended in these cases is the exchange of the osteosynthesis material and placement of bone graft, often evolved with good results, however, in addition to the high cost, there may be complications such as pain, bleeding, hematoma, infection, and consolidation failed [2].

The treatment of pseudoarthrosis using focal extracorporeal shock waves as an option to conventional surgical treatment has shown good results [3]. Treatment with extracorporeal shock waves is shown to stimulate the consolidation without the need for a new surgery, reducing risks and costs when the reason for failure of consolidation is of biological origin and not of instability mechanics, and the defect is smaller than 5mm in long bones [4-7]. The treatment of pseudoarthrosis with shock waves should be carried out preferably with so called focus shock waves by applying high energy. We started our practice in 1999 using this concept with good results [8]. Based on the good results obtained with the use of radial waves in tendinopathies [8] and the positive effect in vitro on osteoblasts and in vivo [9,10] and due to the difficulty of access to equipment generators high energy focal shock waves in Brazil, in 2009 we began the use radial shock waves to cases of superficial bones pseudoarthrosis. We started the treatment with radial shock waves in specific cases of superficial bones and published in 2017 a series of 22 cases being the highest in international literature [10]. We decided to do a series of prospective cases to confirm these good results. In this paper, we analyze the differences between the two types of waves, how the focal and radial shock waves are operating in pseudoarthrosis and if radial shock waves are effective.

Patients and Methods

This study was approved by the Research Ethics Committee of the Santa Casa Medical School and Hospitals, São Paulo, Brazil, under the number 12558513.1.000.5479. Prospective analysis of 40 consecutive cases treated between June 2016 and December 2018. Inclusion criteria were superficial bone not consolidated with at least six months, bone defect less than five millimeters and provide mechanical stability in the fracture focus. The exclusions have followed the standards of the Brazilian Society of Extracorporeal Shock Wave Treatment: use of anticoagulant, pregnant women, the presence of open physics in children and local tumor in addition to failure in fracture stabilization and larger defects of five millimeters.

All patients had the diagnostic confirmed for orthopedic surgeons as a pseudoarthrosis and received indication for performing surgical treatment for the correction of the failure of consolidation. We offer the treatment with radial ESWT as an option to surgery and, therefore, not been done nor control group or placebo treatment not to harm patients. We treated consecutive 40 patients, 22 men and 18 women, with age ranging from 18 to 83 years-old with an average of 30.2 years. The tibia was the most affected bone with 13 cases, followed by metatarsals in 7 cases, 4 distal humerus, 4 ulna, 2 calcaneus, 1 talus, 2 ischio, 2 fibula, 2 clavicle, 1 radio, 1 navicular, 1 scaphoid. The average time between the start of treatment with radial shock waves and the initial fracture was 8.8 months ranging from 6 to 38 months. All were treated by the same doctor and same equipment with 3 weekly interval sessions. In each session were applied radial waves 3000 being the first 500 with 2 bar pressure for analgesia and 2500 waves with 4 bar for effective treatment. X-rays and palpation of the failed site consolidation determined the location of the application of the radial shock waves. The treatment was carried out on an outpatient basis without the need for hospitalization or anesthesia. After the sessions of treatment in cases of lower limb compromise were kept walking with crutches with the same load and in 5 cases where there was no prior osteosynthesis patients used immobilization for 4 weeks. Patients were evaluated with radiographs after treatment during periods of 2.4 and 6 months.

Results

After 6 months of treatment the radiographic consolidation in 31 (77.5%) and in 9 patients (22.5%) there was no healing. All patients reported pain of medium intensity during application of radial shockwaves but there was no stopping treatment due to pain and all reported improvement after the session, without major worsening in the following days (Table 1).

Table 1:

**p<0.01 compared to baseline (mixed model) *** p<0.001 compared to baseline (mixed model) ap<0.05 between the affected and contralateral ROI BMD values (paired samples t-test, two-tailed significance) bp<0.01 between the affected and contralateral ROI BMD values (paired samples t-test, two-tailed significance) cp<0.001 between the affected and contralateral ROI BMD values (paired samples t-test, two-tailed significance

After 6 months of the treatment, all 31 patients with positive results was free of pain and satisfied with the treatment. The patients with bad results were submitted to surgical treatment. As adverse events, occurred edema, bruising and redness in 18% of cases with spontaneous resolution in a few days. There was no major complication or additional treatment needed.

Discussion

In this paper we analyze the literature on some issues that still generate doubts and also our results with this new technique.

1. What are shock waves and the mechanism of action in pseudarthrosis?
2. When should we apply the shock wave? The presence of the osteosynthesis hinders or contraindicates the use of shock waves?
3. How many sessions are necessary? Is there difference of results as to the that is equipment used? What level of energy should be used?
4. What is the effectiveness? Are there complications with the shock wave treatment?
5. It is possible to treat pseudoarthrosis with radial shock waves?

What are shock waves and which the action in the bones?

Focal and radial shock waves are mechanical waves high intensity sound produced by specific equipment being characterized in terms of physical and high-intensity and quick wave length containing a positive initial phase followed by a make less negative. What differentiates the two types of waves, is minor duration and intensity, and the peak energy is approximately a centimeter deep on radial waves [11]. When we use the focal waves, we could program the place of maximum energy that reaches the tissue to be treated between 0.5 and 5cm deep, whereas with radial waves is more superficial between 0.5 and 1.5 [12].

Both the focal as the radial waves are able to stimulate the activity of osteoblasts in vitro as in both animals. Both promote an effect called cavitation, that is related to the stimulus to consolidation of pseudoarthrosis through a phenomenon described as mechanotransduction, in which a mechanical stimulus induces a series of biological reactions by stimulating the production of bone regeneration, increased vascularization and bone matrix production by osteoblasts. [12-16] Focus shock waves are produced by generators that were initially developed for urological treatment of lithiasis, and may be hydraulic, piezoelectric or magnetic. Radial shock waves are produced by pneumatic or magnetic generators [17]. By accident there was the stimulation of the iliac crest in patients treated of ureteral lithiasis who developed a reaction the periosteum of the iliac wing. Since 1981 were developed studies on this unexpected action [18].

At the beginning it was believed only in a mechanical action causing stimulation of the periosteum, but animal studies and clinical trials have shown a series of chemical reactions by stimulating the production of osteoblasts, and tissue regeneration factors increase factors the vascularity that explain the consolidation of pseudoarthrosis and consolidation delays after stimulation with shock waves [19]. These biological actions occur at the time of application with intense stimulation of the periosteum and the following days with increasing concentration of prostaglandins, local factors of tissue regeneration and increased local vascularization factor that can last for up to six months is the average time for consolidation to occur [18-22]. Works on animals demonstrate the stimulus in osteoblasts and bone callus formation of good quality and endurance using both focal and radial waves [21,15].

When should we apply the shock wave? The presence of the osteosynthesis hinders or contraindicates the use of shock waves?

The indication is for cases of delayed consolidation or pseudarthrosis biological failure, when the space between the fragments is up to 5mm in long bones and it is necessary that there is mechanical stability in the fracture focus [22]. The presence of plates, screws, rods and external fixators is no contraindication, because there's no heat reaction or risk of loosening due to mechanical stimulus, on the contrary, the presence of osteosynthesis is required so that there is stability of the focus of pseudarthrosis and allow healing. The doctor must take care to direct the waves in such a way that there are between the generator and the bone the presence of metal plate which can prevent the progression of energy preventing action on your bone to be treated. If there is a failure in stability is necessary to correct with new or use of osteosynthesis immobilization [23].

How many sessions are necessary? Is there difference of results as to the that is equipment used? What level of energy should be used?

There is still a lack of standardization of the treatment on the number of sessions and energy used for each type of pseudarthrosis, which makes the comparison among the papers published difficult. However, most authors use the same energy dosage and number of waves in all kinds of bones being applied on average 3000 shockwaves to each session ranging from one to three sessions [24-26]. Treatment with high energy and deep focal waves is usually done under anesthesia and can be repeated after 4 to 6 weeks of the first stimulus and the majority of patients receives two to three sessions. The energy used ranges from 0.18 to 0.30 millijoules per square millimeter. The best results are with hydraulic generators and magnetic equipment [25,26]. To treat with radial waves not using anesthesia and are made at least three sessions with an interval of a week with 3000 waves each session applied directly to the focus of pseudarthrosis with 4 energy bar which is equivalent to 0.18 to 0.20 millijoules per mm square meter.

What is the effectiveness? Are there complications with the shock wave treatment?

The best results are reported with the use of focal ESWT generating equipment with hydraulic generators and magnetic, the patient sedated and using fluoroscopy to the location of the point of treatment with 65 to 78% of good results [27-29]. As to the type of pseudarthrosis best results are to the hypertrophic, but in also reported good results are atrophic. Immobilization after treatment for 6 to 8 weeks may be necessary in cases of greater instability in the focus of pseudarthrosis [29,30].

Most of the works comprises a series of cases, but there are also studies comparing with traditional surgery in the femur, scaphoid and metatarsals. These studies show results similar to surgical treatment, but with much lower cost, morbidity and complications [31-34]. There are review works simple and systematic reviews of the literature confirming the effectiveness of the use of focal shock waves [35-37]. Adverse effects are pain at the time of application that may require the use of general anesthesia or regional blockade. Are reported swelling, petechiae, bruising and superficial pain in the early days after application with good evolution with medical follow-up. There is no report of serious complications with the treatment. [34,35] Is a treatment exclusively orthopedic doctor since it requires an accurate diagnosis, bone pathology knowledge, knowledge of the regional anatomy preventing vessels and nerves and the assessment of the consolidation.

It is possible to treat pseudoarthrosis with radial shock waves?

There are scientific studies demonstrating the effectiveness of radial waves in vitro, in animals and in humans [15,16,38-42]. Recently there was the use of so-called radial waves to the bone surface treatment with good results [39]. We present in this paper the largest series of prospective cases treated with radial shock waves published in world literature by opening a new line of interest so that other authors can study this new method of treatment.

As weak points, we can consider the small number of cases studied, and the lack of control or placebo group.

The use of radial shock waves for the treatment of superficial bones proved to be a safe, efficient method and less expensive but requires more study to proof of your effectiveness. That new option for treatment of pseudoarthrosis of superficial bones is as effective as surgery and focal ESWT. We believe that this new method of treatment can benefit many patients.

Conclusion

The use of radial shock waves in cases of pseudarthrosis in superficial bone is effective and safe.

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