Diagnostic Approach in X-Linked Adrenoleukodystrophy in the Pediatric Patient. A Case Report

Introduction

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 locus Xq28 gene due to deficiency of the ALDP protein of the peroxisomal membrane resulting in accumulation of long-chain fatty acids (VLCFA) mainly in the adrenal cortex and central nervous system [1]. It has an incidence of 1 in 21,000 hemizygotes and 1 in 16,800 in heterozygotes. Cerebral infantile X-ALD is the most devastating and progressive phenotype, occurs between three and ten years (peak seven years) is characterized by developmental regression, severe sensory and neurological deficits, in addition to clinical data characteristic of adrenal insufficiency (Addison) [2].

Case Presentation

A 7-year-old boy with no major medical or perinatal history. He started his current condition 6 months ago with asthenia and adynamia, loss of previously learned fine motor skills (buttoning pants, tying shoes), decreased interaction with people and impaired academic performance. Likewise, areas of hyperpigmentation were observed in folds (neck, armpits, elbows, English), so he was requested levels of Adrenocorticotropa hormone ACTH levels of 5455pg/ml (normal: 12 - 76pg/ml) and serum cortisol within normal limits for age. Prednisolone was started at physiological doses. He presented an episode of adrenal crisis secondary to community-acquired pneumonia, so the dose was adjusted to stress doses in the previous 5 months. In this hospitalization, contrasted brain Magnetic Resonance Imaging (MRI) was performed, where hyperintensity was found in the T2 sequence at the level of the white matter in the posterior region of the parietal and occipital lobes, as well as at the level of the midbrain and bridge (Figure 1). He was send to the Genetics department with suspicion of X-linked adrenoleukodystrophy. During his follow-up by Pediatric Endocrinology 2 months after diagnosis, he presented progression of neurological deterioration with ataxic gait, impaired verbal communication and urinary and fecal incontinence. The Genetics department who started management with Lorenzo’s oil (40ml/ day) and lovastatin, as well as a diet low in fatty acids, and requested serum determination of very long chain fatty acids (VLCFA) evaluated him. A follow-up was carried out for 3 months, finding poor response to treatment with persistent cognitive impairment, spasticity and rigidity.

Figure 1: Contrast Brain MRI in T2 sequence.
A. Hyper uptake in the region of the internal capsules and parietal lobes;
B. Hyper uptake is observed in the thalamus, as well as in the white matter of the parietal lobes;
C. Hyper uptake is observed in the corpus callosum, in the bridge and mesencephalon.

Discussion

More than 800 variants in the ABCD1 gene mutation are described, which cause defects in ALDP (adrenoleukodystrophy protein) resulting in the elevation of VLCFA mainly hexadecanoic acids (C26:0) and lignoceric acids (C24:0), causing the accumulation of these in the central nervous system among other tissues [1,2]. VLCFA modify phosphatidylcholine in the myelin membrane can cause instability and inflammation due to altered β-oxidation peroxisomal and increased fatty acid elongation, elevated levels of VLCFA in membranes alter myelin structure and function, this mechanism is described in cerebral adrenoleukodystrophy (CALD) [1]. This causes damage to the endothelium of the cerebral microvasculature critical for the initiation and progression of inflammatory demyelination, tight junction proteins have been shown in autopsies to be displaced, along with massive bloodbrain barrier disruption [1,2]. X-ALD is sensitive to oxidative stress that arises from accumulation of VLCFA and when an excess of free radicals occur they cause the opening of the transition pore of mitochondrial permeability resulting in cell death [1]. Clinical phenotypes of ALD have been described: cerebral infantile, adrenomyeloneuropathy (AMN) and primary adrenal insufficiency [2]. Due to the natural evolution of the disease the phenotypes actually represent a spectrum of the condition, practically all males with ALD will develop adrenal insufficiency and progressive myelopathy in adulthood, and may also develop rapidly progressive cerebral demyelination, which can occur during childhood, but also in adulthood [2].

ALD initially presents as adrenal insufficiency between the ages of 3-10 years, of these 35-40% may progress to a rapidly progressive form of inflammatory demyelination (CALD), leading to progressive neurological deterioration with a peak incidence observed between the ages of 3-8 years causing a vegetative state until death within 2-3 years [2,3]. It is clear that other factors modulate this phenotypic conversion in addition that there is an average delay in the diagnosis of adrenal insufficiency of 3.5 years, which is considered a predetermining factor for clinical progression since an asymptomatic period may be followed [2,3]. The presentation of the clinical case had a delay in the diagnosis of more than 6 months, combining the progression of the disease with clinical data such as asthenia and adynamia in addition to hyperpigmentation at the same time demonstrating manifestations of adrenal insufficiency, it is necessary to start the approach by assessing adrenal function [3]. Adding affectation of fine motor skills involvement suggests brain magnetic resonance imaging (MRI) to rule out brain tumor, neuro infection or autoimmune encephalitis [4]. Brain magnetic resonance imaging (MRI) demonstrates demyelination of the brain white matter, which usually precedes clinical symptoms, ALD brain lesions are initially observed in the splenium of the corpus callosum and the parieto occipital white matter [4,5].
Given the age of the patient, the insidious and progressive onset together with the episode of adrenal crisis provoked by an infection in addition to the data provided by the MRI with which a Loes score of 6 was obtained, it is necessary to approach the patient as a childhood cerebral phenotype of ALD, requesting VLCFA levels [4,5]. Plasma VLCFA analysis is the most commonly used diagnostic test for ALD in men [3]. Given the prevalence of 1 in 21,000 newborns in addition to the difficulty in detecting ADL-X in female patients due to negative family history with onset between the ages of 30- 40 years plus few clinical data (progressive spastic paraparesis more common presentation after age 60) and the need for a panel of laboratory tests [2,3]. In February 2016, newborn screening for X-ALD was added to the recommended uniform screening panel in the United States since ALD has been identified as a newborn screening condition (Figure 2) [2,3]. It was recommended that asymptomatic males identified by newborn screening in New York should have their adrenal function quantitatively assessed every 6 months and the first brain MRI performed until 12 months, then annually until age 3 years, then every 6 months, until age 10 years, and annually thereafter [3]. Once identified, it is suggested to refer the family for counseling, as well as confirmatory tests in the members that require them, in addition, the adrenal function is assessed, since it has been demonstrated that in newborn patients there is biochemical evidence of adrenal insufficiency from 5 weeks and at 4.5 months [2,3].

Figure 2: Proposed algorithm for the diagnosis of ALD-X. It is suggested to investigate clinical history in women with clinical data and perform newborn screening [3]. Normal values VLCFA C24:0/C22:0 0.84μg/mL C26:0/C22:0 0.01μg/mL.

Follow-up with brain MRI is suggested to assess disease progression [3,5]. Abnormalities in MRI are evaluated using the Loes scale, points are awarded based on location, extent of brain parenchymal signal changes, ALD patterns, and the presence of focal and global atrophy [5]. Hyperintensity in T1 or T2 may be seen in areas including white matter: supratentorial, corpus callosum, visual pathway, frontopontine or corticospinal tract and major projection fibers [4,5]. The score is rated from 0 (no evidence of disease) to 34 (severe involvement). 5 In conjunction, the neurological function scale that evaluates the clinical progression of the disease in the patient has been used, in our case resulting in a score of 11 (Table 1) [4]. Both scales should be used to assess progression at a minimum of 1 follow-up evaluation [4,5]. CALD is defined as arrested CALD ≥ 2 consecutive MRI scans within a minimum of 6 months with no increase in Loes Score, no contrast enhancement and no progression of brain symptoms (neurological function scale) [4,5]. There is a limitation in the treatment therapies used in patients with ALD, once the diagnosis is made therapeutic interventions are indicated when the Loes score is between 0.5- 9.2.6 Allogeneic hematopoietic stem cell transplantation is effective for cerebral ALD in the early stages of the disease (Loes 0. 5-9 and neurological function score ≤ 1) allowing to stop the disease progression at the brain level, for symptomatic patients with a Loes score ≥ 10 transplantation produces unfavorable results [4,6]. Transplantation does not alter the progression of adrenal insufficiency so corticosteroid replacement should be initiated, hydrocortisone is the glucocorticoid of choice in children and should be started at stress doses as soon as adrenal insufficiency is diagnosed [3].

Table 1: Assessment of brain involvement. Neurologic Function Scale is used to evaluate the general clinical neurologic status in patients with CALD to determine the degree of risk prior to stem cell transplantation and post-transplant for follow-up [4]. A score of 0 represents no signs of brain disease but more severe signs (*) represent 12 points that determine a high-risk progression domain [4]. Loes < 10 are considered seriously for allogeneic hematopoietic stem cell transplantation at standard risk. Loes > 10 have a more complicated.

Supportive therapies such as Lorenzo’s oil (GTO/GTE) (mixture of glycerol trioleate [GTO] and glycerol trierucate [GTE] in a ratio 4: 1, at doses 2-3ml/kg/day, this reduces the synthesis of very long chain fatty acids (VLCFA) by competitive inhibition of the enzyme responsible for the elongation of saturated fatty acids, but is ineffective in halting disease progression (CALD). Metabolic modulators such as bezafibrate demonstrated a reduction of VLCFA in ALD fibroblasts, but not in plasma, recently a combination of multiple antioxidants at high doses normalizes biomarkers of oxidative damage and inflammation [2,6].

Conclusion

In this case, the importance of making a diagnosis when clinical suspicion persists, recognizing disease patterns with mild to severe patient-dependent manifestations, which are used to assess disease prognosis, as well as the importance of VLCFA analysis to prompt diagnosis of ALD early to allow hormone replacement and prevent disease progression to a devastating phenotype. MRI images of the brain obtained as part of the patient evaluation are used to determine the use of a specific therapy by assessing the risk-benefit ratio, as well as to evaluate progression and determine if the disease is arrested.

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The Cultivation of Creativity in the Classroom

Introduction

Conceptually, creativity is defined as the ability to produce a new work or idea based on imagination. Younger psychologists argue that creativity is not a special skill or ability of a few people, but rather is the result of special training and learning through specific processes, which enable each individual to activate inexhaustible forces of his mind [1]. Many view creativity as a tendency to activate or recognize alternative ideas or possibilities, which can prove useful in problem solving, in communicating with others, or even in the field of entertainment. Creativity according to others is to think outside the blueprints or frameworks, approaching new areas and achieving results, which are able to provide answers to problems that concern them [2]. In this process, a clear distinction is made between predetermined abilities. Of course, the first concerns creativity, learning ability and communication. The latter are directly related to production, economy, marketing, etc. Creativity therefore moves within an indefinite pattern and can be evaluated through different processes. Many also argue that creativity can be seen as a process by which new original and useful ideas are activated, which help to deal with everyday problems and challenges. But it is important to see human creativity as the art of the different in terms of thinking. But in order to formulate a definition that will be based on scientific data, it is important to do a historical review and to trace the way in which science used to deal with, and continues to deal with, the concept of creativity. But in order not to get lost in the vastness of the various sciences, we will approach it both as an object of psychological research and as an object of pedagogical practice [3].

It is a fact that creativity has preoccupied researchers and around the subject has developed a large bibliography that gives new dimensions to creative thinking and opens new perspectives. As a starting point for creativity, we refer to the discomfort Guilford posed to the American Psychological Society in 1950 over the way the scientific community approached creativity, which was listed in the international literature as an “American challenge.” This discomfort and Guilford’s concerns in general were the trigger for the development of a number of approaches to creative thinking [4]. The interest of scientists and researchers to deal with the creative thinking of man and the abandonment of the concept of the “divine gift”, gave a series of definitions which we present below in order to arrive at a more widely accepted definition, but also through management of the concept of creativity to be able to understand the nature of creative thinking and the structural principles that govern it. Guilford made a first attempt to define the concept, according to which “creativity covers the most characteristic abilities of creative individuals, which determine the probability for an individual to express a creative behavior, which is manifested by ingenuity, composition and design.” of course, this definition is simplistic, but some facts emerge that are then confirmed by researchers. This ability seems to be linked to certain personality traits.

These characteristics speculate if and how creativity will manifest. Creativity affects all individuals and is not a rare phenomenon only of gifted individuals [5]. “Differentiation between individuals is quantitative, a matter of classification, not qualitative.” Getzels and Jackson (1962) define creativity as the combination of those elements that are considered original and different [5]. They point out that creativity is one of the most valuable human possibilities, but it is difficult to examine it systematically. Lowenfeld and Brittain (1975) argue that creativity is directly related to who gives the definition. Thus, some psychologists distinguish as qualitative elements of creativity:
a. Flexibility of thought
b. The originality of the idea
c. The ability to think differently
d. How to solve problems.

Of course, here we have to contrast Einstein’s view, which argues that formulating a problem is more important than solving it. Piaget (1960) defines creativity as a process of problem solving, problem finding, exploration, experimentation, an intellectual energy that implies respect and thoughtful decision making. Torrance (1966) identifies creativity with the ability of the individual to face various problems, with sensitivity, originality but also with method and calm. Creativity according to Lee, Webberlen and Litt (1987) is a multifaceted phenomenon and every issue that arises is addressed through different processes. We must also cite the view of Bruner (1962) who defines creativity as an energy from which arises a special and effective surprise [3]. Freud (1972) defines creativity as an instinctive impulse that aims at creation but also correlates it with the impulse of destruction. Creativity can include shaping new systems, transferring familiar relationships to a different field, and shaping new correlations. Through the conceptual approach it follows that it is difficult to integrate creativity into a definition. We adopt what Davis (1992) states: “There are as many infinite definitions and ideas of creativity as there are people who have written their ideas on a piece of paper.” Of course, if we want to categorize the prevailing positions on creativity, we could mention:
a. The traditional view, which claims that there are a number of “intelligent”, “gifted” people, this category includes people with exceptional talent or some special skills that stand out from the rest and cite as examples personalities such as Mozart and Einstein and according to this creativity is not the same in all people, so it is not cultivated.
b. The modern view, which argues that talent is mainly the result of practice and hard work, and all individuals have the opportunity to reach a degree of creativity and the cognitive processes followed in the emergence of ideas are no different from every day and therefore creativity can be cultivated.

The nature of Creativity

Creativity is about observing known things, it is based on previous ideas - experiences and the search extends to something new or a different approach. Among the main reasons that drive creativity, we distinguish:
a) The need for an innate impulse inherent in the human mind for something new.
b) The communicative need for exchange of ideas.
c) The human need to solve problems and create new ideas.

The human brain is the one that plays an important role in every creation, whether it is associated with human survival and the construction of the first tools, with mental functions, with artistic creations or even with the confrontation of everyday human problems. Creativity does not start with zero states [6]. It can be built on pre-existing knowledge or experiences. In the nature of creativity, we must mention an important element that runs through the whole process. It is the element of imagination that enables people and much more children to successfully process everyday situations and develop their creative abilities [6]. Imagination and creativity could be said to move in parallel and are interconnected. Of course, we must emphasize that creativity does not start from scratch, like the imagination, in the sense that the pre-existing elements that are inscribed in the consciousness help to create new representations in the form of images or ideas. This begs the question, are the representations of memory the same as the representations that exist and are recorded in the imagination? Their difference is more in the form and not in the content. It is important to point out that there is a danger in childhood that the imaginary will become an extension of reality.

The Evaluation of Creativity

Evaluation is the stage at which an account of what has been produced is made. It is an important stage in the whole process through which the ideas produced are evaluated [7]. Without it, the process would be “incomplete”. Furthermore, every evaluation of ideas has basic principles, such as: “it is a continuous process, it must be done for all ideas, it must have the meaning of collectivity, it must be objective, and it must be a guide for further paths” [8]. It is suggested that the convergent thinking be evaluated separately from the divergent one in order to understand the differences. Evaluating creativity is important for the following reasons:
a) It contributes decisively for the younger generations to show their abilities and to take advantage of their inclinations and interests.
b) It is a determining factor and a steady step towards selfknowledge.
c) It prepares future generations to adapt to the rapid changes that are taking place” [8].

Creativity is not an objective feature, because we have the ability to use indicators to evaluate the creative possibilities through which objective determination is achieved. We should mention that there are no surefire ways to guarantee the reproduction of innovative ideas. Source inspiration does not fall into measurement scales. Of course, there have been references to specific brainstorming processes, but the issue remains open, as discussions persist in the qualitative dimension, which is not measurable [9].

Evaluation Methods

From the search in the foreign language literature regarding the methods of evaluation of the creative inclination and ability, we have distinguished numerous and flexible methods that enable the evaluation. Of course, we should point out the research controversy in the scientific community regarding the evaluation of creativity [10]. Hocevar in a thorough review of creativity presented key points - axes used in creativity studies:
a. Convergent thinking exercises.
b. Divergent thinking exercises.
c. Recording the behavior and interests of individuals.
d. Recording of special personality elements.
There are other ways to measure creativity, such as:
1. Plot titles: here the participants are given the plot of a story and asked to come up with original titles.
2. Quick reactions to word associations: this is where unusual answers are scored.
3. Conception of shapes and forms: here are presented simple drawings of people and objects and they are asked to find common properties and characteristics in two or more paintings. Scoring is again based on unusual answers.
4. Unusual uses: here are given everyday objects, e.g., a toothpick and unusual applications are required.
5. Remote correlations: here participants are asked to create a new word from two other simple ones.
6. Distant effects: this calls for the activation of a list of consequences of unexpected events.
7. Creativity can also be calculated based on the response to a variety of test scenarios, such as:
8. The expression of ideas: the ability to easily develop a variety of reasoning and correlations, when presented with a simple word or image.
9. The combination of ideas in a new way: the development of a wide range of innovative approaches and solutions, when we are asked to explore new possibilities for an ordinary simple object of our daily life (eg a brick).
The emergence of new benefits for existing ideas: the activation of original ideas or solutions based on pre-existing ideas. Investigation: the ability to process an idea in order to make it practically functional. Focus and distinction: identifying the most important elements of an idea and then approaching them in an effort to solve a problem while simultaneously evaluating the difficulties. Perspective exchange: the ability to suggest ways to view and solve a problem in the light of different perspectives.

Children and Creativity the Cultivation of Creativity in the Classroom

Teachers should review the teaching practices they apply in order to be able to judge the extent to which they have been able to instill in students a creative way of thinking. Some ways to boost creativity by teachers are:
Enhancing divergent thinking:
a) Allow the teacher to ask questions of the student.
b) Be educationally receptive and sensitive to the problems faced by students.
c) To make the children realize the maximum importance of the questions, but also not to be afraid to trust their senses.
d) Problems should not be presented simply but discovered.
e) Attempt to try a second Tuesday etc. to find a solution to each problem.
f) The taught subjects of the courses to be examined from different angles.
g) To convey to the students the message that they should not rest on the first correct answer they will give.
h) In general, is there anything going on in the school that could be part of the concept of divergent thinking?
i) In any case, Learning should not be a mechanical storage of knowledge from textbooks and teachers.
j) Existence of motivation and encouragement:
k) Students’ questions should be accepted by teachers so that they can then develop.
l) Children’s curiosity to be supported and additionally provoked.
m) Opportunities for self-directed learning should be provided.
n) The teacher appreciates and supports the personal interests of the student.
o) Unnecessary repetition of a theme should be avoided.
p) Receptivity to the new
q) The school should be not only a place of traditional teaching, but also of enjoyment, fun and challenge for spiritual adventures.
r) Teaching should convey the real world within the school.
s) As a place the school should be offered for the cultivation of imagination.
t) The school must be able to dispel stress and provide a sense of comfort and relaxation to the student.
u) The school must provide opportunities and opportunities for a subject to be examined in an experimental and at the same time pleasant way.
v) Finally, the uniqueness and individual personality of each student should be assessed, and a conservative attitude should not be imposed.
Cultivation of creativity must be an integral part of the educational process (Jullien, 2004). We emphasize that the cultivation of creative tendencies should not be pursued only within the framework of some ‘special hourly support programs that will be repeated at sparse intervals or at a predetermined time and place. The desire to cultivate such an important element must overcome all limitations and be systematically systematized, in every activity that accompanies school and extracurricular life.

Conclusions

Creativity is a multifaceted concept. Its special nature leads to the non-existence of a unified psychological theory that will explain and include all its dimensions. Many people still associate it with the arts and avoid associating it with other cognitive objects such as the sciences which are considered uncreative. They believe that creativity is a special feature of some people who are involved in the arts. The importance of creativity for art is very important but it is equally important in the sciences and in other cognitive areas that result from the composition of two areas. For example, the use of art in the natural sciences and vice versa. Today we have come to the conclusion that creativity is characteristic of every human being. All people can be creative as long as they are given the opportunity and find themselves in an environment where the conditions are right for them to develop and cultivate their creative skills. The development of creativity in the school context is important and there are specific ways to enhance and promote it that must be taken care of by teachers. The evaluation of creativity also plays an important role, which is a key factor in the course of children’s education at all levels of education.

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Rapid and Practical Screening Method for the Detection of Colistin-Resistant Bacteria in Food

Introduction

Colistin is recognized as one of the few remaining available antibiotics for the treatment of intractable infections caused by multidrug-resistant Gram-negative bacteria [1]. Recent studies have shown that bacteria carrying the mcr gene, which confers colistin resistance to most members of the Enterobacteriaceae, are widely disseminated, particularly in Asia [2,3]. Since colistin is widely used in animal husbandry [4], the spread of colistin-resistant (CR) bacteria in communities via livestock food is a potential risk factor. Moreover, CR bacteria are often found in animals and animalfood [5-7]; thus, monitoring CR bacteria in animal-food is essential. However, the conventional culture method [8] for detecting CR bacteria in food is laborious and time-consuming. Rapid detection of colistin resistance genes at the research level is now possible using the SYBR green method [9], but its widespread practicality is limited due to the need for complex steps and equipment involved in DNA extraction from samples and determination of result specificity. To overcome this limitation, we here report a simple, rapid, and practical detection method of Escherichia coli harboring mcr-1, as a representative CR bacterium, using a highspeed real-time polymerase chain reaction (PCR) kit. We further verified the utility of this method for detecting CR bacteria in retail meat samples. Although a real-time PCR assay for the detection of mcr genes from bacterial isolates has already been established, this newly proposed detection method holds practical relevance for widespread use, as the entire procedure, from food sample processing to the final result, can be completed within only 1 h.

Materials and Methods

A total of 27 retail meat samples, including pork and chicken, were collected from 10 markets (two supermarkets and eight local traditional markets) in Vietnam and five supermarkets in Japan during November and December 2019. None of the eight traditional markets in Vietnam maintained a refrigerator for meat preservation. In contrast, the two supermarkets in Vietnam and all five supermarkets in Japan had refrigerators for food storage. Each sample was collected from one meat type per market. Bacterial cultures and DNA extraction were performed on the collection day. Ten grams of each meat sample were placed in a stomacher bag (AS ONE, Osaka, Japan) containing 90 mL buffered peptone water. The samples were hand-homogenized for 2 min. The resulting homogenate was inoculated on CHROMagar COL-APSE (CHROMagar, Paris, France), a selective medium for CR Gram-negative bacteria, and cultured at 37 °C for 24 h. CR E. coli-like colonies were distinguished based on colony color (dark pink to reddish) after cultivation [8,10]. A representative colony was isolated by sub-culturing on MacConkey agar, and bacterial identification was performed. The colistin minimum inhibitory concentration (MIC) was estimated, and colistin resistance genes (mcr-1 to -5) were detected by multiplex PCR as described previously [6,11].
In parallel, DNA was extracted from 1 mL of the homogenate using the Kaneka Easy DNA Extraction Kit version 2 (Kaneka, Tokyo, Japan). The presence of E. coli and the colistin resistance gene mcr-1 in the DNA extracts was determined by real-time PCR using a mobile PCR device, PicoGene PCR1100 (Nippon Sheet Glass, Tokyo, Japan). PCR primers and TaqMan probes for realtime PCR detection of E. coli 16S rRNA and mcr-1 were prepared as described previously (Table 1) [12]. Details regarding the realtime PCR, including PCR mixtures and thermal cycling conditions, are provided in Tables 2 & 3, respectively. The DNA extract of the CR E. coli strain (E362) [6] carrying mcr-1 was utilized as a positive control in PCR. The entire 50 PCR cycles were completed within only 21 min. Moreover, the real-time PCR device could simultaneously measure fluorescence at three different wavelengths for the same sample. Two fluorescent dye-labeled TaqMan probes (Integrated DNA Technologies, Singapore), Cy5 for E. coli 16S rRNA and FAM for mcr-1, were used for each sample. The entire protocol is outlined in Figure 1. Figure 2 shows representative real-time PCR profiles of the samples.

Figure 1: Outline of the screening protocol using mobile real-time PCR PicoGene® PCR1100. BPW, buffered peptone water.

Figure 2: Representative plots obtained from real-time PCR amplification of mcr-1 and E. coli 16S rRNA genes in meat samples.
a) Positive control, mcr-1 E. coli.
b) mcr-1–negative pork sample, H-A market pork.
c) mcr-1–positive chicken sample, H-E market chicken.

Results and Discussion

The detection sensitivity of the method was assessed using pork meat samples spiked with an mcr-1-positive E. coli strain culture. The lower limit of mcr-1-E. coli detection for the entire method, from DNA extraction to detection by real-time PCR, was 7 × 102 CFU/g; however, a minimum of 7 × 103 CFU/g was required for quantification using a linear correlation. In the validation study using retail meat samples, CR E. coli-like bacteria were detected using the culture-based method in eight out of ten chicken and in three out of seven pork samples purchased in Vietnam (Table 4). The semi-quantitative levels of CR bacteria in these samples were in the range 103‒108 CFU/g (Table 4). All representative CR E. coli isolates from each sample were confirmed to be resistant to colistin (MIC ≥ 4 μg/mL) and possessed mcr-1 but not mcr-2 to -5, except for the H-E market pork sample, which harbored mcr-3 in addition to mcr-1, as determined by multiplex PCR. No samples from the Japanese supermarkets were contaminated with CR bacteria. All samples, except for the H-E market pork sample, that were positive via the culture-based method were also positive by real-time PCR (Table 4). Some culture-negative samples such as H-B market pork, T-B market chicken, T-B market pork, and T-E market chicken were PCR-positive. Such contradictory results may be attributed to the features of the real-time PCR method and its ability to detect mcr-1 even in dead cells and/or non-E. coli cells. In contrast, a pork sample from the H-E market showed CR E. coli colonies after culturing but tested negative for mcr-1 by real-time PCR. Such discrepant cases could be due to a low level of mcr-1–positive bacteria below the detection limit of the real-time PCR method or the presence of bacteria expressing non-mcr CR determinants [13].

The new method presented herein detects the target gene and facilitates quantitative analysis. In addition, the method using TaqMan probes has high detection specificity, and is simple because it does not require specificity verification by melting curve analysis, even for one-step extracted DNA from food. The results output the ratio of bacteria carrying mcr-1 to the total number of E. coli cells, which may be mcr-1–positive or –negative bacteria (Figure 2). The detected quantitative mcr-1 levels were higher than the CR E. coli-like bacterial levels determined via the culture-based method because the real-time PCR method detects all mcr-1 regardless of bacterial species. The quantitative linear range detected via realtime PCR was between 103 and 106 CFU/g. Although the detected signal was below the quantitative linear range limit in some samples, they were still considered to have positive results via realtime PCR. The approach described in this study provides limited information regarding the degree of contamination; nevertheless, the developed method is reliable and practical owing to a short processing time, enabling the rapid screening of contaminating bacteria with mcr-1 in food.

Conclusion

A new rapid and practical screening method was developed for detecting CR E. coli in food samples. The developed method is advantageous because it is easy to perform, has a short processing time, and provides reliable results that are consistent with those obtained by traditional methods.

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Remote Monitoring of the Health Status of Pregnant Women in the COVID-19 Pandemic

The Role of Remote Technologies in the Quality Management System and Safety of Medical Care

On April 26, 2021, Deputy Chairman of the State Duma Irina Yarovaya at a meeting of the Presidium of the Council of Legislators of the Russian Federation under the Federal Assembly of the Russian Federation called for simplifying the exchange of data between medical institutions and patients. In the Sverdlovsk region, an automated information system of mobile notifications «AIST_SMART» for pregnant patients and doctors began to operate. Using a smartphone or, say, a tablet, pregnant patients in their personal account get the opportunity to keep an electronic diary of self-control of their health. The diary has the functions of automatic interpretation of the results and the formation of signal information for the obstetrician-gynecologist. Now pregnant women do not need to fill out paper diaries of self-control, call their doctor or the reception of the antenatal clinic or wait for a doctor’s call in order to report the results - the process is fully automated. The women’s consultation received an IT tool for remote interaction with pregnant women and women in child child. The introduction of «AIST_SMART» technologies made it possible to replace paper diaries with electronic ones. Medical data of the patient are collected in a single database and allow you to track the dynamics of the patient’s health around the clock. The results of electronic diaries are automatically processed by the system and if no abnormalities are detected, the data is simply recorded in the system and does not disturb the doctor (Figure 1).

In case of detection of deviations in the patient’s state of health, the system marks the identified deviations and sends a notification to the doctor about the current state (Figure 2). Mobile notifications instantly convey accurate and detailed information about the patient’s state of health and thus contribute to the timely decision on hospitalization in case of detection of criteria for weighting the course of NCVI. All notifications in case of deviations are automatically sent to the attending physician and the doctor in the Obstetric Remote Consultation Center (hereinafter referred to as the ADCC) for the routing of the patient 24/7. Remote health monitoring functions as follows.

Figure 1: The data of the expanded diary of self-control at the NKVI, all indicators are normal.

Figure 2: The data of the expanded diary of self-control at COVID-19 with deviations in the state of health.

Registration in the System «AIST_SMART»

To register the patient in the personal account at the initial appointment of a pregnant patient, a consent-instruction [1] is issued to connect to the mobile service «AIST_SMART» with an individual QR code. At home, the patient reads the QR code using the camera of her smartphone or tablet and, according to the instructions, undergoes the registration procedure, forming a digital four-digit PIN-code. From now on, it is guaranteed 24/7 technical support. The QR code serves as the patient’s identifier and the link between her electronic medical record (EHR) in the AIST «RAM» and the personal account in the «AIST_SMART» system. To register a doctor in your personal account, you must log in to the medical information system - AIST «RAM», in which all medical personnel of the obstetric service in the region work. Open the «Personal Account» tab and register by scanning an individual QR code. So, in order to access electronic self-control diaries, the doctor and the patient connect to the AIST_SMART service, and after registering in the system, notifications about the results of remote health monitoring will be received on their mobile device. The doctor does not need to call on the phone to find out how she feels, what her temperature is, the symptoms of SARS, etc.

How the Mobile Alert System Works

Formation of Notification of the Result of Self-Control Diaries

This process is fully automated. AIST_SMART performs the role of an intellectual assistant to the obstetrician-gynecologist/ midwife. The patient fills in the diary data, and the doctor receives ready-made results with automatic interpretation. Now the patient will not forget to call the antenatal clinic, and the doctor will be able to make decisions on the tactics of conducting comprehensively, taking into account the results of the patient’s home self-control and his obstetric status.

Patients with COVID-19 are Asymptomatic/Mild and Receiving Care on an Outpatient Basis (at home)

Upon receipt of the results of testing in a pregnant woman / maternity for COVID-19, the data are entered by medical personnel in the AIST «RAM». Notifications about the results are automatically generated in the personal account «AIST_SMART» (Figures 3 & 4). These notifications are automatically sent to both the patient and the doctors. With what there is control that the patient is also informed about the result (Figure 5). If a positive result is detected on the COVID-19, the patient receives notifications 2 times a day about the need to fill out a self-control diary, which is also informed by the doctor - full feedback (Figure 6). The doctor of the ADC, based on the results of the self-control diary (Figure 7) and obstetric status according to the data in the electronic medical record (hereinafter referred to as the EHR) in the AIST «RAM», where there is information about all the results of the examination, the course of pregnancy and diagnoses, decides on further management tactics: to continue outpatient treatment or hospitalization in a covid hospital. The ADCC doctor fixes his decision in the EHR, making out a remote consultation for the attending physician of the antenatal clinic or obstetric hospital (if the patient is in the hospital at the time of detection of the COVID-19).

Figure 3: Mobile NOTIFICATION of PCR result for COVID-19: not detected.

Figure 4: Mobile NOTIFICATION of PCR result for COVID-19: DETECTED.

Figure 5: Marking about the patient’s reading of the results of the examination.

Figure 6: Mobile notification that a reminder has been sent to the patient to complete a self-monitoring diary.

If a decision is made on the need for hospitalization, the doctor of the ADC through a confidential «working» chat in AIST_SMART can contact the patient and clarify her consent to hospitalization and the possibility of transportation by personal transport. If consent is obtained (Figure 8), the ADC doctor makes an additional referral for (re-) hospitalization to a particular covid hospital for pregnant women and women in childcare, taking into account available places. The patient receives a notification about the referred referral indicating the covid hospital, the date and time of hospitalization (Figure 9). If it is necessary to organize transportation, the doctor of the ADC has resources through communication with the medical organization where the patient is on the dispensary register and agreeing on the method and time of transportation by the NSR team in compliance with epidemiological rules (Figure 10).

Figure 7: Dynamics of the state of health according to the electronic diary of self-control.

Figure 8: Communication with the patient through confidential “working” chat in AIST_SMART.

You do not Need to Receive a Paper Direction

If necessary, you can print the direction at the place of treatment of the patient, using a single information space of the regional obstetric monitoring of AIST «RAM». All the directions that a woman received during pregnancy are reflected in her personal account in the «My directions» section. The patient can open any document, even if the connection with the internet has disappeared.

Figure 9: Notification of referral to a Covid hospital and labeling of reading by a patient.

Advantages of Remote Monitoring of Health

The transition to electronic diaries of self-control allows you to identify the weighting of the course of ARVI / ARI in the case of outpatient treatment (at home) with COVID-19, and timely send the patient to hospitalization to prevent adverse events, which is from the main directions of the quality management system and safety of medical care. AIST_SMART allows you to create constant feedback [2] with the patient and thereby form a patient-centric model of care as one of the priority areas for the development of modern medicine and healthcare in general. All of the above increases the compliance of doctor-patient interaction and directly affects the quality and safety of medical care in the difficult conditions of the NCVI pandemic, which meets the modern needs of society and solves the tasks set by the Government of the Russian Federation in the field of digitalization of healthcare [3-8].

Figure 10: Finding out the possibilities of transportation and hospitalization to the covid hospital through a confidential “working” chat in AIST_SMART.

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Acetabulum Fractures: Mechanism of Injury, Demographic Features and Associated Injuries

Introduction

The acetabulum is a cup shaped depression on the outer surface of the hip bone and it articulates with the head of the femur. Acetabular fractures occur when the head of femur is pushed into the pelvis by a lateral blow to the hip or by an anterior blow to the knee with hip in flexion and abduction [1]. Acetabulum fracture has rare incidence of about 5/100,000 people per year, as compared to proximal femur fractures, which has about a hundred times higher incidence, based on geographical areas [2]. However, this rate is on the rise worldwide as a result of increase in road traffic accidents and high impact injuries1.About 80% of acetabular fractures result from high energy trauma like in road traffic accidents and around10.7% result from fall from a significant height [3]. Acetabulum fracture present more often in multiple trauma patient and are considered as serious injury [3]. Patients present to emergency department with history of pain or a hip deformity, usually with other associated injuries such as hip dislocation, femoral neck fracture or sciatic nerve palsy. They can also present with trauma to the surrounding structures like peri-pelvic soft tissues, extremity fractures, trauma to major abdominal viscera and chest injuries [4]. Pelvic insults can be diverse, ranging from minor lacerations to major debilitating complex acetabular fractures [4]. Different factors are associated with mortality and morbidity of patient including mechanism and the energy of initial insult, age, male gender, cardiac diseases, dementia, institutionalization and rehabilitation. That should be carried out after hip trauma and plays a significant role in patient recovery [5-7].

In general, operative treatment of an acetabular fracture should not be performed as an emergency except when it is a part of open fracture management or is performed for a fracture associated with an irreducible dislocation of the hip. In such cases, the top priority would be resuscitation followed by Advanced Trauma Life Support protocols [8]. The aim of our study is to assess the pattern of acetabulum fractures presenting to our unit and the injuries they are associated with in relation to the initial mechanism and severity of trauma.

Methods

This study is a case series for which data was collected from the Department of Orthopedics & Spine Surgery Hayatabad Medical Complex Peshawar. Patients who met the inclusion criteria from January 2015 to December 2020 were selected. The inclusion criteria consisted of adult patients with traumatic acetabular fracture. The exclusion criteria included pediatric patient with traumatic acetabular fracture, pathologic acetabulum fracture, periprosthetic acetabulum fracture and patients who were previously operated on the same hip joint. All patients were admitted under the care of consultant orthopedic surgeon and were operated on a dedicated list .Data was analyzed using SPSS version 22 .Cross tabulations were made and recorded where required.

Results

Figure 1: Gender.

Figure 2: Age Group.

Figure 3: Mode of Injury.

We included 69 patients in this study, out of which 61 were male and 8 were female (Figure 1). In our study 15 patients were between the age of 21-30, 20 patients were between the age of 31- 40 and the rest of 34 were from the age group of above 40. The youngest patent was of 22 years of age, while the oldest one was of the age of 72 in our study. Average age at the time of injury was 34 years (Figure 2). Out of our data pool 65 patients got admitted via Accident and Emergency and only 4 patients presented to our out-patient departmente-3]. Average Injury Severity Score at the time of injury was calculated to be 12.8. Commonest mechanism of injury was reported to be high energy trauma 62(89.8%). Road traffic accident was the commonest mode of injury i.e., 47(68.11%) (Figure 3). According to the Letournel classification, two fracture types were most common i.e., posterior wall fracture 20 (28.99%) and both column fracture 17(24.64%) (Figure 4). Thirty-nine patients had associated injuries out of which injured hip dislocation was prevalent i.e.11(28%). Open reduction and internal fixation was the preferred management for 49(71%) patients while 19(27.54%) patients were conservatively managed, depending upon the severity of fracture, joint incongruity and patient fitness for anesthesia (Figure 5). Out of those that were surgically managed 40(81%) patients fracture was approached via Kocher-langenbeck approach (Figure 6). The results presented in Table 1 (Figure 7).

Figure 4: Commonest Fracture.

Figure 5: Management.

Figure 6: Approach.

Figure 7: Admission.

Table 1: Patient demographics and fracture characteristic.

Discussion

Acetabular fractures are serious orthopedic injuries and they can prove to be a complex surgical issue. In our study the most common cause for acetabular fracture was the road traffic accident (RTA).68.11% cases were accounted due to RTA. The rest was injured due to history of fall from height. The results were comparable with Hussain et al 1, where 83% cause for the acetabular fractures was RTA in their study. The second most common in their study was fall which is similar to our study. The study results shows that the acetabular fractures was in higher frequency in male due to their style of work and the frequency was low in the females. 88% injuries were accounted in males. The results are similar to the study by Giannoudis, et al. [3] where injuries were mostly accounted for males. The study found that the mean age for the patient was 34 years, which was similar to other studies [9]. The current study found that two fracture types were most commonly presented i.e. posterior wall fracture20(28.99%)and both column fracture17(24.64%).Thirty-nine patients had associated injuries out which injured hip dislocation was prevalent i.e. 11(28%). The same were also experienced in their study by Hussain, et al. [1]. In our study we found that open reduction and internal fixation was the preferred and major management practices for the patient. According to study 71% cases was fixed using open reduction and internal fixation. The same was similar with the study of (S. Hoge and B. J 2019) [10] who found that most of the fracture required open reduction and internal fixation. Similar operation rate were reported by other authors [11-13,14]. The study found that out of those patients who were surgically managed 81% patients’ fracture was approached via Kocher-langenbeck approach, which almost similar to the rates in literature [14-17].

Conclusion

Acetabular fractures are common in young adults and the most common mechanism of injury is road traffic accidents. The common fractures are posterior wall and both column injuries and associated with hip dislocation. The preferred method of treatment is surgical fixation through Kocher langenback approach.

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Anti-Lung Cancer Effect and Mechanism of Ginsenosides

Introduction

Lung cancer is the leading cause of cancer-related mortality around the world, with an estimated 1.8 million death [1], posing a serious threat to human health. In recent years, plant-derived natural active ingredients become a research hotspot, and show the advantages of rich variety and low toxicity. Ginsenosides, derived from the plants of Araliaceous family, including ginseng (Panax ginseng C. A. Meyer) notoginseng (Panax notoginseng (Burkill) F. H. Chen ex C. H.) and American ginseng (Panax quiquefolium L.), are responsible for most of the pharmacological activities of ginseng. Moreover, some ginsenosides have shown great anti-cancer activity [2]. In recent years, some studies have reported that ginsenosides performed their anti-lung cancer effects by affecting some signaling pathway and down-regulating various oncogenic proteins, however no specific reviews conduct by now. So the purpose of this review is to provide a summary of the anti-cancer effects and the potential mechanisms about ginsenosides of some most recent findings. We will hope that this review may provide valuable insights into application of ginsenosides for treatment of lung cancer.

Ginsenosides

Ginsenosides, also known as triterpene saponins, are a class of sterol compounds, derived from ginseng which has been widely used as a Chinese herbal medicine for thousand years. Some of ginsenosides have been reported to be effective ingredients against lung cancer due to their anti-tumor activity of ginseng. Recent studies have demonstrated that most ginsenosides are metabolized to their aglycones in the gastrointestinal track as forms of 20S-protopanaxadiol (PPD) and 20S-protropanaxatriol (PPT) [3], their structures as shown in Figure 1. Up to now, nearly 200 ginsenosides have been reported [4]. According to the structural skeletons of aglycones, ginsenosides are divided into three types: dammarane’s, oleananes and ocotillol triterpenes. Among them, the dammarane-type triterpene saponins account for the vast majority and are considered to be the main pharmacologically active ingredients of ginsenosides. The dammarane-type triterpene saponins are divided into two groups: the protopanaxadiol-type ginsenosides (PPD), including ginsenosides Rg3, Rk1, Rh2 and Rd. The protopanaxatriol-type ginsenosides (PPT), including ginsenosides Rh1 and Rk3 [5,6]. Their chemical structures are shown in Figure 2.

Figure 1: The chemical structures of ginsengenin.

Figure 2: The chemical structures of ginsenosides.

Anti-Lung Cancer Effects and Mechanisms of Ginsenosides

Natural compounds have always been a very good source of anti-cancer drugs and have attracted increased attention. There is increasing evidence indicating that ginsenosides may be able to alter abnormal alterations due to cancer through certain mechanisms. To provide a summary of the anti-lung cancer effects and mechanisms of ginsenosides, we collected data from previous scientific researches published over the last 10 years. In these relevant studies, some of ginsenosides have been shown to possess significant anti-lung cancer activity by inducing cell apoptosis, inhibiting cell proliferation, inhibiting tumor invasion and migration, and inducing cell cycle arrest.

Effect of Ginsenosides on Apoptosis of Lung Cancer Cells

Apoptosis, also known as programmed cell death, plays an important role in regulating proliferation and death of normal or cancer cells. Induction of apoptosis in cancer cells is one of the mechanisms of anti-tumor activity in most antineoplastic drugs [7]. Zhang, et al. [8]. selected A549 cells for experimental research on 20(S)-PPD and found that 20(S)-PPD caused A549 cells lost mitochondrial membrane, released cytochrome C and up-regulated proteins levels of caspase-9 and caspase-3. These results revealed that 20(S)-PPD triggered mitochondrial-mediated caspasedependent apoptosis to exhibit a significant pro apoptotic effect by down-regulating PI3K/AKT signaling pathway in A549 cells. Xie, et al. [9] treated H23 and A549 cells with different concentrations of ginsenoside Rg3 (Rg3) for 24h, and then observed that the proportion of apoptotic cells in A549 and H23 cells increased significantly after 24h of Rg3 treatment. Hu, et al. [10] found that ginsenoside Rk1 (Rk1) increased the proteins expression of Bax, Cleaved caspase-3, Cleaved caspase-8, Cleaved caspase-9 and PARP in A549 and PC9 cells, and decreased the protein expression of Bcl- 2 by suppressing NF-κB signaling pathway. In addition, Joo, et al. [11] found that Rg3 increased active of caspase-8 and caspase-3, whereas decreased procaspase-9 in a dose-dependent manner in A549 cells. The results also observed that Rg3 decreased the levels of p-STAT3, p-Akt, and p-Erk. These results revealed that Rg3 induced apoptosis in A549 cells by down-regulating epidermal growth factor receptor (EGFR) signaling pathway. The above studies demonstrated that ginsenosides induced apoptosis of lung cancer cells by interacting with signaling pathways including PI3K/ Akt, NF-κB and EGFR.

Effect of Ginsenosides on Cell Proliferation of Lung Cancer Cells

Several experimental studies suggested that ginsenosides inhibited the proliferation of lung cancer cells to exert their antilung cancer activity. Tan, et al. [12] found that ginsenoside Rh1 (Rh1) significantly inhibited the proliferation of A549 cells in a time- and dose-dependent manner. Rh1 also significantly downregulated the expression levels of GSK-3β (Ser9) and β-catenin in A549 cells in a dose-dependent manner. The results indicated that Rh1 inhibited the proliferation of A549 cells by suppressing the Wnt signaling pathway. Zhang, et al. [13] found that ginsenoside Rh2 (Rh2) significantly up-regulated E-cadherin expression and downregulated the expression of vimentin, suggested that Rh2 inhibited A549 cells proliferation. Rh2 also suppressed key Wnt signaling genes, Wnt3, TCF7 and FZD8, and hedgehog signaling genes, Smo, Gli1, Gli2 and Gli3. Moreover, Rh2 decreased the protein expression levels of β‑catenin (Wnt signaling), Smo (hedgehog signaling) and GLI1 (hedgehog signaling) in A549 cells, suggested that Rh2 suppressed both signaling pathways. In conclusion, the study documented that Rh2 suppressed Wnt and hedgehog signaling pathways, inhibited lung cancer cell proliferation. Hu, et al. [10] found that Rk1 inhibited the proliferation of A549 and PC9 cells in a time- and dose-dependent manner. Furthermore, in the colony formation assay, Rk1 significantly inhibited the colony formation of A549 and PC9 cells. The results also found Rk1 inhibited the activation of NF-κB signaling pathway. In conclusion, the results indicated that Rk1 significantly decreased the proliferation of lung adenocarcinoma cells in vitro (Figure 3).

Figure 3: Effect of ginsenosides on apoptosis.

Effect of Ginsenosides on Angiogenesis of Lung Cancer Cells

Tumor angiogenesis plays a key role in the formation of new blood vessels, which is essential to tumor growth and metastasis by supplying oxygen and nutrients. Some of ginsenosides, such as Rg3 and ginsenoside Rk3 (Rk3), have been reported to inhibit angiogenesis by interacting with angiogenesis-related signaling pathways. Geng, et al. [14] established mouse Lewis lung cancer animal model to explore the mechanisms of Rg3 in vivo, and found that Rg3 significantly reduced the micro vessel density of tumorbearing mice and inhibited tumor angiogenesis by suppressing expression of VEGF, MMP-9 and HIF-1α. Additionally, Duan, et al. [15] confirmed that Rk3 inhibited angiogenesis via CD34 staining and chick embryo chorioallantoic membrane assay in xenograft tumor models (Figures 4 & 5).

Figure 4: Effect of ginsenosides on cell proliferation.

Figure 5: Effect of ginsenosides on angiogenesis.

Effect of Ginsenosides on Invasion and Migration of Lung Cancer Cells

Epithelial-mesenchymal transition (EMT) is an important factor in lung cancer metastasis. In a study [16], after treated with different concentrations of ginsenoside Rd (Rd), the authors found that Rd inhibited invasion and migration in a concentration dependent manner in A549 cells. In another study, Tian, et al. [17] found that Rg3 inhibited lung cancer cells migration and invasion due to inhibitory of EMT-labeled protein. Furthermore, in this study, Rg3 also inhibited the activation of EGFR, and then inhibited MAPK and NF-κB downstream signaling pathways. In summary, by inhibiting EGFR activation, Rg3 suppresses MAPK and NF-κB signaling pathways to effectively inhibit EMT and lung cancer cells invasion (Figure 6).

Figure 6: Effect of ginsenosides on invasion and migration.

Effect of Ginsenosides on Cell Cycle of Lung Cancer Cells

Cell cycle is a highly ordered way of cell operation. Proteins related to the cell cycle in the process of regulation control the infinite proliferation of tumor cells, which achieve the purpose of treating tumors [18]. Liang, et al. [19] found that Rg3 downregulated the proteins expression of CDK2, Cyclin A2 and Cyclin E1 in A549 cells. According to the quantitative real-time reverse transcription-PCR (qRT-PCR) and immunoblotting analysis, Rg3 was certified to play a key role on EGFR/Ras/Raf/MEK/ERK signal pathway regulation. The results showed that Rg3 arrested the cell cycle at the G0/G1 phase via the EGFR/Ras/Raf/MEK/ERK pathway. Zhu [16] treated A549 and H460 cells with different concentrations of Rd for 24h. The results showed that Rd effectively arrested the cell cycle at the G1/S phase. The western blotting results showed that the proteins expression of E2F1, Cyclin D1, Cyclin E1, CDK2, CDK4 and p-Akt were decreased and the proteins expression of p27 and p21 were increased in a concentration-dependent manner. The results revealed that cells after Rd treatment, the phosphorylation level of Akt was decreased, and the expression of G1/S conversion node proteins were decreased, which affected the cell cycle process by PI3K/Akt signaling pathways (Figure 7).

Figure 7: Effect of ginsenosides on cell cycle.

Conclusion and Perspectives

At present, some of ginsenosides play key roles in several malignancies such as lung cancer. Despite several limitations, this review provides assurances that molecular mechanisms of anti-lung cancer activity employed by ginsenosides mainly involve induction of apoptosis, inhibition of proliferation, angiogenesis, invasion and migration, and regulation of cell cycle (Figure 8). In these above studies, ginsenosides exhibited great anti-lung cancer activities both in vitro and in vivo. Furthermore, we found that multiple studies selected Rg3 as an attractive candidate to investigate its anti-lung cancer effects and mechanisms. It may be due to the fact that Rg3 is the main ingredient of Shenyi Capsule (National Drug Administration standard number: Z20030044), which is an important Chinese anticancer drug [20]. As early as 1996, some researchers conducted toxicological tests on Rg3, and the results showed that continuous administration of Rg3 had no obvious embryonic toxicity and teratogenicity, no obvious toxic reaction and no mutagenicity in rats. Relevant studies have reported that Rg3 combined with first-line chemotherapy improved efficacy of chemotherapy and reduced toxicity of chemotherapy drugs [21]. The combination of Rg3 and Osimertinib was also reported to synergically improve the anti-tumor effect [22]. The 25-OCH3-PPD derivatives were synthesized with the natural ginsenoside 25-OCH3- PPD from ginseng leaves as the lead compound. These derivatives were screened for cytotoxic activity against 167 human cancer cell lines. The results showed that compared with 25-OCH3-PPD, four compounds showed higher anti-tumor activity, with an increase of nearly 5-15 times [23]. Bi, et al. [24] investigated the tumor activity of three derivatives of 25-hydroxy protopanaxadiol (25-OH-PPD) against lung cancer. The three compounds significantly inhibited the growth of A549 and H460 cells, while they did not reduce body weight of xenograft mice by oral administration. The above studies fully indicated that ginsenosides showed great potential in the treatment of lung cancer. However, there are many studies on common ginsenosides, but few on some rare ginsenosides, so we will hope that more and more studies related to rare ginsennosides will be conducted, so as to provide new ideas for the treatment of lung cancer and bring new hope to patients.

Figure 8: Anti-lung cancer effect of ginsenosides.

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Knowledge: Understanding, Structuring and Employing

Introduction

Scientific Knowledge

Scientific Knowledge (and epistemology, which deals with the way of cooking it, in a sense, often almost literal, with a perspective of “recipes” of the “old” cook books, with x grams of this and y grams of that - what in epistemology is serious, both for the functions it must perform, or for the reasons we list below on “routines and innovation”) is like a... potato – we can fry it, bake it, grill it, ....Which does not mean, in any way, that we can use it in anyway. We have to consider the “dishes” in which it will be integrated, the taste of those who will eat it, the effects that result, the resulting cost / satisfaction ratio, the usefulness it will have, the risks it can bring, the benefits it offers, etc. This is either in the case of potatoes and in the case of scientific knowledge, of course. Today, both in science and in the kitchen, we must be able to distinguish between two completely different options, in their dynamics, in their consequences, in their causes, in the short, medium and long term.

Routines

Repeat, day by day, the same process, as regularly and faithfully as possible in order to always obtain the same results (in the cooking or looking for the replication of results). In these cases, automation or even robotization is, practically always, the safest, most economical and most efficient way to carry out the process. Cooks or scientists naturally move to equipment and operating controllers (until they are dispensed because useless, since the maintenance itself is also automated);

Innovation

Perform, day by day (or when inspiration permits), “unique pieces”, exploring opportunities, conditionings and conjunctures, seeking to innovate and optimize solutions that meet needs or aspirations. To answer to requests with so many features (see, above – …“we have to consider the dishes in which it will be integrated, the taste of those who will eat it, the effects that result, the resulting cost / satisfaction ratio, ...), at the same time, it becomes complex, even if the response obtained in the end is very simple – the complexity is on the road, in the search for solutions (like what nature has done for millions of years).
In a minimally structured and developed society (many do not respond to one of these characteristics, or both, despite the faces they present and even if they are considered “mighty” – often because they are focused on very praised but out-of-date concerns, forgetting the “new essentials”, with advertising machines and technologies, these rather updated) increasingly the routines need fewer people so that the subsistence conditions (basic but essential) are satisfied and are, therefore, increasing human resources (human capital) available for innovation, if education has fulfilled its function (as will certainly happen in a properly structured society, of course). Wealth (lato senso and not merely financial or economic), there, increases exponentially. Other societies keep “falling behind” (at least relatively) or going into crisis because they do not have the necessary “traction”, although they may seem to be working normally.[Note: the traction image is clear and explain the articulation of 1. there is not the necessary friction, on the one hand, and on the other hand, 2, the power is wasted or even counterproductive - a mutually destructive relationship].

Changes in Logic – and Mistakes that are Often Made, but not Less Serious

The changes in “logic” (in the sense of structures, strategies and their rules – still in an Aristotelian view that is contradicted in its “three principles” – a) of identity, b) non-contradiction and, c) of the two options, yes or no –each of which is completely contradicted, for example, but not only, by quantum physics) are thus essential (even before the “great” rupture that is imposed - great is a form of expression, because a rupture, in the sense that Thomas Kuhn uses the term, is a break, as below we will see in a perspective that considers the inherent dialectics, therefore always “enormous”), so that balances can be maintained and preserved the coherence that allows us to survive (as well as possible, of course).
In fact, “logic changes” are essential and as important as upgrading equipment, strategies, etc... But the “logics” used are often forgotten, because they are implicit and we rarely explain them, ignoring even their existence in most cases.
The examples are many and well known, let’s just remember:
1. The Earth moves, Galileo once said (but softly, despite the powerful friends he had in the Vatican; unlike his contemporary, Giordano Bruno, who ended up at the stake). And yet, we take it as a fixed reference of movements (and respective inherences);
2. If we had a vision that encompassed the ability to detect the x-rays, this (same) world would be looked as quite differently. If most of us were blind (and not, fortunately, a minority) the conception of this (equal) world would be another.
3. If we want to innovate by adding “old parts” (like a little of an elephant, a giraffe legs, ...) – how is visible in what is presented to us in most fiction (? lack of imagination?) the result is “cowboys riding dragons or pink zebras”. To try to innovate by following different paths, namely by verifying the results of other principles and forms of guidance – as we often see in forms of micro-organisms that come out of the picture to which we are accustomed, the results are quite different.
4. The continents move (derive), not even in death things change ceases, and no one is eternal...;
5. The opposite of an error may not be “the good solution”.
We all know this, but most (all?) forget that accepting any of those evidence requires restructuring the coherences in which we are situated and the balances we consider (meaning everything).
Changing logic is not easy. See Thomas Kuhn with his “The logic of scientific revolutions”.

Some Examples of Errors

Not adjusting the logics to existing conditions has costs which are often higher than the costs of change.
However, we prefer to ignore this need, or even its existence. See:
1. To think of education as a process similar to osmosis. An osmosis that controls and regulates the exchanges that take place in the millions of membranes integrated in the human body, facilitating or inhibiting exchanges, through the use of the most diverse criteria. But in the case of education, it is not enough to immerse individuals in a good environment so that they can acquire good habits, wisdom, or even just knowledge.
2. Medicines are good for health – if they do anything it is because they act. But then can they act too much or not enough? Don’t you agree?
3. Man is an omnivore, metabolizing foods of animal or plant origin – which means that it has adapted in its constitution in this sense. Why do some want to change adjustments from thousands of years in a few months? Isn’t it forcing nature? As the examples are evident, and practically infinite, we think it is useless to add to the list.

Rethinking Man and Its Functionality

Complexity, as we have shown above, is often in the processes of investigation and search, and it does not necessarily have to be in the solutions found. In multiple fields and areas of knowledge, as well as in their applicability, we find solutions not only simple, but also evident when we enter their framework. However, although any of our readers do not ignore that the interpretation we make of the world, of the context in which we live and of which we are an integral constituent, is based on the stimuli we receive, which are transformed into sensations and interpreted as perceptions, which allows us to elaborate a meaning, we continue to think (simultaneously, what is a paradox), that this image of the world we build corresponds to a “reality”. That others come in the same way, and some, more radical, that any deviation from their meaning is a failure or may even correspond to nonsense. So when we said, early on that “epistemology is a potato” we wanted to signify our enormous respect for epistemology that helps us interpret the world in a slightly more consistent way, as well as by the potato (symbolically the food) that allows us to harvest the energy (which comes from the sun and the “dust of the stars”, let us not forget it, but that without the potato would escape us and we would be unable to harvest) necessary to live in this world and to be an active component of it.
Some who consider epistemology to be superior to potatoes thought it was a derogatory relationship for epistemology; others, especially if they are hungry, would trade all the epistemology in the world for a few simple (our provocation) potatoes. Knowledge, what we can understand, in the structures it takes and in the uses we give it, not being more important than the oxygen we breathe, than “the potatoes we eat”, than everything around us and with which we sometimes interact directly, is something essential in this path we walk.
However, even speaking (talk - sounds that are transmitted, but that even when we use the same words can mean such different things) about the legacy that was left to us by Einstein, by Thomas Kuhn, Karl Popper, ... and thousands of others, going through some grunts of Neanderthals or roars of dinosaurs (if they roared), we forget to make the necessary adjustments so that we can maintain the coherence of our designs and the balances that make them useful tools in the framework in which we are situated... and the way we integrate there. Speaking (grunting, roaring ...) are forms of erudition (verbiage which does not mean wisdom, nor knowledge), which we must give meaning (a sense, a significant and a signifier) so that it can become a useful tool (we despise, here, the erudition that is nothing but ostentatious or splurge, which are sometimes also useful too).We tried to show contradictions and aspects to be considered in the rationale of the questions that lead to a restructuring of the way of thinking man.
Man evolved, in a process that lasted millions of years and of dialectics in which he created the senses (which he was able to) that allowed him to detect the stimuli that could be advantageous (transforming himself), interacting in such a way that, at the level of his tiny (even seen within the planet Earth) dimension, to transform. In a dialogue that some are late to recognize from the pedestal on which they placed themselves as superior beings in the building of creation [note: although some microorganisms sometimes try to alert this pretentious man, that his power is, after all, very, very, fragile].But once some paradoxes have been released for the limitations of the space of an article we warn of the problem, we do not want to stick to some slogans and provocations, and we will leave indications about a suggestion of solution that we develop, we debate and we justify, ..., in the form of a book with the title “The Next Technological Jump”. The preparation of the processes can be complex, but the answer obtained in the end may even be very simple, as we’ve stated above. It’s time to try to show it because, we think, we’re in one of these cases. In this line we propose two concepts to perform a break with the locks that are at the origin of the confusions that we expose above.

A Proposal

Let us dare to go a little further into the unknown (investigate is this, a leap into the unknown, not a step to gather some stones / data, on the frontier of knowledge – without belittling the stones / data, of which we have been leavingsome above).Darwin, with the publication in 1859 (a handful of years from now, only) gave his face (literally, for the insults and aggressions to which he was subjected to innovate) to a break that not only came out of his journey on the Beagle but is also the product of a fummer of ideas about the evolutionary process of life and “The origin of species”. We suggest joining the description of the process in which the struggle for life and the resulting natural selection created a pressure on the appearance, transformation and disappearance of species (species, controversial concept), two concepts that are tools for the consolidation of the rupture.

The Concept of Arat - A Transformation Conditioner

The struggle for life and the resulting natural selection takes place. But what leads to transformation? The mere chance of the appearance and disappearance of “species” that is promoting and generating differentiations?
Or are these transformations also directed and conducted by beacons that will yield the process and give it guidance (do not confuse with determinism)?.The reaction to stimuli / aggressions is a characteristic of living beings (put in a brief and simplistic way). We can thus conceive of a “mechanism” in which these reactions condition and adjust the process by articulating aggression / stimulus, the resulting reaction that triggers an adaptation process, which leads to transformation (temporary or definitive, and may even be transmitted to future generations - ARAT. Chance, that happens ... by chance, it is no longer dominant. An adaptation that has a sequence, and there for a continuity, provoked by the MENTAL SCHEMES produced.

The Concept of Mental Scheme

A stabilizer of the transformations carried out. Any procedure (movement or stay still), when repeated enough times, leaves marks, creates rails, which facilitate its repetition thus making it more likely. In the nervous system, for example, but not exclusively, myelinated circuits or synapses are created, with excitatory or inhibiting potentials that facilitate the appearance of a potential of action and its repetition. But the nervous system is not a privileged situation, although it is often, until now, considered the “place of thought”, as “the heart is the center of emotions” .... The process is described and commented on above. If we look around us with some care, we see that everything that moves leaves a trail, a mark, naturally some more evident than the others, as well knew the “track dogs” in the hunts and the police of the criminal investigation, for example. And when it stands still, too.
These complementary concepts allow us to understand and explain the transformations that take place in man (in life?), based on the causalities underlying them. They avoid, for example, that we limit ourselves to the description of the changes that we can detect and even the search for the dynamics that we can explore to discover the possibilities of what happens (happened and will happen) in the evolutionary process of man. They are tools for clarifying and substantiating strategies for understanding, structuring, and using knowledge.
If we apply these concepts to the situations we’ve described above, we can easily see how they allow us to undo the paradoxes in which those situations are blocked and the difficulties of appreciation that condition us.

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