Collagen

This is from the NBME question bank. Each of the question stirs up my interest in looking for the answer. This time, I shall talk about the wonderful world of collagen.

Case as follows:
A 2-year-old boy has brittle depigmented hair, cerebral atrophy, delayed myelination, motor delay, and mental retardation. Lysyl oxidase activity is decreased. The function of which of the following substances is most likely to be defective in this patient?

A) Albumin
B) Ceruloplasmin
C) Chondroitin sulfate
D) Collagen

Obviously the answer has to be collagen isn't it? One will ask so what's the diagnosis? Possible answer is Menkes Disease, which is an X-linked neurodegenerative disease of impaired copper transport. (obtained from http://emedicine.medscape.com/article/1180460-overview) It is also known as the kinky hair disease. The disease speaks for itself, kinky hair. Everything links to the defect of the collagen synthesis itself as well as the copper metabolism.

As an IMU student, we might think that copper metabolism? Isn't that something to do with Wilson's disease, better known as hepatolenticular degeneration in which there is autosomal recessive genetic disorder in which copper metabolism is affected and that copper builds up in the body. The most well known symptom is the Kayser-Fleischer rings which we always say when during our OSCE practice. We haven't seen one before so we don't know how it looks like. Other symptoms include neuropsychaitric symptoms, RTA, cardiomyopathy etc. One important thing about copper is that copper is an important component of several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase. The main enzyme we are going to talk now is lysyl oxidase.

So what's so great about this enzyme? Lysyl? Something to do about collagen? Yes, absolutely. Collagen occurs in all multicellular animals and is the most abundant protein of vertebrates. It is a extracellular protein that is organised into insoluble fibers of great tensile strength. This suits collagens role as components of connective tissues such as bone, teeth, cartilage, tendon etc.(from Vishna' lecture note)
Mammals have at least 17 genetically distinct polypeptide chains (called  chains) comprising 10 collagen variants as listed below:

Type Distribution
I Skin, bone, tendon, blood vessels andcornea
II Cartilage
III Blood vessels, foetal skin
IV Basement membrane

Collagen has a distinctive amino acid composition-nearly one third of its residues are Gly, another 15-30% are Proline, 4-hydroxyproline,and hydroxylysine. The hydroxylated residues appear only after collagen polypeptides are synthesised. The enzyme that converts Proline to Hydroxyproline is prolyl hydroxylase. Hyroxyproline is important as it confers stability upon collagen (intramolecular hydrogen bonds that may involve bridging water molecules). However, prolyl hydroxylase requires ascorbic acid (Vit C) to maintain its enzymatic activity. Thus for people with scurvy: skin lesions, blood vessels fragility, results because collagen cannot form fibres properly. This explains the importance of Vit C not only as an antioxidant itself but also a cofactor for prolyl hydroxylase in healthy growth of collagen in mammals. Reaction is as follows for prolyl hydroxylase:
Proline + α-ketoglutarate + O2 + Fe2+ → 4-hydroxyproline + Fe4+ + CO2 + succinate

One point which I want to point out in the case mentioned is the enzyme lysyl oxidase. A brief introduction of the enzyme by wikipedia:

Lysyl oxidase also known as protein-lysine 6-oxidase is a protein which in humans is encoded by the LOX gene. Its inhibition can cause lathyrism, but at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous. Lysyl oxidase is an extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues in collagen and elastin precursors.

This enzyme requires copper, therefore in any form of disease which impairs the synthesis of copper, it will result in this enzyme difficiency and the disease which can be resulted involves the as mentioned in the italic statement as well as the symptoms occuring in Menkes disease.The Menkes gene is located on the long arm of the X chromosome at Xq13.3, and the gene product (ATP7A) is a 1500–amino acid P-type adenosine triphosphatase (ATPase) that has 17 domains—6 copper binding, 8 transmembrane, a phosphatase, a phosphorylation, and an ATP binding.(from: http://emedicine.medscape.com/article/1180460-overview) This is the syndrome the boy is suffering from.

Another collagen disease is Ehlers-Danlos Syndrome. The famous one in which everyone see the clinical picture and say the condition is the Type I and II which have hypermobility of joint, skin hyperextensibility and wide atrophic scars. (from : http://emedicine.medscape.com/article/943567-overview) Type IV is the vascular one in which it is important to take note of and diagnose it as it will have disastrous consequences.

Type IV is the vascular/ecchymotic form. Patients with type IV Ehlers-Danlos syndrome have prominent venous markings, which are readily visible through the skin. Diagnostically, this type is most important because patients are subject to spontaneous rupture of the bowel, medium-sized arteries, or both. Often, rupture leads to early death. Median life expectancy in these patients is 45-50 years.

So that's about collagen for the while. I shall end this topic with collagen and aging.

Collagen and Aging
The sixth theory of aging is the Collagen Theory of Aging, This theory says that as we age, our collagen in our bodies gets older. When that happens the old collagen gets stiff and does not act as flexibly, causing problems, e.g., causes hypertension by not expanding to accomodate the flow of blood through the vessels, stiff collagen causes organs to malfunction as they seem to be "crispy" and hinder metabolic reactions.

Rehabilitation of a Colles Fracture – Physiotherapy

Author: Jonathan Blood-smyth

Colles' fractures, named after Abraham Colles who first described in 1814 the common fracture of the last inch of the radius and ulna near the wrist, is a very common consequence of a fall on the outstretched hand (FOOSH). Typical treatment is immobilisation in a plaster of Paris or similar material for five to six weeks to allow bony union, followed by a rehabilitation period of a month or more, a short period of which might involve a wrist brace for comfort during activity. Due to the functional importance of the hand, the period of immobilisation is kept to a minimum to prevent dysfunction of the hand and wrist.

Physiotherapy examination starts once the hand has been released from the Plaster of Paris, manually feeling the fracture site which should not be more than minimally uncomfortable, signifying the fracture is well on the way to healing. Hand colour should be normal, the hand should not be swollen much nor have severe muscle wasting. Wrist movements are often restricted in one or two planes but all the movements should not normally be reduced or not significantly. Pain may be present but again should not be severe or occur on all hand movements.

Two hourly range of motion exercises are the first treatment taught to the patient by the physiotherapist and in many cases the wrist movements improve sufficiently for this alone to be required. Elbow and shoulder movement should be reviewed to rule out restrictions before moving on to the rotatory forearm movements of pronation and supination which are important for normal hand use. Further movements assessed are flexion and extension of the wrist, fingers and thumb, along with thumb adduction and abduction. Wrist extension and forearm supination are the most commonly affected movements.

After the plaster comes off the wrist often feels vulnerable, partly because the plaster is seldom left on until the bone is entirely healed to prevent the onset of complications due to immobilisation. Physiotherapists may give the patient a futura type brace, a fabric brace with Velcro straps and a metal piece for the underside of the wrist to stiffen it. This is not meant to keep the wrist immobilised further but to support the wrist while the patient is performing functional activities and then to be removed for light activities and regular exercise performance.

If the ranges of motion do not improve as they should then the physiotherapist will consider using joint mobilisations to ease the movements. Accessory movements can be performed to the inferior radio-ulnar joint to help pronation and supination, and to the radiocarpal (wrist) and midcarpal joints, with the physiotherapist fixing one side of the joint as he or she moves the other side of the joint passively. This can be done gently or more vigorously at the end of range to push against the restrictions within the joint. Mobilisations can also be performed with the joint at the end of its available movement to give it the sliding and gliding movements it requires.

Strengthening the wrist occurs with a gradual increase in functional activities but joining a hand class can instruct the patient in practicing the large variety of small movements that the hand can perform and needs to strengthen for optimum hand function. Repetitive work at pieces of apparatus can strengthen and harden the hand to turning, twisting, pulling, grasping and fine work with the thumb and index finger. This can move on to work with weights or functional activities if the person needs to return to manual labour or another job requiring upper limb strength.

Urgent treatment is indicated if the hand is extremely painful, tightly swollen and has poor movements, before a pain syndrome develops. At this stage medical review is important to make sure there are no complications with the fracture such as poor healing or lack of healing. Analgesia and contrast baths can help with the pain, desensitisation with the hypersensitive areas which can develop and massage and exercise with the swelling. Patient education is vital so they know they have to work hard and through the pain to rehabilitate their hand.

About the Author:

Jonathan Blood Smyth is a Superintendent of Physiotherapy at an NHS hospital in the South-West of the UK. He specialises in orthopaedic conditions and looking after joint replacements as well as managing chronic pain. Visit the website he edits if you are looking for physiotherapists in Birmingham.

Article Source: http://www.articlesbase.com/health-articles/rehabilitation-of-a-colles-fracture-physiotherapy-727809.html

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Good website: http://cellbio.utmb.edu/microanatomy/bone/practice_examcb.htm

Pathophysiology and Aging of Bone

Sources: http://www.springerlink.com/content/x208624555xgu576/

This is an article in regards to pathophysiology and aging of bone by Peitschmann et al.

I will list out the points of interest in this article.

Bone loss due to aging:

1) overall decline in protein synthesis and protein turnover and accumulation of damaged molecules
2) number of adhesion colony forming cells significantly lower in marrow cells
3) requirement of higher concentration of growth factors and hormones
==> Impaired growth of human endosteal bone cells from men aged over 50 years
4) lower production of osteocalcin after stimulation with 1,25-(OH)2D3

Age related osteopenia may result from inversely related changes in pool size of hematopoietic osteoclast precursor cells and osteogenic stromal cells; reduced production of osteoprotegerin and enhanced RANKL expression would additionally promote the formation of osteoclasts.

Currently available markers of bone formation are:
total and bone-specific alkaline phosphatase activity, osteocalcin and type I collagen terminal extension peptides.
Bone resorption is assessed by
urinary excretion or serum levels of bone type I collagen degradation products eg. pyridinium crosslink and N- and C-telopeptide of collagen crosslinks.

Factors affecting invidividual bone mass include:
A) Peak bone mass (the amount of bone mass achieved at skeletal maturity)
B) Subsequent rate of bone loss

What is bone quality, one may ask. According to Mary Bouxsein: "the totality of features and characteristics that influence a bone's ability to resist fractures". Nevertheless, compromised trabecular architecture portrays as an independent causal factor in the pathogenesis of vertebral fractures.

It is well established that estrogen deficiency is a major determinant of the accelerated bone loss in postmenopausal women. This leads to the most infamous term called "osteoporosis" which everyone in the world knows and aware about it. One of the major worry which medical personnals are concerned of is the fracture of the neck of the femur in osteoporotic patients. Of course there are other fractures that could happen in osteoporotic bone in this case, eg. Colles fracture and crush fractures of thoracic and lumbar verterbra. For short, osteoporosis contributes in the increment of fragility (low energy) fractures and severity of traumatic (high energy) fractures.

HORMONAL INFLUENCES IN BONE LOSS

Androgen deficiency can impale high-turnover osteopenia in males (be it rats or males). Unfortunately, there isn't a clear distinction in this statement as some studies quoted positive correlation between free androgen index and femoral neck bone mineral density. It is interesting to note that in the study conducted by Kelly and coworkers (1990) reported that radial bone mineral density could be predicted by an index of free testosterone and weight. However, the fact that bioavailable estrogen was most strongly associated with bone mineral density, and thus, bioavailable of estrodiol rather than testosteonr is used as the most consistent predictors of bone turnoever and bone loss. There is another possible role of using dehydroepiandrosterone (DHEA) and DHEA sulfate to correlate bone density in healthy women.

OTHER INFLUENCE

We know that growth hormones stimulate growth. Nevertheless it stimulates the growth of bones. It is not surprising to note that growth hormone secretion declines as we age. Role of growth hormone/insulin-like growth factor is clearly shown in cases with growth hormone deficiency, leading to dwarfism and acromegaly in cases of excess growth hormones. 1,25-dihydroxyvitamin D3 acts as a central regulator of calcium and phosphorus homeostasis. It is interesting to note that there exists an association between bone mineral density and vitamin D receptor allele. As shown in literatures, vitamin D receptor polymorphisms appear to influence bone mineral density in primary as well as secondary osteoporosis.

To summarize, estrogen deficiency acts as the major determinant of bone loss in women and men whilst Vit D3 portray as a factor of bone turnover in elderly.

RIGGS, KHOSLA AND MELTON UNITARY MODEL OF INVOLUTIONAL OSTEOPOROSIS

Involutional osteoporosis is defined as the common form of osteoporosis that begins in middle life and becomes increasingly more frequent with age and there are two tyesp: type I ("postmenopausal") and type II ("senile").
Type I osteoporosis presents during the first 15-20 years after menopause and is characterized by excessive loss of trabecular bone, which causes the fractures typical of postmenopausal osteoporosis such as vertebral fractures and Colles' fracures. Type II is characterized by loss of trabecular and cortical bone, and the most frquent fractures involve the proximal femur and vertebra.

One point of interesting note is that cigarette smoking has been identified as risk factor for low bone mineral density. It is shown that 25-OH vitamin D and osteocalcin levels are low in smokers. Impairment of intestinal calcium absorption may contribute to the bone loss as well.

To conclude, humans will get old, we can get old. Nevertheless, with the understanding of these conditions, it is possible that one can prevent osteoporosis by doing the right activities to minimize of one's risk of getting osteoporosis. So start a healthy diet, do exercise and stop smoking!!!

Obs & Gyn

This is from: http://ob-ultrasound.net/

Written here are the 4 lengths discussed during my lecture dated 21st Jan 2009. Though it is MSK week, there are couple of things the lecturer wants us to know.

Determination of gestational age and assessment of fetal size.
Fetal body measurements reflect the gestational age of the fetus. This is particularly true in early gestation. In patients with uncertain last menstrual periods, such measurements must be made as early as possible in pregnancy to arrive at a correct for the patient. In the latter part of pregnancy measuring body parameters will allow assessment of the size and growth of the fetus and will greatly assist in the diagnosis and management ofintrauterine growth retardation (IUGR).
The following measurements are usually made:
a) The Crown-rump length (CRL)
This measurement can be made between 7 to 13 weeks and gives very accurate estimation of the gestational age. Dating with the CRL can be within 3-4 days of the last menstrual period. An important point to note is that when the due date has been set by an accurately measured CRL, it should not be changed by a subsequent scan. For example, if another scan done 6 or 8 weeks later says that one should have a new due date which is further away, one should not normally change the date but should rather interpret the finding as that the baby is not growing at the expected rate.
b) Biparietal diameter(BPD)
The diameter between the 2 sides of the head. This is measured after 13 weeks. It increases from about 2.4 cm at 13 weeks to about 9.5 cm at term. Different babies of the same weight can have different head size, therefore dating in the later part of pregnancy is generally considered unreliable. Dating using the BPD should be done as early as is feasible.
c) The Femur length (FL)
Measures the longest bone in the body and reflects the longitudinal growth of the fetus. Its usefulness is similar to the BPD. It increases from about 1.5 cm at 14 weeks to about 7.8 cm at term. Similar to the BPD, dating using the FL should be done as early as is feasible.
d) The Abdominal circumference (AC)
The single most important measurement to make in late pregnancy. It reflects more of fetal size and weight rather than age. Serial measurements are useful in monitoring of the fetus. AC measurements should not be used for dating a fetus.
The weight of the fetus at any gestation can also be estimated with great accuracy using polynomial equations containing the BPD, FL, and AC. computer softwares and lookup charts are readily available. For example, a BPD of 9.0 cm and an AC of 30.0 cm will give a weight estimate of 2.85 kg.