Causes of death: natural, violent, illness. It's all about breathing. Tired of people
More than 55 million people die every year in the world. Among the main ones, the leading ones are endogenous factors associated with the aging of the body and its heredity. Therefore, death statistics largely depend on the economic and social situation.
Main reasons
The mortality rate reflects the level of well-being of society and the quality of healthcare. The leading causes of death account for 54% of the total. TOP 10 in 2015:
| Reasons | Number (million people) |
| Coronary heart disease | 8,7 |
| Stroke | 6,3 |
| Lower respiratory tract infections | 3,2 |
| Chronic obstructive pulmonary disease | 3,2 |
| Respiratory cancer | 1,7 |
| Sugar | 1,6 |
| Alzheimer's disease and other dementias | 1,5 |
| Diarrheal diseases | 1,4 |
| 1,4 | |
| Road traffic accidents | 1,3 |
The UAE and Qatar have the lowest mortality rates. Much higher in African countries. On the territory of the Russian Federation, the indicators are high even among the working population. Death statistics in Russia reflect the specificity of its situation. When compared with countries with similar levels of wealth, the mortality rate in Russia is higher:
- men – 3–5 times;
- women - 2 times.
About 2 million people die in the country every year. Main causes of death according to statistics (2016):
- diseases of the circulatory system– 900 thousand people, of which more than 400 thousand died from coronary disease;
- oncology– about 300 thousand;
- accidents and– more than 150 thousand;
- excessive alcohol consumption– about 55 thousand
Sudden death
Sudden death syndrome is becoming increasingly common around the world. WHO statistics range from 20 to 150 cases per 100 thousand population. Young and completely healthy people die for no apparent reason. There is still no unified theory of this phenomenon. In Russia, the statistics of sudden death annually totals more than 60 thousand cases.
Babies often die from sudden respiratory failure. An autopsy cannot determine its cause. Statistics of deaths in sleep indicate a sufficient prevalence of this phenomenon. In people older than 1 year, it can occur due to atrial fibrillation or cardiac arrest due to mitral valve prolapse.
A separate problem in sports medicine is unexpected death during competitions or training.
Death on the roads
The statistics of deaths in car accidents increases every year. About 1.3 million people aged 15 to 29 years die from injuries each year. Half of them are among the most vulnerable road users:
- motorcyclists – 23%.
- cyclists – 4%;
- pedestrians – 22%.
Drug addiction problems
In Russia, drug addiction increases every year. Data for 2016:
- 8 million people regularly take drugs. Of these, 60% are citizens aged 16–39 years;
- use drugs periodically – about 18 million;
- Every year the number of drug addicts increases by 90 thousand people.
Statistics of deaths from drugs total 70 thousand people a year. However, other reasons are often officially recorded:
- accidents caused by inadequate condition;
- suicide;
- cases of violent death;
- pathologies of internal organs;
- -infections.
Statistics of death from an overdose of drugs or psychotropic substances record 8 thousand cases annually. The most vulnerable category are teenagers who, at the age of 10, begin to try psychoactive drugs.
Consequences for the child's body
In recent years, there has been an increased mortality among adolescents from substance abuse. Main reasons:
- rapid development of addiction;
- availability of substances;
- destructive effect on the child's body.
Possible consequences:
- pulmonary hemorrhage;
- liver damage;
- tumors in the kidneys and lungs;
- dysfunction of the brain.
According to the UN, the death toll statistics have increased several times. Every year the number of people using alcohol increases by 8%. different types drugs:
- marijuana – 160 million people;
- cocaine – 14 million;
- heroin – 10.5 million
According to Wikipedia, marijuana has been legalized in some countries around the world. Marijuana death statistics recorded a surprising case in 2017. An 11-month-old baby has died in the United States. The cause of death was damage to the heart muscle caused by high levels of the main substance in the blood. active substance marijuana.
Alcoholism and smoking
Statistics of deaths from alcohol are regularly kept medical institutions. About 15–20% of all deaths are associated with a heart attack after drinking alcohol. Losses from are comparable to losses in. The number of alcoholics in the Russian Federation is more than 3% of the population. Although only 1.5% of dependent people are registered. Number of deaths caused by regular alcohol consumption:
- women – 14%;
- men – 30%.
The death statistics also raise serious concerns. According to WHO:
- annually more than 5 million people. dies from smoking-related diseases. According to forecasts, by 2020 their number will increase to 10 million;
- In Russia, the mortality rate annually ranges from 400 to 500 thousand people.
The statistics on deaths from cigarettes are amazing. The share of citizens who died from smoking is almost half of the total. There are already cases of death from electronic cigarettes which have become popular among teenagers.
Infant mortality
More than 1.2 million children aged 10–19 die every year. Statistics of child deaths show that the largest share is due to road accidents - 115 thousand. The second reason is respiratory diseases and various infections. Death statistics for children under 5 years of age are usually associated with:
- with pneumonia;
- prematurity;
- birth asphyxia;
The main risk group is children. The most high performance in African countries where access to quality health care is limited.
Deadly games
In 2016, death groups became widespread among teenagers. children increased by 60%. The children's consciousness was manipulated remotely, encouraging them to commit suicide using game techniques. Online death statistics in 2016 recorded 720 cases.
The police blocked almost 5 thousand links leading to prohibited sites. Such groups usually include children from disadvantaged families who need psychological support.
Statistics of deaths from " blue whale" shows that the game is gaining popularity in Europe. Its victims are teenagers from 12 to 18 years old. The first attempts were recorded in the Baltic states.
Difficult birth
Statistics on deaths during childbirth also show high rates:
- 2015 – more than 300 thousand cases. Almost 99% are in developing countries;
- 2016 – more than 200 thousand.
In 75% of cases, death is caused by:
- severe bleeding after ;
- postpartum infections;
- high pressure.
Causing death by negligence is becoming increasingly common. The statistics of those registered are almost 15–20% of their total number. Every year, about 1.5 thousand deaths occur due to negligence, ignorance or side effects medicines.
Heart disease
The statistics of deaths from heart disease and other pathologies increases every year. While mortality from dangerous infections has decreased significantly. Over 10 years (2006–2016):
- mortality from infectious diseases and birth complications decreased by 24%;
- death statistics decreased by 46%.
Today, cardiovascular diseases take first place. Every year they claim the lives of 17 million people. Indicators differ depending on the type of disease. The death rate from heart attacks is approximately 20–25%. Death from stroke occurs in 34% of citizens. About 40–42% die from ischemic disease.
The statistics of deaths from heart disease in Russia is about 55% of the total.
Oncological diseases
According to scientists, it will soon take the leading position in mortality. Cancer death statistics - 10 million people are diagnosed every year. More than 8 million patients die.
The most common area is malignant tumors of the female genital organs. Statistics of deaths from the uterus show that the disease is often detected at a late stage of development. Most cases are fatal.
IN recent years The statistics of death from basal cell carcinoma has increased significantly. There is a chance of survival if treatment is started in a timely manner.
Dangerous infections
With the onset of spring in Russia, the danger of ticks increases. The statistics of deaths from encephalitis is 1–3% of the total number of cases in middle lane. In the Far Eastern regions the figure reaches 20%. The number of registered cases annually is about 3 thousand.
The threat of other dangerous infections is also high. Statistics of rabies deaths in Asian and African countries record thousands of cases every year, despite the availability of effective vaccines.
In recent years, death from influenza has become a frequent occurrence. Statistics note that the cause is not the disease itself, but the complications it gives to the heart and lungs. Between the ages of 5 and 19 years, the mortality rate from influenza is 0.9 cases per 100 thousand people.
The death rate from chickenpox is 1 case per 60 thousand patients. In adults, the chances of dying if the disease increases by 30–40 times.
Chasing a dream
Another reason for leaving life is the pursuit of beauty. Death statistics from plastic surgery still low. Death under anesthesia occurs in 1 person per 250 thousand operations. However, every life has value.
Since the middle of the last century, the number of cases associated with eating disorders has doubled. The death rate from anorexia among girls 15–24 years old is 12 times higher than from other girls. Anorexia and bulimia often cause suicide.
The danger of surrogates
Rising prices for vodka lead to an increase in the consumption of cheap alcohol. Statistics of deaths from surrogates:
- 2013 – 13.5 thousand
- 2014 – 14.0 thousand;
- 2015 – 14.2 thousand
Death statistics worldwide are higher than for women. On average, men live 5.5 years less. Main causes of male mortality:
Conquering the peaks
Climbing to the top of a mountain can be deadly. The main goal Everest is a destination for many climbers. The statistics of deaths during the history of its conquest reached 250 people.
Climbing the legendary peak of the Caucasus seems deceptively easy. Death statistics on Elbrus record 15–20 deaths every year.
Expeditions to the top of Mount Kazbek are popular. Death statistics in Kazbek are not officially published. However, several climber fatalities are reported each year.
Extreme sports
There is a high probability of death in extreme sports. Parachute death statistics:
- USA– from 1991 to 2000, more than 30 fatal jumps were recorded annually.
- Russia– more than 90 people died between 1998 and 2005.
The death statistics for paragliders count 12–13 deaths annually. BASE jumping is becoming increasingly popular. Death statistics highlight the main causes of tragedies:
- incorrect jumping technique;
- poor quality equipment;
- errors in trajectory calculations.
An equally popular trend is selfies among roofers. Death statistics are increasing every year. Selfie comes out on top in the ranking of causes of death.
Death rates from falling from height increase with age. Number of cases per 100 thousand people:
- 15–19 years old – 0.6;
- 55–64 years – 4.7;
- over 65 years old – 38.5.
Statistics of deaths from accidents annually total 100 thousand deaths.
Situation in different countries
Death statistics in Belarus largely depend on the type of disease (2016):
- circulatory arrest – 65.9 thousand people;
- oncology – 17.9 thousand;
- other diseases – about 12 thousand.
Death statistics in Ukraine place the country in 4th place in the world. Mortality rates are 14.4 cases per 100 thousand population.
Death statistics in the Russian Federation are gradually decreasing:
- 2001 – 2254.85 thousand;
- 2006 – 2166.70 thousand;
- 2010 – 2028.51 thousand;
- 2015 – 1908.54 thousand;
- 2017 – 1824.340 thousand.
Statistics of deaths in the Russian army:
- 2012 – 630 people;
- 2013 – 596 people;
- 2014 – 790 people;
- 2015 – 626 people.
Death statistics in the United States show that from 2001 to 2011, more than 11 thousand people died annually from firearms alone. While the terrorist attacks claimed the lives of 517 citizens. Later the figures dropped to 7 thousand.
Additional reasons
There is still ongoing debate about deaths from vaccinations. Statistics record only isolated facts around the world that require more thorough research.
Of the total number of deaths on the planet, a certain part is caused by injuries, negligence, natural phenomena. Let's look at a series of examples:
- statistics of deaths in the bathroom - 1 case per 807 thousand people;
- Every year about 30 thousand people die from electric shock;
- in the United States, from 1998 to 2015, 663 children died after being left in cars;
- statistics of deaths from lightning strikes - 1 case per 71 thousand people;
- the risk of dying in a car accident is 1 in 20 thousand people;
- mortality from tornadoes in America is 1 per 60 thousand people;
- statistics on deaths from garage poisoning carbon monoxide in Russia – more than 300 people per year.
Statistics violent deaths brought Russia to 3rd place. The indicators in 2015 were 10.2 people per 100 thousand population. Every year, between 12 and 14 thousand women die from domestic violence.
Annual death statistics for dentists indicate that more than 30 patients have died as a result of the cardiotoxic effects of lidocaine.
Statistics of deaths of journalists for all time recorded the death of 850 media representatives. Distribution by country:
- Iraq – 146 people.
- Philippines - 71.
- Algeria – 60.
- Russia – 53.
- Colombia – 43 people.
Dangerous animals
The statistics of animal deaths in the world exceeds the number of deaths in wars:
- Every year, about 100 thousand people die from a deadly infection carried by shellfish;
- 10 thousand lives are claimed by “sleeping sickness” from the bite of the Tsetse fly;
- thousands of people die from malaria mosquito bites;
- shark death statistics are only 10–15 per year.
Injury sports
One of the most dangerous sports is boxing. However, severe head injuries in the ring account for a small percentage of all injuries. Death statistics are 1.3 per 100 thousand people. Most of the deaths occur in Asian countries, where fighters do not enjoy the necessary protection.
Military conflicts and terrorism
Terrorism has become one of the main problems of the 21st century. Statistics of deaths from terrorism in 2016 – 13.7 thousand killed and 16.6 thousand wounded. Most of the victims are in Iraq and Syria. As the scale of military conflicts expands, the statistics of deaths from hunger increases. Up to 10 million people die every year. Total number hungry – 850 million people. Of these:
- Asian region – 520 million
- Africa – 243 million
- Latin America and the Caribbean – 42 million
5 (100%) 1 vote
The death of Lenin - what Vladimir Ilyich really died from. Cause of death
Throughout 1923, newspapers reported on Lenin's state of health, creating a new myth about the leader who steadfastly fought the disease: reads newspapers, is interested in politics, and hunts. It is known that Lenin suffered a series of strokes: the first turned 52-year-old Ilyich into an invalid, the third killed him.
In the last months of his life, Lenin hardly spoke, could not read, and his “hunting” looked like walking in a wheelchair. Almost immediately after his death, Lenin's body was opened to determine the cause of death. After a thorough examination of the brain, it was determined that there was a hemorrhage. They announced to the workers: “the dear leader died because he did not spare his strength and did not know rest in his work.”
During the days of mourning, the press strongly emphasized the sacrifice of Lenin, the “great sufferer.” This was another component of the myth: Lenin, indeed, worked a lot, but he was also quite attentive to himself and his health, did not smoke, and, as they say, did not abuse.
Almost immediately after Lenin’s death, a version appeared that the leader was poisoned on Stalin’s orders, especially since no tests were done that would have detected traces of poison in his body. It was assumed that another cause of death could be syphilis - the drugs at that time were primitive and sometimes dangerous, and venereal diseases in some cases can indeed provoke a stroke, but the leader’s symptoms, as well as the post-mortem autopsy, refuted these speculations. Detailed Report The first public bulletin, which was released immediately after the opening, contained only summary causes of death. But already on January 25, “official autopsy results” appeared with numerous details
In addition to a detailed description of the brain, the results of a skin examination were given, down to the indication of each scar and injury, the heart was described and its exact size, the condition of the stomach, kidneys and other organs were indicated. British journalist, head of the Moscow branch of the New York Times, Walter Duranty, was surprised that such detail did not make a depressing impression on the Russians; on the contrary, “the deceased leader was the object of such intense interest that the public wanted to know everything about him.”
However, there is information that the report caused “shocked bewilderment” among the non-party Moscow intelligentsia and they saw in it a purely materialistic approach to human nature characteristic of the Bolsheviks. Such detailed anatomy and emphasis shifted to the inevitability of death could have another reason - the doctors, who “failed” to save the patient, were simply trying to protect themselves.
Fires - like any manifestation of unbridled elements - always bring destruction and death with them. But those that flare up in public and residential buildings with large numbers of people have particularly severe consequences.
The death of people in fires is largely due to the lack of fire-fighting knowledge and skills among Russian citizens. People often do not know not only the basic rules fire safety, but even the telephone numbers of the nearest fire station. Not to mention actions at the initial moment of fire development before the arrival of fire departments, and methods of self-rescue in an extreme situation. This is especially true for residential buildings, where the largest number of fires and deaths occur.
What causes people to die in a fire? What do you need to know about a fire to stay alive?
1. Fire blinds you, you cannot see in the fire.
If you have never experienced the real factors of a fire, you will be in a state of complete shock.
To your horror, you will learn that in a real fire you cannot see anything. The flame turns everything black. It brings no light. Nothing is visible, only heat and ashes, terrible darkness. You absolutely cannot navigate, you cannot find the exit door you know. Complete loss of orientation due to panic. The fire is black as night, which will lead to inevitable death.
In order to avoid this, use in buildings:
- emergency lighting;
- light indicators “evacuation (emergency) exit”;
- fire safety signs used on escape routes,
including glow in the dark;
- electric lights.
2. Smoke and gas kill, not flame.
A modern apartment is literally filled with objects and materials that, when burned in huge quantities, release more than 70 types of toxic substances (carbon monoxide, carbon dioxide, diphosgene, phosgene, hydrogen cyanide, etc.). A few breaths in such an atmosphere - and a person can no longer be saved.
Most people die not from fire or collapsed structures, but from smoke and lack of oxygen. Moreover, more than half of those affected by smoke die at the scene of the fire. 42% of survivors suffer severe poisoning, every third of them dies in the hospital without regaining consciousness. About 70% of all those killed in a fire die from exposure to smoke, and the speed of its spread is high: 2-3 minutes in a corridor, 1-1.5 minutes in a stairwell of a ten-story building.
The most dangerous thing is if a fire occurs in a residential building in the middle of the night. Do you think you'll wake up and take action? However, the scary fact is that you won't wake up to the smell of smoke. It will only make you fall asleep even more deeply. You fall into a deep sleep, as if you were under anesthesia. You can't move. Smoke deadens your brain.
Ninety percent of the people firefighters find in smoke look like they were asleep.
If you are in a room filled with smoke, you not only cannot see, but you also cannot breathe. It is similar to if you are drowning and your head is under water. You're scared. You forget everything you thought you knew about the fire. You get lost, panic, behave unpredictably, because... are not psychologically prepared for such an extreme situation.
To combat smoke the following are used:
- smoke-free staircases (due to air pressure or floor-by-floor entrances through the airy outer zone along balconies or loggias);
- removing smoke from rooms and corridors through automatically opening smoke exhaust valves by turning on powerful exhaust fans;
- installation in corridors staircases self-closing doors with sealed doorways that prevent the spread of smoke;
- automatic system arrangement fire alarm(smoke and thermal sensors, manual fire alarm buttons, fire alarm bells, fire alarm stations);
- fire warning and evacuation control systems;
- means personal protection respiratory organs in case of fire;
- autonomous fire detectors powered by batteries for apartments in residential buildings;
- group and individual rescue kits, rope ladders.
3. Heat from fire can cause instant death. Heat is terrible. He kills. The heat alone is fatal within seconds. It's very difficult to describe in words. At 65°C, your body stops functioning, your lungs literally evaporate, and you lose consciousness.
In a room, a fire lasting just over one minute creates a temperature in the smoke layer of 370°C. If the head is unprotected, then instant death occurs. At the top, the temperature and smoke concentration are even higher. When everything that can burn in the room is burning, the heat will reach its climax. The smoke itself is ready to explode, it seems that the entire structure will fly into the air. There is no chance of staying alive in this heat.
4. A fire leaves no time to think. You need to have time to escape from the fire.
Most people think they have time when there is a fire. But this is not true; in a fire there is no time.
A fire starts in a trash can. He goes unnoticed. A minute later the sofa catches fire and smoke begins to fill the room. The temperature is rising. After two minutes the person may lose consciousness.
Three minutes later the whole room is on fire. No one can survive anymore. In four minutes the corridors will become impassable. It only takes 5 minutes for a fire inside a house to cause the death of all its inhabitants. So, from 3 to 5 minutes and that’s the end of it all! It turns out that during a fire, time can become your worst enemy.
How long does it take to survive a kitchen fire? Most people think they have 10 minutes. But in fact, after 30 seconds the fire will become uncontrollable. You need to have time to jump out without stopping or thinking about things, close the door behind you (but not lock it) and notify the fire department.
In order to have time to evacuate, there is an unshakable rule: in children's institutions junior groups, preschool age they don’t dress him, but wrap him in a blanket and take him out of the danger zone. School students are led out under the guidance of teachers or educators who are personally responsible for the group of children with whom they studied. In hotels, it is prohibited to pack suitcases, etc. for quick evacuation.
5. In case of fire, panic may occur.
People panic and behave unpredictably. Sometimes when panic occurs, he dies more people than from fire hazards. It is quite obvious that a person who was psychologically prepared and trained in such an extreme situation would behave differently.
6. The death of people in fires is largely due to the lack of basic fire-fighting knowledge and self-defense skills among the population.
Statistics show that most people do not think about fires, do not care about the safety of their homes, and neglect their own safety and the health of their loved ones. This is evidenced by the absence of a fire extinguisher, which would allow elderly people and schoolchildren to easily extinguish a fire that started on a TV, electrical appliance, grease, or oil in the kitchen. Almost a few citizens have provided their apartments with commercially available autonomous fire detectors powered by regular battery. They are installed in the hallway, kitchen, room, and when smoke appears, they emit a sharp sound, loud enough to attract attention and wake up those sleeping. Unfortunately, in society there is a clear underestimation of the reality of the fire threat and its dangerous factors.
Evidence of this is our attitude towards balconies and loggias of residential buildings. Most of them are glazed, the hatches of the emergency staircases of the balconies are tightly closed, openings are laid for the passage through the loggias, and furniture is installed in the partitions. All this will not allow you to independently evacuate to a non-burning floor, or to stand behind the partition of a balcony or loggia in the event of a fire in your apartment if you were unable to leave it on time or because the main evacuation staircase was blocked by smoke. In this case, there will be little chance of surviving until the fire department arrives, especially for those who do not think about it today, do not have personal respiratory protection equipment, or rope ladder, a rescue kit for evacuation through balconies, loggias, windows, electric lights, and also ignores conducting fire drills at home, as citizens of developed foreign countries do.
FGKU "9th detachment of the Federal Border Guard Service in the Altai Territory"
If your close person is in the terminal stage of the disease, it is incredibly difficult to accept that he will soon be gone. Knowing what to expect can make things easier.
This article examines 11 signs that death is approaching and discusses ways to cope with the death of a loved one.
How to understand that he is dying
When a person is terminally ill, they may be in hospital or receiving palliative care. It is important for loved ones to know the signs of approaching death.
Human behavior before death
Eats less
As a person approaches death, he becomes less active. This means that it the body requires less energy than before. He practically stops eating or drinking as his appetite gradually decreases.
Those caring for a dying person should allow the person to eat only when he is hungry. Offer the patient ice (or fruit ice) to maintain hydration levels. A person may stop eating completely a few days before death. When this happens, you can try using a moisturizing balm on your lips to prevent drying out.
Sleeps more
During the 2 or 3 months before death, a person begins to spend more and more time sleeping. Lack of wakefulness is due to the fact that the metabolism becomes weaker. No metabolic energy
Anyone caring for a dying loved one should do everything they can to ensure their sleep is comfortable. When the patient has energy, you can try to encourage him to move or get out of bed and walk around to avoid bedsores.
Tired of people
The energy of the dying person fades away. He can't spend as much time with other people as he used to. Perhaps he will also be burdened by your company.
Vital signs change
As a person approaches death, their vital signs may change as follows:
- Blood pressure decreases
- Breathing changes
- Heartbeat becomes irregular
- Pulse weak
- Urine may be brown or rusty in color
Toilet habits are changing
As a dying person eats and drinks less, their bowel movements may become smaller. This applies to both solid waste and urine. When a person completely refuses food and water, he stops using the toilet.
These changes may be upsetting to loved ones, but they are to be expected. Perhaps the hospital will install a special catheter that will alleviate the situation.
Muscles lose their strength
In the days leading up to death, a person's muscles become weak. Muscle weakness means that an individual will not be able to perform even simple tasks that were previously available to him. For example, drinking from a cup, turning over in bed, and so on. If this happens to a dying person, loved ones should help them lift things or turn over in bed.
Body temperature decreases
When a person dies, his blood circulation deteriorates, so the blood concentrates in the internal organs. This means that not enough blood will flow to the arms and legs.
Reduced blood circulation means that a dying person's skin will become cold to the touch. It may also appear pale or mottled with blue and purple spots. A person who is dying may not feel cold. But if this does happen, offer him a blanket or blanket.
Consciousness is confused
When a person dies, their brain is still very active. However sometimes those who are near death begin to become confused or express their thoughts incorrectly. This happens when a person loses control over what is happening around him.
Breathing changes
Dying people often have breathing problems. It may become more frequent or, conversely, deep and slow. The dying person may not have enough air, and the breathing itself often becomes confused.
If the person caring for your loved one notices this, there is no need to worry. This is a normal part of the dying process, and usually does not cause pain to the dying person. In addition, if you have any concerns about this, you can always consult a doctor.
Painful sensations appear
It can be difficult to come to terms with the inevitable fact that a person's pain levels may increase as they approach death. Seeing a painful expression on a person's face or hearing the groans a patient makes is, of course, not easy. A person caring for a dying loved one should talk to their doctor about the use of pain medications. The doctor can try to make this process as comfortable as possible.
Hallucinations appear
It is quite common for dying people to experience visions or Although this may seem quite frightening, there is no need to worry. It is better not to try to change the patient’s opinion about visions, to convince him, as this will most likely only cause additional difficulties.
How to survive the last hours with a loved one?
With the onset of death, human organs stop working, and all processes in the body stop. All you can do in this situation is just be there. Show concern and try to make the last hours of the dying person as comfortable as possible.
Continue to talk to the dying person until he passes, because often the dying person hears everything that is happening around him until the last minute.
Other signs of death
If a dying person is connected to a heart rate monitor, loved ones will be able to see when their heart stops beating, signaling death.
Other signs of death include:
- No pulse
- Lack of breathing
- No muscle tension
- Fixed eyes
- Emptying your bowel or bladder
- Closing the eyelids
After confirming the death of a person, loved ones will be able to spend some time with someone who was dear to them. Once they say goodbye, the family usually contacts the funeral home. The funeral home will then take the person's body and prepare it for burial. When a person dies in a hospice or hospital, staff contact the funeral home on behalf of the family.
How to cope with the loss of a loved one?
Even when death was expected, it is extremely difficult to come to terms with it. It is important that people give themselves time and space to grieve. Don't give up on the support of friends and family either.
EXPERIMENTAL ARTICLES
UDC 577.15:576.367
Acadesine causes non-apoptotic death of tumor cells
V. A. Glazunova1*, K. V. Lobanov2, R. S. Shakulov2, A. S. Mironov2, A. A. Shtil1 "N.N. Blokhin Russian Oncology Research Center of the Russian Academy of Medical Sciences, 115478, Moscow, Kashirskoe sh. ., 24
■State Research Institute of Genetics and Selection of Industrial Microorganisms, 117545, Moscow, Dorozhny pr-d, 1 *E-mail: [email protected] Received by the editor December 27, 2012
ABSTRACT The effect of acadesine (5-aminoimidazole-4-carboxamide-1-0-O-ribofuranoside) on tumor and non-tumor cells of various species and tissue origin was studied. It has been established that acadesine causes non-apoptotic death of tumor cells; The sensitivity of non-tumor cells to the action of this compound is significantly lower. Acadesine causes the death of tumor cells with a drug resistance phenotype due to the expression of the P-glycoprotein transporter and inactivation of the proapoptotic protein p53. A necessary condition cell death is the activity of adenosine transporters, whereas the function of AMP-activated protein kinase is not required. The predominant death of tumor cells under the influence of acadesine and the peculiarities of the mechanism of its cytotoxicity make this compound promising as an antitumor agent. keywords acadesine, cell death, tumor cells.
introduction
Acadesine (5-aminoimidazole-4-carboxamide-1-P-O-ribofuranoside, AICAR) is being tested in clinical trials as a drug for the treatment of chronic lymphocytic leukemia. Important property acadesine - its primary toxicity to tumor cells with less pronounced damage to non-tumor cells. Previously, it was shown that acadesine is capable of stimulating AMP-activated protein kinase (AMPK), an important regulator of cell energy balance that controls oxidation fatty acids, glucose metabolism, synthesis of proteins, fatty acids and cholesterol. The mechanism of action of acadesine is due to its phosphorylation by adenosine kinase to form ZMP (5-amino-4-imidazolecarboxamide ribotide), an intermediate in the de novo synthesis of purine bases. ZMP, by mimicking the metabolic effects of AMP, is able to activate AMPK. The antitumor effect of acadesine is associated with the induction of apoptosis. At the same time, there is evidence of non-apoptotic cell death and an AMPK-independent mechanism of action of acadesine on tumor cells.
IN this work The effect of acadesine on mammalian cells has been studied. It has been shown that acadesine causes the death of tumor cells of various tissues.
of new origin, including cells resistant to a number of antitumor drugs. The mechanisms of cell death are different from apoptosis; their important feature it turns out that adenosine transport is necessary. Non-tumor cells are less sensitive to the action of acadesine. The selectivity of the cytotoxic effect and the peculiarities of the mechanisms of tumor cell death may be important factors that determine the prospects for using acadesine in tumor therapy.
experimental PART
The following human cell lines were used in the experiments: HCT116 (colon adenocarcinoma), HCT116p53KO (isogenic subline in which p53 does not function), K562 (promyelocytic leukemia), K562/4 (subline obtained after selection for survival in the presence of doxorubicin; expressed multidrug resistance protein (MDR) P-glycoprotein; Pgp), MCF-7 (breast adenocarcinoma), MCF-7Dox (sublineage after selection for survival in the presence of doxorubicin; Pgp-mediated MDR phenotype), fibroblast culture PFC-2, blood lymphocytes from healthy donors, as well as mouse cells: P388 (lymphocytic leukemia) and Sp2/0 (myeloma). Reagents were purchased from PanEco, Russia (except where otherwise specified). Cells were cultured in mo-
Dulbecco's modified Eagle's medium with the addition of 5% fetal calf serum (Bio-Whittaker, Austria), 2 mM L-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin at 37°C, 5% CO2 in a humidified atmosphere. In the experiments, cultures in the logarithmic growth phase were used. Lymphocytes were isolated from the peripheral blood of donors by centrifugation in a Ficoll-urografin density gradient (d = 1.077 g/cm3).
Acadesine was obtained at GosNIIGenetika using a microbiological method using an original recombinant strain. In addition, the cytotoxicity of acadesine from Sigma was assessed. The same company purchased dipyridamole, an adenosine receptor inhibitor, 5-iodotubercidine, an adenosine kinase inhibitor that prevents the conversion of acadesine to ZMP, and zVAD-fmk (carbobenzoxyvalylalanyl-aspartyl-fluoromethylketone), a pan-caspase inhibitor. All compounds were dissolved in dimethyl sulfoxide or water (10-20 mM) and stored at -20°C. On the day of the experiment, dilutions of the drug were prepared in a culture medium. To assess the cytotoxicity of acadesine, we used the MTT test, staining of cells with propidium iodide and annexin V conjugated with fluorescein isothiocyanate (FITC), determination
cell cycle in flow cytometry and electrophoretic analysis of genomic DNA integrity. In some experiments, the reference drug was the alkyl cationic glycerolipid gas-P-(4-[(2-ethoxy-3-octadecyloxy)prop-1-yloxycarbonyl]butyl)-N-methylimidazolium iodide, an apoptosis inducer.
RESULTS AND DISCUSSION
Preferential sensitivity of tumor cells to acadesine
In preliminary experiments, we established that the microbiologically obtained acadesine preparation and commercial acadesine are identical in physicochemical properties, purity, storage stability and cytotoxicity (data not shown). For further studies, we used acadesine obtained by the author's method. In table Figure 1 shows the cytotoxicity of acadesine for transformed and non-transformed cells (cultured or freshly isolated) of various species and tissue origin.
From the data presented in table. 1, it follows that the most sensitive to the action of acadesine are
Table 1. Cytotoxicity of acadesine for mammalian cells
Acadesine chains, mM
G G.125 G.25 G.5 1.G 2.G
K562 1GG* 1GG 70 46 9 G
P388 1GG 36 30 20 9 G
Sp2/0 1GG 34 29 14 G G
K562/4 1GG 1GG 72 42 8 G
MCF-7 1GG 1GG 82 50 15 2
MCF-7Dox 1GG 1GG 86 48 17 1
HCT116 1GG 1GG 50 36 23 G
HCT116p53KO 1GG 1GG 54 34 25 G
HPF-2, proliferating 1GG 1GG 1GG 96 96 86
HPF-2, non-proliferating** 1GG 1GG 1GG 1GG 95 92
Donor lymphocytes 1GG 1GG 1GG 98 94 90
Note. The results of the MTT test after 72-hour incubation of cells are presented. "The survival of cells incubated without acadesine was taken as 100%. Each value is the average of five independent experiments, standard deviation< 0%. ""Пролиферацию фибробластов останавливали культивированием клеток до монослоя (контактное торможение деления клеток).
P388 cells (mouse leukemia) and Sp2/0 (mouse myeloma): at an acadesine concentration of 0.125 mM, ~1/3 of the cell population survives. Other transformed cell lines studied also die when exposed to submillimolar concentrations of acadesine. It is important that the cytotoxicity of acadesine is almost the same in the case of the leukemic line K562 and its subline with Pgp-mediated MDR (K562/4). The same is true for the MCF-7 breast adenocarcinoma line and the MDR subline (Table 1). A comparison of the cytotoxicity of acadesine against the HCT116 line and the HCT116p53KO subline (resistant to a number of DNA-damaging antitumor compounds) showed that inactivation of the proapoptotic protein p53 does not lead to an increase in cell survival in the presence of acadesine.
Equally important is the significantly higher survival of non-tumor cells in the presence of acadesine: the death of donor lymphocytes and non-transformed fibroblasts was practically absent even when exposed to acadesine in millimolar concentrations for 72 hours of continuous exposure (Table 1). Thus, acadesine causes preferential death of transformed cells (suspension and epithelial), including sublines resistant to other antitumor compounds. Non-tumor cells are damaged by acadesine to a much lesser extent. These features make it promising to use acadesine as an antitumor agent. However, for this it is important to establish the mechanisms of acadesine toxicity for tumor cells.
Acadesine induces non-apoptotic cell death
The effect of acadesine on the distribution of ploidy of the colon adenocarcinoma cell line HCT116 was studied by flow cytometry. 24 hours after the addition of acadesine (0.25 mM), the accumulation of cells in the S phase was determined, and after 48 hours (Fig. 1), mass cell death was determined (the area to the left of the G1 peak; hypodiploid nuclei).
The accumulation of fragmented DNA may be a sign of apoptotic cell death if DNA cleavage occurs in the internucleosomal spaces, as evidenced by the formation of a set of fragments 140-170 bp long. with electrophoresis. To test this possibility, DNA integrity was determined in HCT116 cells treated with acadesine. It turned out that acadesine, unlike the reference drug - an alkyl cationic glycerolipid, does not lead to the appearance of a “ladder” of DNA fragments characteristic of apoptosis (Fig. 2).
Fluorescence
Rice. Fig. 1. Distribution of HCT116 cell line across phases of the cycle under the influence of 0.4 mM acadesine. A - intact cells; B - accumulation in the S phase after 24 hours; B - accumulation in the sub^1 area after 48 hours
An argument in favor of a non-apoptotic mechanism of death of HCT116 cells under the influence of acadesine is the results of cell staining with annexin U-FITC and propidium iodide (Fig. 3). Annexin U binds phosphatidylserine at the plasma membrane (translocation of phosphatidylserine from the inner lipid layer of the membrane
Rice. 2. DNA integrity in HCT116 cells.
1 - Intact cells;
2 - acadesine, 0.4 mM, 24 h;
3 - alkyl cationic glycerolipid, 6 µM, 24 h (method control)
Rice. 3. Staining of HCT116 cells with annexin V-FITC and propidium iodide. Pseudocolors: red - intact cells; purple - acadesine (0.4 mM, 24 h); blue - alkyl cationic glycerolipid (method control; see caption to Fig. 2)
externally is considered a sign of apoptosis). Propidium iodide is able to penetrate cells undergoing necrosis (violation of the integrity of the plasma membrane). HCT116 cells treated with acadesine (0.4 mM, 24 h) were not stained with annexin V-FITC; in contrast, the cells accumulated propidium iodide (Fig. 3), suggesting a necrotic component of the death mechanism. Similar results were obtained when recording necrotic cells using trypan blue (data not shown). It is likely that disruption of the integrity of the plasma membrane is a late event in acadesine-induced cell death. The comparison drug, an alkyl cationic glycerolipid, caused an increase in annexin V-positive cells characteristic of apoptosis (Fig. 3).
Since apoptotic cell death suggests an active role for caspases, the effect of the pan-caspase inhibitor zVAD-fmk on the cytotoxicity of acadesine was studied. HCT116 cells were incubated with 200 μM zVAD-fmk for 30 min, after which acadesine was added to the cultures and incubation continued for 24 hours. The presence of zVAD-fmk did not reduce cell death, which confirms the conclusion about the non-apoptotic mechanism of acadesine cytotoxicity.
Interaction with adenosine receptors is necessary for the death of tumor cells under the influence of acadesine
The transfer of acadesine from the extracellular environment into cells can be carried out by adenosine transporters. We studied the effect of dipyridamole, an inhibitor of these transporters, on the cytotoxicity of acadesine in the P388 cell line. It turned out that in the presence of dipyridamole, cells are insensitive even to relatively high (up to 0.8 mM) concentrations of acadesine (Table 2).
To clarify the role of the acadesine-MP-AMPK metabolic pathway in the cytotoxicity of acadesine
Table 2. Cytotoxicity of acadesine in combinations with dipyridamole or 5-iodotubercidin
Exposure to Acadesine, mM
0 0.08 0.1 0.2 0.4 0.8
Acadezine 100* 79 З8 ЗЗ 20 18
Acadesine + dipyridamole, 5 µM 100 100 99 99 100 101
Acadesine + 5-iodotubercidin, 0.05 µM 100 76 39 31 22 16
*Survival (%) of P388 leukemia cells according to the MTT test after incubation for 72 hours.
(its phosphorylation by adenosine kinase to form ZMP and activate AMPK), cells were incubated with acadesine and the adenosine kinase inhibitor 5-iodotubercidin. The inhibitor did not affect the cytotoxicity of acadesine (Table 2). It follows that cell death in response to acadesine is not due to the formation of ZMP and activation of AMPK.
Thus, the study of the mechanisms of cytotoxicity of acadesine revealed a number of features indicating the non-trivial nature of the pharmacological effects of this compound. Acadesine causes the death of cultured tumor cells with a significantly less pronounced effect on non-tumor cells. Acadesine is toxic to cells with molecular determinants of drug resistance - Pgp expression and non-functioning p53. It is important to emphasize the non-apoptotic nature of tumor cell death under the influence of acadesine. These results allow us to regard acadesine as a unique reagent for studying the mechanisms of tumor cell death and a promising drug candidate.
The question remains open about the intracellular target of acadesine, the interaction with which causes the death of tumor cells. We have shown that the condition for cell death is the functioning of adenosine transporters, while activation of AMPK is not required. It is reasonable to assume that tumors expressing these adenosine transporters and receptors will be most sensitive to acadesine. The role of purine base transport in cell death is not well understood; analysis of differential expression of adenosine transporters and receptors in tumors is required different types. It is likely that increased expression of these molecules will be a new molecular marker of tumor sensitivity to acadesine and a criterion for selecting patients for appropriate therapy.
The work was supported by the Ministry of Education and Science Russian Federation(State contract No. 16.N08.12.1010), and was also partially supported by the Dynasty Non-profit Programs Foundation.
REFERENCES
1. Acadesine. AICA Riboside, ARA 100, Arasine, GP 1 110.
Drugs R D. 2008. V. 9. No. 3. P. 169-175.
2. Jose C., Bellance N., Chatelain E.H., Benard G., Nouette-Gau-lain K., Rossignol R. // Mitochondrion. 2012. V. 12. P. 100-109.
3. Jose C., Hebert-Chatelain E., Bellance N., Larendra A., Su M., Nouette-Gaulain K., Rossignol R. // Biochim. Biophys. Acta. 2011. V. 1807. P. 707-718.
4. van den Neste E., van den Berghe G., Bontemps F. // Expert Opin. Invest. Drugs. 2010. V. 19. No. 4. P. 571-578.
5. Javaux F., Vincent M.F., Wagner D.R., van den Berghe G. // Biochem. J. 1995. V. 305. P. 913-919.
6. Merrill G.F., Kurth E.J., Hardie D.G., Winder W.W. // Endocrinol. Metab. 1997. V. 273. No. 6. P. 1107-1112.
7. Su R.Y., Chao Y., Chen T.Y., Huang D.Y., Lin W.W. // Mol. Cancer Therapy. 2007. V. 6. No. 5. P. 1562-1571.
8. Theodoropoulou S., Kolovou P.E., Morizane Y., Kayama M., Nicolaou F., Miller J.W., Gragoudas E., Ksander B.R., Vavvas D.G. // FASEB. 2010. V. 24. P. 2620-2630.
9. The Handbook of Metabolomics. Methods in Pharmacology and Toxicology / Eds Whei-Mei Fan T. et al. 2012. V. 17. P. 439-480.
10. Walker J., Jijon H.B., Diaz H., Salehi P., Churchill T., Madsen K.L. // Biochem. J. 2005. V. 385. P. 485-491.
11. Campas C., Santidrian A.F., Domingo A., Gil J. // Leukemia. 2005. V. 19. P. 292-294.
12. Lopez J.M., Santidrian A.F., Campas C., Gil J. // Biochem. J. 2003. V. 70. P. 1027-1032.
13. Guigas B., Sakamoto K., Taleux N., Reyna S.M., Musi N., Viollet B., Hue L. // IUBMB Life. 2009. V. 61. No. 1. P. 18-26.
14. Lobanov K.V., Errais Lopez L., Korolkova N.V., Tyaglov B.V., Glazunov A.V., Shakulov R.S., Mironov A.S. // Acta Naturae. 2011. T. 3. No. 2 (9). pp. 83-93.
15. Lysenkova L.N., Turchin K.F., Korolev A.M., Bykov E.E., Da-nilenko V.N., Bekker O.B., Trenin A.S., Elizarov S.M., Dezhen-kova L.G., Shtil A.A., Preobrazhenskaya M.N. // J. Antibiotics. (Tokyo). 2012. V. 65. No. 8. P. 405-411.
16. Simonova V.S., Samusenko A.V., Filippova N.A., Tevyashova A.N., Lyniv L.S., Kulik G.I., Chekhun V.F., Shtil A.A. . // Bulletin. exp. biol. honey. 2005. T. 4. pp. 451-455.
17. Markova A.A., Plyavnik N.V., Pletneva M.V., Serebrennikova G.A., Shtil A.A. // Wedge. oncohematol. 2012. T. 5. No. 2.
18. Shchekotikhin A.E., Glazunova V.A., Dezhenkova L.G., Shevtsova E.K., Traven’ V.F., Balzarini J., Huang H.-S., Shtil A.A., Preobrazhenskaya M.N. //Eur. J. Med. Chem. 2011. V. 46. P. 213-218.
19. Gadalla A.E., Pearson T., Currie A.J., Dale N., Hawley S.A., Sheehan M., Hirst W., Michel A.D., Randall A., Hardie D.G., Frenguelli B.G. // J. Neurochem. 2004. V. 88. P. 1272-1282.
