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Abacavir hypersensitivity syndrome

Hypersensitivity to abacavir is strongly associated with a single-nucleotide polymorphism at the human leukocyte antigen B*5701 locus. There is an association between the prevalence of HLA-B*5701 and ancestry. The prevalence of the allele is estimated to be 3.4 to 5.8% on average in populations of European ancestry, 17.6% in Indian Americans, 3.0% in Hispanic Americans, and 1.2% in Chinese Americans. There is significant variability in the prevalence of HLA-B*5701 among African populations. In African Americans, the prevalence is estimated to be 1.0% on average, 0% in the Yoruba from Nigeria, 3.3% in the Luhya from Kenya, and 13.6% in the Masai from Kenya, although the average values are derived from highly variable frequencies within sample groups.

Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea, and diarrhea; some patients may also develop a skin rash. Symptoms of AHS typically manifest within six weeks of treatment using abacavir, although they may be confused with symptoms of HIV, immune restoration disease, hypersensitivity syndromes associated with other drugs, or infection. The FDA released an alert concerning abacavir and abacavir-containing medications on July 24, 2008. They recommend pre-therapy screening for the HLA-B*5701 allele and the use of alternative therapy in subjects with this allele. Genetic testing for the HLA-B*5701 allele is recommended before starting or restarting treatment with abacavir or abacavir-containing medications. Skin-patch testing may also be used to determine whether an individual will experience a hypersensitivity reaction to abacavir, although some patients susceptible to developing AHS may not react to the patch test. The development of suspected hypersensitivity reactions to abacavir requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients who do not possess the HLA-B*5701 allele. On March 1, 2011 the FDA informed the public about an ongoing safety review of abacavir and a possible increased risk of heart attack associated with the drug.

Immunopathogenesis

The mechanism underlying abacavir hypersensitivity syndrome is related to the change in the HLA-B*5701 protein product. Abacavir binds with high specificity to the HLA-B*5701 protein, changing the shape and chemistry of the antigen-binding cleft. This results in a change in immunological tolerance and the subsequent activation of abacavir-specific cytotoxic T cells, which produce a systemic reaction known as abacavir hypersensitivity syndrome.

The human skeleton is the internal framework of the body. It is composed of 270 bones at birth – this total decreases to 206 bones by adulthood after some bones have fused together. The bone mass in the skeleton reaches maximum density around age 30. The human skeleton can be divided into the axial skeleton and the appendicular skeleton. The axial skeleton is formed by the vertebral column, the rib cage and the skull. The appendicular skeleton, which is attached to the axial skeleton, is formed by the pectoral girdles, the pelvic girdle and the bones of the upper and lower limbs.

The human skeleton serves six major functions; support, movement, protection, production of blood cells, storage of ions and endocrine regulation.

The human skeleton is not as sexually dimorphic as that of many other primate species, but subtle differences between sexes in the morphology of the skull, dentition, long bones, and pelves exist. In general, female skeletal elements tend to be smaller and less robust than corresponding male elements within a given population. The pelvis in female skeletons is also different from that of males in order to facilitate child birth.

Divisions

Axial skeleton

Main article: Axial skeleton

The axial skeleton (80 bones) is formed by the vertebral column (32–34 bones; the number of the vertebrae differs from human to human as the lower 2 parts, sacral and coccygeal bone may vary in length), the rib cage (12 pairs of ribs and the sternum), and the skull (22 bones and 7 associated bones).

The upright posture of humans is maintained by the axial skeleton, which transmits the weight from the head, the trunk, and the upper extremities down to the lower extremities at the hip joints. The bones of the spine are supported by many ligaments. The erectors spinae muscles are also supporting and are useful for balance.

A human is able to survive with just the axial portion of their skeleton.

Appendicular skeleton

Main article: Appendicular skeleton

The appendicular skeleton (126 bones) is formed by the pectoral girdles, the upper limbs, the pelvic girdle or pelvis, and the lower limbs. Their functions are to make locomotion possible and to protect the major organs of digestion, excretion and reproduction.

Functions

A human skeleton on exhibit at The Museum of Osteology, Oklahoma City, Oklahoma

The skeleton serves six major functions; support, movement, protection, production of blood cells, storage of minerals and endocrine regulation.

Support

The skeleton provides the framework which supports the body and maintains its shape. The pelvis, associated ligaments and muscles provide a floor for the pelvic structures. Without the rib cages, costal cartilages, and intercostal muscles, the lungs would collapse.

Movement

The joints between bones allow movement, some allowing a wider range of movement than others, e.g. the ball and socket joint allows a greater range of movement than the pivot joint at the neck. Movement is powered by skeletal muscles, which are attached to the skeleton at various sites on bones. Muscles, bones, and joints provide the principal mechanics for movement, all coordinated by the nervous system.

Protection

The skeleton protects many vital organs:

• The skull protects the brain, the eyes, and the middle and inner ears.
• The vertebrae protect the spinal cord.
• The rib cage, spine, and sternum protect the lungs, heart and major blood vessels.
• The clavicle and scapula protect the shoulder.
• The ilium and spine protect the digestive and urogenital systems and the hip.
• The patella and the ulna protect the knee and the elbow respectively.
• The carpals and tarsals protect the wrist and ankle respectively.

Blood cell production

The skeleton is the site of haematopoiesis, the development of blood cells that takes place in the bone marrow. In children, haematopoiesis occurs primarily in the marrow of the long bones such as the femur and tibia. In adults, it occurs mainly in the pelvis, cranium, vertebrae, and sternum.

Storage

The bone matrix can store calcium and is involved in calcium metabolism, and bone marrow can store iron in ferritin and is involved in iron metabolism. However, bones are not entirely made of calcium, but a mixture of chondroitin sulfate and hydroxyapatite, the latter making up 70% of a bone. Hydroxyapatite is in turn composed of 39.8% of calcium, 41.4% of oxygen, 18.5% of phosphorus, and 0.2% of hydrogen by mass. Chondroitin sulfate is a sugar made up primarily of oxygen and carbon.

Endocrine regulation

Bone cells release a hormone called osteocalcin, which contributes to the regulation of blood sugar (glucose) and fat deposition. Osteocalcin increases both the insulin secretion and sensitivity, in addition to boosting the number of insulin-producing cells and reducing stores of fat.

Gender differences

Anatomical differences between human males and females are highly pronounced in some soft tissue areas, but tend to be limited in the skeleton. The human skeleton is not as sexually dimorphic as that of many other primate species, but subtle differences between sexes in the morphology of the skull, dentition, long bones, and pelves (sing. pelvis) are exhibited across human populations. In general, female skeletal elements tend to be smaller and less robust than corresponding male elements within a given population.

Skull

A variety of gross morphological traits of the human skull demonstrate sexual dimorphism, such as the nuchal crest, mastoid processes, supraorbital margin, supraorbital ridge, and mental eminence.

Dentition

Human inter-sex dental dimorphism centers on the canines, but it is not nearly as pronounced as in the other great apes.

Long bones

Long bones are generally larger in males than in females within a given population. Muscle attachment sites on long bones are often more robust in males than in females, reflecting a difference in overall muscle mass and development between sexes. Sexual dimorphism in the long bones is commonly characterized by morphometric or gross morphological analyses.

Pelvis

Human pelves exhibit greater sexual dimorphism than other bones, specifically in the size and shape of the pelvic cavity, ilia, greater sciatic notches, and the sub-pubic angle. The Phenice method is commonly used to determine the sex of an unidentified human skeleton by anthropologists with 96% to 100% accuracy in some populations.

Disorders

See also: Bone disease

There are many classified skeletal disorders. One of the most common is osteoporosis. Also common is scoliosis, a side-to-side curve in the back or spine, often creating a pronounced "C" or "S" shape when viewed on an x-ray of the spine. This condition is most apparent during adolescence, and is most common with females.

Osteoporosis

Main article: Osteoporosis

Osteoporosis is a disease of bone, which leads to an increased risk of fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old sex-matched healthy person average) as measured by DXA; the term "established osteoporosis" includes the presence of a fragility fracture. Osteoporosis is most common in women after the menopause, when it is called postmenopausal osteoporosis, but may develop in men and premenopausal women in the presence of particular hormonal disorders and other chronic diseases or as a result of smoking and medications, specifically glucocorticoids, when the disease is craned steroid- or glucocorticoid-induced osteoporosis (SIOP or GIOP).

Osteoporosis can be prevented with lifestyle advice and medication, and preventing falls in people with known or suspected osteoporosis is an established way to prevent fractures. Osteoporosis can also be prevented with having a good source of calcium and vitamin D. Osteoporosis can be treated with bisphosphonates and various other medical treatments.

References

Category:Endocrine system Skeleton, Human Category:Osteology