CELL CYCLE AND CELL MEMBRANE: 1. DESEASE: • Cell membrane alteration. • Origin, causes and consequences. • Treatment. • Social impact. • References.
2. INTERVIEW
CELL ... THE ORIGIN OF EVERYTHING
Published by: SEBASTIÁN PARRA CADENA 7-39 10/02/18
CYSTIC FIBROSIS
CELL MEMBRANE ALTERATION
Figure 1. Chromosome 7, CFTR gene. (http://learn.genetics.utah.edu/content/disorders/singlegene/).
Cystic fibrosis is a genetic disorder that affects the respiratory and digestive systems. People with cystic fibrosis inherit a defective gene on chromosome 7 called CFTR (cystic fibrosis transmembrane conductance regulator). The protein produced by this gene normally helps salt (sodium chloride) move in and out of cells. If the protein doesn't work correctly, that movement is blocked and an abnormally thick sticky mucus is produced on the outside of the cell. The cells most seriously affected by this are the lung cells. The thick mucus also blocks ducts in the pancreas, so digestive enzymes can't get into the intestines. Without these enzymes, the intestines cannot properly digest food. Finally, cystic fibrosis affects the sweat glands. Too much salt is lost through sweat, which can disrupt the delicate balance of minerals in the body.
Figure 2. Cell membrane alteration. (http://learn.genetics.utah.edu/content/disorders/singlegene/).
HOW DO PEOPLE GET CYSTIC FIBROSIS? Cystic fibrosis is a recessive disorder, which means that both parents must pass on the defective gene for any of their children to get the disease.
Figure 3. Recessive disorder. (http://learn.genetics.utah.edu/content/disorders/singlegene/).
SYMPTOMS
Figure 4. Organs Affected By Cystic Fibrosis. (http://learn.genetics.utah.edu/content/disorders/singlegene/).
Cystic fibrosis signs and symptoms vary, depending on the severity of the disease. Some people may not experience symptoms until adolescence or adulthood. People with cystic fibrosis have a higher than normal level of salt in their sweat.
Respiratory signs and symptoms The thick and sticky mucus associated with cystic fibrosis clogs the tubes that carry air in and out of your lungs. This can cause signs and symptoms such as: A persistent cough that produces thick mucus (sputum) Wheezing Breathlessness Exercise intolerance Repeated lung infections Inflamed nasal passages or a stuffy nose Digestive signs and symptoms
The thick mucus can also block tubes that carry digestive enzymes from your pancreas to your small intestine. Without these digestive enzymes, your intestines aren't able to completely absorb the nutrients in the food you eat. The result is often: Foul-smelling, greasy stools Poor weight gain and growth Intestinal blockage, particularly in newborns (meconium ileus) Severe constipation
RISK FACTORS Family history. Because cystic fibrosis is an inherited disorder, it runs in families. Race. Although cystic fibrosis occurs in all races, it is most common in white people of Northern European ancestry.
COMPLICATIONS Respiratory system complications Damaged airways (bronchiectasis). Chronic infections. Growths in the nose (nasal polyps). Coughing up blood (hemoptysis). Pneumothorax. Respiratory failure. Acute exacerbations.
Digestive system complications Nutritional deficiencies. Diabetes. Blocked bile duct. Intestinal obstruction. Distal intestinal obstruction syndrome (DIOS). Reproductive system complications infertile Other complications Thinning of the bones (osteoporosis). Electrolyte imbalances and dehydration.
TREATMENT Although there is no cure for cystic fibrosis, new treatments are helping people with the disease live longer than before. Most treatments work by clearing mucus from the lungs and preventing lung infections. Common treatments include: •
Chest physical therapy, in which the patient is repeatedly clapped on the back to free up mucus in the chest.
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Inhaled antibiotics to kill the bacteria that cause lung infections.
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Bronchodilators (also used by people with asthma) that help keep the airways open.
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Pancreatic enzyme replacement therapy to allow proper food digestión.
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Gene therapy (a treatment currently in clinical trials), in which the healthy CFTR gene is inserted into the lung cells of a patient to correct the defective gene.
PREVENTION If you or your partner has close relatives with cystic fibrosis, you both may want to undergo genetic testing before having children.
SOCIAL IMPACT: This disease not only affects the physical condition, but also the mental and social health of the patient and his family, generating different emotions that include the feeling of guilt, impotence and fear. The economic cost to the family is very high, which can generate tensions for family members. They are people who do not have a good quality of life and possibly require the support of others in their daily activities. Children can be ignored and rejected by other people, these patients may have high school absenteeism. The costs for care of these people are very high for health services.
REFLECTION: It is a deadly disease and has no cure and people die very young; in previous times, children who had this disease could not live long, but thanks to technological, scientists and medical advances, now people live longer and with a better quality of life. If couples want to have children, it is very important to have blood tests to determine if they are carriers of the disease and thus reduce the probability of having children with cystic fibrosis.
BIBLIOGRAPHY Genetic Science Learning Center. (2014, February 15). Single Gene Disorders. Retrieved February 09, 2018. From http://learn.genetics.utah.edu/content/disorders/singlegene/
Mayo Clinic Staff. 1998-2018 Mayo Foundation for Medical Education and Research (MFMER). Cystic fibrosis. From https://www.mayoclinic.org/diseases-conditions/cysticfibrosis/symptoms-causes/syc-20353700
MYASTHENIA GRAVIS
CELL MEMBRANE ALTERATION Myasthenia gravis is caused by an error in the transmission of nerve impulses to muscles. It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junction—the place where nerve cells connect with the muscles they control.
Neurotransmitters are chemicals that neurons, or brain cells, use to communicate information. Normally when electrical signals or impulses travel down a motor nerve, the nerve endings release a neurotransmitter called acetylcholine. Acetylcholine travels from the nerve ending and binds to acetylcholine receptors on the muscle. The binding of acetylcholine to its receptor activates the muscle and causes a muscle contraction.
In myasthenia gravis, antibodies (immune proteins) block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle from contracting. In most individuals with myasthenia gravis, this is caused by antibodies to the acetylcholine receptor itself. However, antibodies to other proteins, such as MuSK (Muscle-Specific Kinase) protein, can also lead to impaired transmission at the neuromuscular junction. These antibodies are produced by the body's own immune system. Myasthenia gravis is an autoimmune disease because the immune system—which normally protects the body from foreign organisms—mistakenly attacks itself.
Figure 5: Receptors: Chemicals messengers, called neurotransmitters, fit precisely into receptor sites on your muscle cells. In myasthenia gravis, certain receptor sites are blocked or destroyed, causing muscle weakness. (Mayo fundation for medical education and research. (https://www.mayoclinic.org/diseases-conditions/myastheniagravis/symptoms-causes/syc-20352036)
SYMPTOMS Although myasthenia gravis may affect any skeletal muscle, muscles that control eye and eyelid movement, facial expression, and swallowing are most frequently affected. The onset of the disorder may be sudden and symptoms often are not immediately recognized as myasthenia gravis. Muscle weakness caused by myasthenia gravis worsens as the affected muscle is used repeatedly. Because symptoms usually improve with rest, your muscle weakness may come and go. However, myasthenia gravis symptoms tend to progress over time, usually reaching their worst within a few years after the onset of the disease. Although myasthenia gravis can affect any of the muscles that you control voluntarily, certain muscle groups are more commonly affected than others.
Eye muscles In more than half the people who develop myasthenia gravis, their first signs and symptoms involve eye problems, such as: Drooping of one or both eyelids (ptosis). Double vision (diplopia), which may be horizontal or vertical, and improves or resolves when one eye is closed. Face and throat muscles In about 15 percent of people with myasthenia gravis, the first symptoms involve face and throat muscles, which can cause: Altered speaking. Your speech may sound very soft or nasal, depending upon which muscles have been affected. Difficulty swallowing. You may choke very easily, which makes it difficult to eat, drink or take pills. In some cases, liquids you're trying to swallow may come out your nose. Problems chewing. The muscles used for chewing may wear out halfway through a meal, particularly if you've been eating something hard to chew, such as steak. Limited facial expressions. Your family members may comment that you've "lost your smile" if the muscles that control your facial expressions have been affected. Neck and limb muscles Myasthenia gravis can cause weakness in your neck, arms and legs, but this usually happens along with muscle weakness in other parts of your body, such as your eyes, face or throat. The disorder usually affects arms more often than legs. However, if it affects your legs, you may waddle when you walk. If your neck is weak, it may be hard to hold up your head.
When to see a doctor: Talk to your doctor if you have difficulty: Breathing Seeing Swallowing Chewing Walking Using your arms or hands Holding up your head
COMPLICATIONS Complications of myasthenia gravis are treatable, but some can be life-threatening. Myasthenic crisis Myasthenic crisis is a life-threatening condition that occurs when the muscles that control breathing become too weak to do their jobs. Emergency treatment is needed to provide mechanical assistance with breathing. Medications and blood-filtering therapies help people to again breathe on their own. Thymus tumors About 15 percent of people with myasthenia gravis have a tumor in their thymus, a gland under the breastbone that is involved with the immune system. Most of these tumors, called thymomas, aren't cancerous (malignant). Other disorders People with myasthenia gravis are more likely to have the following conditions:
Underactive or overactive thyroid. The thyroid gland, which is in the neck, secretes hormones that regulate your metabolism. If your thyroid is underactive, you may have difficulties dealing with cold, weight gain and other issues. An overactive thyroid can cause difficulties dealing with heat, weight loss and other issues. Autoimmune conditions. People with myasthenia gravis may be more likely to have autoimmune conditions, such as rheumatoid arthritis or lupus.
DIAGNOSIS To diagnose your condition, your doctor will review your symptoms and your medical history and conduct a physical examination. Your doctor may conduct several tests, including: Neurological examination Your doctor may check your neurological health by testing your: Reflexes Muscle strength Muscle tone Senses of touch and sight Coordination Balance The key sign that points to the possibility of myasthenia gravis is muscle weakness that improves with rest. Tests to help confirm the diagnosis may include: Edrophonium test Ice pack test Blood analysis
Repetitive nerve stimulation Electromyography (EMG) Imaging scans Pulmonary function tests
TREATMENT Today, myasthenia gravis can generally be controlled. There are several therapies available to help reduce and improve muscle weakness. Medications Cholinesterase inhibitors. Medications such as pyridostigmine (Mestinon) enhance communication between nerves and muscles. These medications don't cure the underlying condition, but they may improve muscle contraction and muscle strength. Possible side effects may include gastrointestinal upset, nausea, and excessive salivation and sweating. Corticosteroids. Corticosteroids such as prednisone inhibit the immune system, limiting antibody production. Prolonged use of corticosteroids, however, can lead to serious side effects, such as bone thinning, weight gain, diabetes and increased risk of some infections. Immunosuppressants. Your doctor may also prescribe other medications that alter your immune system, such as azathioprine (Imuran), mycophenolate mofetil (CellCept), cyclosporine (Sandimmune, Neoral), methotrexate (Trexall) or tacrolimus (Prograf). Side effects of immunosuppressants can be serious and may include nausea, vomiting, gastrointestinal upset, increased risk of infection, liver damage and kidney damage.
Intravenous therapy Plasmapheresis (plaz-muh-fuh-REE-sis). This procedure uses a filtering process similar to dialysis. Your blood is routed through a machine that removes the antibodies that block transmission of signals from your nerve endings to your muscles' receptor sites. However, the beneficial effects usually last only a few weeks. Intravenous immunoglobulin (IVIg). This therapy provides your body with normal antibodies, which alters your immune system response. Monoclonal antibody. Rituximab (Rituxan) is an intravenous medication that is used in some cases of myasthenia gravis. This drug depletes certain white blood cells, altering the immune system and improving myasthenia gravis. Surgery About 15 percent of the people with myasthenia gravis have a tumor in their thymus gland, a gland under the breastbone that is involved with the immune system. If you have a tumor, called a thymoma, doctors will conduct surgery to remove your thymus gland (thymectomy). If you don't have a tumor in the thymus gland, surgery to remove the thymus gland may improve your myasthenia gravis symptoms. It may eliminate your symptoms, and you may be able to stop taking medications for your condition. However, you may not notice the benefits of a thymectomy for several years, if at all.
SOCIAL IMPACT It is a debilitating disease that can generate dependence. Patients with the disease may need help to perform some activities in their daily lives. The family must understand how the person feels as he adapts to the illness.
For people with myasthenia gravis and their family members, coping with the disease may be difficult. For the diagnosis different tests are used and different treatments are employed that can generate high costs for the health system. With treatment, most individuals with myasthenia can significantly improve their muscle weakness and lead normal or nearly normal lives. Sometimes the severe weakness of myasthenia gravis may cause respiratory failure, which requires immediate emergency medical care. Some cases of myasthenia gravis may go into remission—either temporarily or permanently—and muscle weakness may disappear completely so that medications can be discontinued.
BIBLIOGRAPHY By Mayo Clinic Staff. https://www.mayoclinic.org/diseases-conditions/myastheniagravis/diagnosis-treatment/drc-20352040
"Myasthenia Gravis Fact Sheet", NINDS, Publication date May 2017. NIH Publication No. 17-768. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/FactSheets/Myasthenia-Gravis-Fact-Sheet
BOVINE PRENATAL LETHAL CHONDRODYSPLASIA (BPLC)
CHARACTERISTICS Dysplasia is an abnormality of the histogenesis that manifests through one or more morphological defects resulting from the disorganization of the cells and other components of a tissue, which consequently has abnormal architecture. If a dysplasia affects the cartilaginous tissue it is known as chondrodysplasia and has negative reflexes on the development of the whole skeleton, commonly causing disproportion between the skeletal segments [2,3]. Dysplasia in general can be linked to environmental factors or be caused by genetic factors, with the latter being the most significant from a clinical-genetic viewpoint .
The term bovine prenatal lethal chondrodysplasia (BPLC) comprises a heterogeneous group of genetic chondrodysplasias characterized by extremely severe micromelic dwarfism that causes intrauterine death, normally between the 6th and 8th month of gestation. Because of the affected individuals have a typical phenotype that bears some resemblance to a bulldog, cattle farmers know them as “bulldog calves�, and this expression has also been used frequently in veterinary medicine.
PATHOANATOMICAL FEATURES Although there may be some morphological variations from one case to another, in all cases the most prominent trait of BPLC is extremely disproportionate dwarfism, which manifests through marked micromelia, short vertebral spine, bulky abdomen and macrocephaly, in addition
to shortened facial bones and protruding tongue, creating the appearance of a bulldog. The main aspects of the clinical phenotype are outlined below.
Figure 6: Clinical phenotype of a female Nellore calf with prenatal lethal chondrodysplasia (bulldog calf).
Gross anatomy Head: There is strongly marked brachycephaly. The cranium is dorsally reduced in the craniocaudal direction and increased in the laterolateral direction, with the frontal and parietal regions prominent; the base is narrower and can have several bones fused. There is lingual protrusion, marked prognathism and, usually, a cleft palate.
Thorax: The thoracic cage is reduced, with malformed ribs, causing compression of the lungs, which can develop with a multilobulated appearance. There is platyspondylia, above all in the thoracic segment, resulting in a much shortened vertebral column. In some cases, it can be less than half the length of that of a normal fetus of the same age .
Abdomen: The combination of approximately normal-sized abdominal viscera and a very short lumbar spine leaves the abdomen bulky and protruding. There may be omphalocele or even evisceration.
Limbs: The thoracic and pelvic limbs present marked micromelia, with hypoplastic joints and with no mineralized tissue. The shortening is greater in the proximal bones, also affecting the scapulae and the pelvis.
Tegument: Depending on the gestational age of the affected fetus, the body may have no hair, or have hair only in some areas or be totally covered in hair. Figure 1 shows several of the abnormalities described above in an affected Nellore calf with a gestational age of approximately eight months.
GENETIC FEATURES Although cases of BPLC in different breeds have had essentially the same clinical phenotype, the data currently available do not make it possible to affirm that they have the same cause. It is likely that they are etiologically different, i.e., they may be caused by different genes (locus heterogeneity).
Inheritance pattern of BPLC in the Dexter breed: BPLC in the Dexter is caused by incompletely dominant mutations in the aggrecan gene (ACAN gene). If we represent the ACAN gene as “a” and the mutant allele as “A”, the long-legged Dexter has an “aa” genotype (homozygote), the short-legged Dexter has an “Aa” genotype (heterozygote), and the bulldog Dexter has an “AA” genotype (homozygote). Thus, the homozygosity of the “A” allele causes a defect in the endochondral ossification that is so severe that it is incompatible with life. Therefore, based on the principle of Mendelian genetics, if two heterozygote Dexters are crossed,
there is a 25% chance of the offspring having long legs, a 50% chance that it will have short legs, and a 25% chance that it will be affected by BPLC (bulldog calf), as shown in Figure.
Figure 7: Risk of prenatal lethal chondrodysplasia in a mating of short-legged Dexters.
Molecular aspects of BPLC in the Dexter breed In 2007, Cavanagh et al. discovered that mutations in the ACAN gene are the cause of BPLC in the Dexter breed. The ACAN gene is located in band 5 of region 1 of the long arm of bovine chromosome 21 (BTA21q15). It encodes the aggrecan, a protein present in the extracellular matrix of the cartilaginous tissue and is necessary for its normal formation. It was formerly known as chondroitin sulfate proteoglycan core protein 1 (CSPGCP or CSPG1). Cavanagh et al. found two mutations of the ACAN gene responsible for BPLC in all the cases that they tested. The most frequent was an insertion of 4 bp in the Exon 11 (2266_2267insGGCA), creating a reading frame and a premature termination codon. The most rare was a transition in the exon 1 (–198C>T), creating a new initiation codon situated 199 bp before the normal initiation codon. Both the mutations cosegregate with the chondrodysplasia of the Dexter. Currently, diagnostic tests are available for both these mutations in several countries.
IMPORTANCE OF THE DISEASE STUDY AND ITS IMPACT the Dexter breed the bulldog calf was a severe and non-viable form of achondroplasia in calves. The study allows to identify genetic alterations and where they are located. The use of study techniques helps to identify animals that are carriers of a hereditary defect and prevent the transmission of this defect in the population, decreasing the probablity that recessive genes are expressed and with them the appearance of genetic diseases.
BIBLIOGRAPHY https://www.omicsonline.org/open-access/genetic-and-pathoanatomical-features-of-thebovine-prenatal-lethal-chondrodysplasia-2161-1041-3-1000132.php?aid=30383.
OVINE HEREDITARY CHONDRODYSPLASIA (SPIDER LAMB SYNDROME)
CHARACTERISTICS Ovine hereditary chondrodysplasia (Spider Lamb Syndrome) is a semi-lethal inherited disorder associated with skeletal deformities in young sheep. Structural abnormalities observed in afflicted lambs include facial defects, humped or twisted spines, abnormally long legs, bent and/or splayed legs, flattened ribs, and an underdeveloped musculature. While the deformities may not be apparent at birth, they are often visible by 4-6 weeks of age.
Figure 8: Ovine hereditary chondrodysplasia (Spider Lamb Syndrome).
GENETIC FEATURES Normal fibroblast growth factor receptor 3 (FGFR3) acts as a negative bone growth regulator by restricting chondrocyte proliferation and endochondral bone elongation. In sheep, a heritable mutation that inactivates FGFR3 produces skeletal overgrowth when homozygous.
Research into the cause of Spider Lamb Syndrome identified a mutation within the gene for fibroblast growth factor receptor 3 (FGFR3). It has been shown that a non-synonymous
transversion of T> A in the highly conserved tyrosine kinase II domain of a positional candidate gene, receptor 3 of fibroblast growth factor (FGFR3), is responsible for SLS.
Because the syndrome is a recessive genetic disorder, a lamb is only afflicted if both parents pass on the mutation. Thus, it is critical to identify carriers of the mutation. Carriers (animals with only one copy of the mutation) are structurally normal with no evidence of disease.
IMPORTANCE OF THE DISEASE STUDY AND ITS IMPACT Because this is a genetic condition, it is very difficult to eliminate from one's flock. Lambs that are born homozygous for Spider Lamb Syndrome typically do not survive to breeding age. Even if these lambs survive to breeding age, they should not be used for breeding since their progeny have at least a 50% probability of being born as carriers for the gene. Ewes that are carriers (heterozygous) for Spider Syndrome are difficult to detect and for most practical situations, the only test of determining if a ewe is a carrier for the gene is from breeding that ewe and obtaining spider lambs from that ewe. Identifying these genetic conditions would help reduce economic losses for sheep producers.
BIBLIOGRAPHY http://www.optimalag.com/cleonscorner/Article016.aspx https://www.ncbi.nlm.nih.gov/pubmed/17032787
INTERVIEW Why is the cell membrane important? The cell membrane (plasma membrane) is a thin semi-permeable membrane that surrounds the cell. Its function is to protect the integrity of the interior of the cell and the organelles by allowing certain substances into the cell, while keeping other substances out. The cell membrane also serves to help support the cell and help maintain its shape. Another function of the membrane is to regulate cell growth. What happens if the cell membrane does not work properly? It produce alterations in the metabolism of the cell that can cause cell damage and produce diseases. Can these cell damage be identified? Science has advanced considerably in the early identification of changes that occur in the cell and this would help in understanding the origin of diseases. What is this for? Knowing the cause of the changes in the cell would help scientists to prevent and treat a significant number of diseases improving the quality of life of patients. Then, you consider that the cell is the most important thing of living beings? I think so, because the cell is the basic unit of all living beings and there all the vital functions occur: reproduction, growth, nutrition, breathing.