Week 9 Flashcards
1
Q
Describe the development of the Thyroid?
A
- Thyroid tissue arises in midline at a point on tongue known as foramen caecum
- Epithelial cells sink downwards anterior to hyoid & larynx (week7)
2
Q
What does the Thyroglossal duct do?
A
Connects developing thyroid to the tongue
3
Q
List what you would expect to see in a histology of the Thyroid Gland?
A
- Follicle
- Follicular cells
- Colloid
- Para-follicular C-cells
4
Q
Where synthesises & secretes thyrotropin-releasing hormone (TRH)?
A
Small-bodied neurons in arcuate nucleus & median eminence
5
Q
What carries TRH to the anterior pituitary?
A
Long portal vessels
6
Q
How is T4 released?
A
Inside lysosomes of the follicular cells, enzymes will cleave 2 peptides on the backbone of thyroglobulin molecule
7
Q
Describe the 1. “Trapping” process during the synthesis & secreting of T3 & T4?
A
- TSH increases activity of Na/I co-transporter (NIS) on basolateral membrane of thyroid follicular cell
- Increased iodine trapping
8
Q
What happens to the ratio of follicular-cell iodine to plasma iodine during “Trapping”?
A
Increases under conditions of high TSH
9
Q
Describe what happens to the trapped iodine during synthesis & secretion of T3 & T4?
A
- Leaves cell, via pendrin, & enters lumen
- Thyroid peroxidase on luminal surface of secretory vesicle oxidises I- to Io
10
Q
What does the follicular cell also secrete?
A
Thyroglobulin
11
Q
Describe the 3. “Iodination” process during the synthesis & secretion of T3 & T4?
A
TSH stimulates iodination of thyroglobulin in the follicular lumen
12
Q
Describe the 4. “Conjugation” process during the synthesis & secretion of T3 & T4?
A
TSH stimulates conjugation of iodinated tyrosine to form T4 & T3 linked to thyroglobulin
13
Q
Describe the 5. “Endocytosis” process during the synthesis & secretion of T3 & T4?
A
TSH stimulates endocytosis of iodinated thyroglobulin into follicular cells from thyroid colloid
14
Q
Describe the 6. “Proteolysis” process during the synthesis & secretion of T3 & T4?
A
TSH stimulates proteolysis of iodinated thyroglobulin, forming T3 & T4 in the lumen of lysoendosome
15
Q
Describe the 7. “Secretion” process during the synthesis & secretion of T3 & T4?
A
TSH stimulates secretion of T4 & T3 into the circulation
16
Q
Describe the “Hyperplasia” process during the synthesis & secretion of T3 & T4?
A
TSH exerts growth-factor effect, stimulating hyperplasia within the thyroid gland
17
Q
What is 99.5% of T3 bound to in the blood plasma?
A
TBG (thyroxin-binding globulin)
18
Q
What is 99.98% of T4 bound to in the blood plasma?
A
TBG (thyroxin-binding globulin)
19
Q
How/What converts T4 to T3?
A
5’/3’ monodeiodinase activity removes the 5’ iodine
20
Q
How do T4 & T3 enter the cytosol of a cell?
A
Either diffusion or carrier-mediated transport
21
Q
What does TBG (thyroxin-binding globulin) do?
A
Along with other thyroid hormone binding proteins found in plasma (transthyretin & albumin) buffer free T3 & T4 levels in blood
22
Q
What is the chain reaction when basal metabolic rate (BMR) increases?
A
Increased O2 consumption –> Increased heat production
23
Q
What does hyperthyroidism do to the basal metabolic rate (BMR)?
A
Increased basal metabolic rate (BMR) upto 100%
24
Q
What does hypothyroidism do to the basal metabolic rate (BMR)?
A
Decreased basal metabolic rate (BMR) to 50-60%
25
Describe the physiological actions of the thyroid hormones on carbohydrate, fat & protein stores?
- Increased Glucose uptake from GI Tract & Glucose utilisation
- Increased Liver glycogenolysis & gluconeogenesis
- Increased Lipolysis in adipose tissue (plasma FFA)
- Increased Tissue oxidation of FFA
- Increase protein turnover with net increase in anabolism
- Increase in specific enzymes/membrane proteins/hormone receptors
26
What other hormones does thyroid hormones have a permissive action on?
- GH, prolactin, gonadal & adrenal steroids
| - Essential for normal development & function of central & peripheral nervous systems
27
Describe the effect of hypothyroidism on the brain?
- Poor mental ability
| - Lack of memory & initiative
28
What 3 things does fetal hypothyroidism lead to?
1. Neuronal hypoplasia
2. Delayed myelination in specific neurones
3. Mental retardation
29
Describe the Thyroid disorder- Goitrogens?
- Excess iodide
| - Thiocyanate or perchlorate cause excess TSH secretion & hypertrophy of thyroid & hypothyroidism
30
Describe the Thyroid disorder- Pituitary tumours?
- Excess TSH= hypertrophy of thyroid & hyperthyroidism
| - Lack of TSH= atrophy of thyroid & hypothyroidism
31
Describe the Thyroid disorder- Graves Disease?
- Long-acting thyroid stimulator (LATS- autoimmune stimulation of thyroid)
- Hypertrophy of thyroid & hyperthyroidism
- Exophthalmos
32
Describe the Thyroid disorder- Hashimoto's disease?
- Autoimmune destruction of thyroid
| - Atrophy of thyroid & hypothyroidism
33
When can Goitre's be present?
In Hyper- or Hypothyroidism
34
What % of GP consultations are for neurological symptoms?
17%
35
What is Spina bifida?
Group of congenital conditions where there's an incomplete development/covering of brain &/or spinal cord, caused by failure of foetal spine to close normally in 1st month of pregnancy
36
List the proposed aetiologies for Spina Bifida?
- Multi-factorial inheritance
- Potato blight
- Vitamin deficiencies/folate
- Maternal fever
- Zinc deficiency
- High sound intensity
- Viral infection
- Alcohol
- Mineral deficiency
- Medication: Phenytoin, Epilim
37
What is Cerebral Palsy (CP)?
- Spectrum of motor disorders affecting posture, movement & co-ordination
- Caused by brain lesion --> abnormal development of CNS
38
Describe the stages of Spinal cord during embryology?
- Neural plate 14 days
- Neural folds at 20 days
- Ant. neuropore closes 26 days
- Post. neuropore closes 29 days
39
What are the 2 minor spinal cord embryological defects?
1. Spina Bifida occulta
| 2. Sacral dimple
40
What are the 2 cranial & vertebral neural tube abnormalities?
1. Anencephalus
| 2. Spina bifida
41
Describe MILD spina bifida?
- Sac contains meninges & CSF but not spinal cord
- Mild disability
- Least common
42
When is Spina Bifida described as a serious disability?
If cord is displaced from neural canal or has not developed
43
Describe the neurological consequences of severe Spina Bifida?
- Lower motor neurone lesion
| - Paralysis, loss of sensation & reflexes distal to abnormality
44
What are the pros & cons of surgical closure of the severe Spina Bifida defect?
- PROS: stop the high risk of infection due to the open wound
- CONS: not improve damage which is already done
45
Describe the neonatal consequences of severe Spina Bifida?
- High risk meningitis in open lesions in the neonate
| - Hydrocephalus in 70-90% because of interruption of the circulation of CSF
46
What can be a consequence of shunting in hydrocephalus?
Shunts can become infected or blocked
47
What are neurological disorders 4 associated conditions?
1. Renal anomalies
2. Sphincter function
3. Intellectual impairments
4. Musculoskeletal
48
How can you diagnose neurological disability in antenatal care?
- Ultrasound spinal anomalies identifiable at 16-18 weeks
| - α fetoprotein raised in neural tube defects maternal serum at 16-20 weeks, amniocentesis
49
Describe the neurological consequences of an L4 lesion?
- No motor function below knee, apart from tibialis anterior
- Weak glutei
- No sensation distal to L4
- Sphincters non-functioning (S2,3,4)
50
Describe the possible musculoskeletal problems associated with neurological disorders?
- LMN, muscle weakness/paralysis
- Difficulties walking
- Spinal deformity
- Disuse osteoporosis, risk of fracture
- Skin ulceration
51
What are the 2 problems with paralytic deformities of the feet?
1. Difficulties with shoe wear
| 2. Plantar ulceration
52
Describe Scoliosis?
- Due to combo of
congenital abnormalities of the spine & muscle weakness
- If surgical correction is required, usually done after age of 10 years to allow sufficient spinal
growth beforehand
53
What are 4 factors influencing walking?
1. Neurological level
2. Intellectual impairment
3. Psychological
4. Age
54
What is the prognosis for independent walking as a adult?
- Thoracic & upper lumbar lesions: none
| - Lower lumbar & sacral: can walk but will need splints to compensate for paralysed muscles
55
Is mobility the same as walking?
NO
56
Describe the flexed knee gait in a L4 lesion?
- Patient relied on intact quadriceps
- Paralysed calf muscles result in excess ankle dorsiflexion
- Muscle fatigue
- Energy inefficient gait
- Knee pain
57
Describe why there are mobility challenges when a child grows into an adult with a L4 lesion?
Increasing height & weight as child grows but muscle strength does not change
58
Describe the challenges to mobility as an adult with a L4 lesion/
- Muscle fatigue & knee pain may worsen & becomes more reliant on a wheelchair
- Able to drive in adapted vehicle
- Self propelling or electric wheelchair for shorter distances
- Will require adapted housing if living independently
59
Describe Charcot joints?
Loss of protective sensation & proprioception in a joint can result in joint destruction
60
What are the 4 expectations of lower urinary tracts?
1. Bladder should fill to good capacity
2. Empty to completion
3. Emptying should be under voluntary control
4. Filling & emptying should not be
detrimental to renal function
61
Describe the consequences of urinary incontinence (S2-4) in neurogenic bladder?
Incomplete emptying
leads to back pressure on ureters & eventual renal
parenchymal damage & failure if untreated
62
What are the possible treatments for urinary incontinence?
- Nappies in kids
- Permanent bladder catheterisation (UTIs)
- Clean intermittent catheterisation often best option (carer or patient self)
- Urinary diversion for physical or social reasons (stoma bag)
63
Describe the reasons/problems with Faecal incontinence?
- Often a barrier to social acceptance
- Paralysis of external anal sphincter & mechanism to indicate a full rectum
- Some have weak abdominal & perineal muscles
64
What are the possible treatments for faecal incontinence?
- Daily rectal enema
- Constipation may require laxatives or manual evacuation
- Surgical diversion for physical or social reasons
65
What are the sexual problems associated with neurological disorders?
- Libido may be normal - Sensation absent (S2-4)
- Erections possible due to spinal reflex
- Fertility females normal, males usually sterile
- Menstruation may cause further social difficulty
66
Describe different forms of education for people with neurological disorders?
- Mainstream school
- Special needs school: learning & physical disability
- College to acquire life skills for those with learning difficulties
67
What do patients whose disabilities preclude employment do?
Attend a day centre
68
What is the disability paradox?
Poor function but excellent quality of life
69
What are the challenges to independent living as an adult?
- Learning/ Behavioural difficulties
- Social continence not achieved
- Cannot transfer independently
- Ageing parents
- Live in a sheltered facility & looked after by a team of carers
70
What are the 2 types of Euthyroid?
1. Diffuse- younger people
| 2. Multinodular- older
71
What are the 2 types of Hypothyroid & what cases them?
1. Iodine deficiency- endemic, versus seaweed increase
| 2. Goitrogens- drugs (lithium, amiodarone) diet (cabbage, turnips)
72
What is the pathogenesis of goitre's?
- Reactive
- Iodine block
- Genetic
73
Describe the characteristics of a benign mass?
Usually movable, soft & non tender
74
Describe the characteristics of a malignancy?
Hard nodule, fixation to surrounding tissue & regional lymphadenopathy
75
Describe the signs & symptoms of hyperthyroidism?
- Nervousness
- Heat intolerance
- Diarrohea
- Muscle weakness
- Loss of weight & appetite
76
Describe the signs & symptoms of hypothyroidism?
- Cold intolerance
- Constipation
- Fatigue
- Weight gain, in children, primarily accumulation of myxedematous fluid
- Slow speech
- Deep hoarse voice
- Thickening of skin
77
Why do signs & symptoms of local nerve involvement trigger rapid investigation?
- Involvement may be indicative of local invasiveness from malignancy
- Most important signs are dysphagia & hoarseness
78
Describe the different diagnosis's in Thyroid function tests?
- Elevated thyroid-stimulating hormone (TSH) may indicate thyroiditis
- Very low TSH level indicates autonomous or hyperfunctioning nodule
79
What is the Antithyroid antibodies helpful in diagnosing?
Chronic lymphocytic thyroiditis (Hashimoto thyroiditis)
80
What is complete blood count (CBC) helpful in diagnosing?
Abscess
81
What are the 4 different techniques for diagnosing thyroid pathology?
1. Thyroid function test
2. Antithyroid antibodies
3. Complete blood count (CBC)
4. Fine needle aspirate
82
What are the 5 different imaging studies used for thyroid pathology?
1. Ultrasonography
2. Radioiodine scintigraphy
3. Chest radiography
4. Computed tomography (CT)
5. MRI
83
What is Ultrasonography useful for in thyroid pathology?
Determine whether nodule is cystic, solid, or mixed
84
What is Radioiodine scintigraphy useful for in thyroid pathology?
Determine whether nodule is cold, warm, or hot
85
Why is a Chest radiography used in thyroid pathology?
If malignancy is suspected, given the high incidence of early metastases to the lungs
86
What is CT & MRI useful for in thyroid pathology?
Analyse the extent of disease by scanning the neck & chest
87
List the different disease categories diseases of the thyroid?
1. Trauma & toxicity
2. Goitre, solitary nucleus, neoplasms
3. Chronic inflammation (immune or not)
4. Acute thyroiditis, abscess
5. Metabolic, genetic
88
What is the commonest type of hyperthyroidism?
Graves (may present as diffuse toxic goitre)
89
What are the 3 different types of hyperthyroidism?
1. Graves
2. Functional goitre
3. Toxic adenoma
90
What are the 2 types of hypothyroidism?
1. Congenital
| 2. Autoimmune
91
What are the 3 causes of autoimmune hypothyroidism?
1. Defective TH production
2. Loss of parenchyma
3. Deficient TSH
92
Describe Graves (hyperthyroidism)?
- Autoimmune
- Under 40 years
- Female 10 : male 1
- Immune: IgG against TSH receptor on thyrocytes
- Strong family history HLA DR3 & CTLA-4
93
Who is Hashimoto thyroiditis (chronic autoimmune) most common in?
Females 30-50yrs
94
Describe Hashimoto thyroiditis (chronic autoimmune)?
- Present as hyper- / hypo- thyroidism
- Autoreactive CD8 T lymphocytes
- Autoreactive antibodies: thyroid microsomal in almost all 95% thyroglobulin in 2/3's, minority have blocking TSH receptor antibodies
- Family history strong & other autoimmune diseases
95
What are 2 other causal risks for Hashimoto thyroiditis (chronic autoimmune)?
1. Increased iodine intake
| 2. Viral infection
96
Name a benign thyroid neoplasm?
Follicular adenoma
97
Describe the 2 types of malignant thyroid neoplasms?
1. Primary- 1% of cancers: PAPILLARY, FOLLICULAR, anapaestic, medullary, lymphoma
2. Metastatic- lymphoma
98
Describe a Follicular adenoma (benign)?
- 30-50y
- Female>males
- 1-3 cm at presentation
- Different histological subtypes
- Sometimes functional
- Ras mutation?
99
Describe the prevalence of Papillary carcinoma (malignant)?
- Around 80% of thyroid cancers
- 20-50y
- Females 3 : males 1
100
What are the 3 different causes of Papillary carcinoma (malignant)?
1. RADIATION (Chernobyl)
2. Family history
3. Unknown
101
Describe the molecular pathology of Papillary carcinoma (malignant)?
- Rearrangement of RET oncogene in most
| - B-RAF mutation in half, increased risk of LN mets
102
Describe the prevalence of Follicular carcinoma (malignant)?
- Around 20% of thyroid cancers
- Older than 40
- Female 3 : male 1
103
Describe the molecular pathology in Follicular carcinoma (malignant)?
- RAS oncogene
- PAX8/PPARG rearrangements
- Minimally invasive versus invasive
- Blood spread
104
Describe the prevalence of Anaplastic carcinoma (malignant)?
Female 4 : Male 1
105
Describe the molecular pathology of Anaplastic carcinoma (malignant)?
- 1/2 have had chronic goitre
- May have had previous thyroid neoplasia
- p53 mutation common
106
Describe the prevalence of Medullary carcinoma?
20% familial (in younger patients)
107
Describe the molecular pathology of Medullary Carcinoma?
RET proto-oncogene activation
108
What are 3 diseases of the parathyroid glands?
1. Primary hyperparathyoridism
2. Secondary hyperparathyoridism
3. Tertiary hyperparathyoridism
109
What are the 3 different types of Primary hyperparathyoridism?
1. Adenoma: 4/5's
2. Hyperplasia (some familial)
3. Parathyroid carcinoma (less than 1%)
110
What is the cause of Secondary hyperparathyoridism?
Low calcium (chronic renal failure & vitamin D deficiency)
111
What is the cause of Tertiary hyperparathyoridism?
Raised calcium in secondary hyperparathyoridism
112
What do you need to remember about endocrine neoplasia?
There are multiple (MEN1 & MEN2 examples)
113
What is a stressor?
Stimulus that disrupts homeostasis & causes stress response
114
What is the stress response?
Suite of physiological & behavioral responses to a stressor that help to restore homeostasis
115
Describe the 2-step physiological stress response?
1. Sympathetic nervous system- Quick, within sec's, release of epinephrine (adrenaline)
2. HPA Axis (hypothalamic-pituitary-adrenal axis)- Slower, mins-hrs, release of cortisol
116
What 3 things does the adrenal cortex release?
1. Glucocorticoids
2. Mineralocorticoids
3. Sex hormones
117
What 2 things does the adrenal medulla release?
1. Epinephrine
| 2. Norepinephrine
118
Describe the HPA Axis (hypothalamic-pituitary-adrenal axis)?
Hypothalamus --> CRH --> Pituitary gland --> ACTH --> Adrenal cortex --> Cortisol --> Hypothalamus
119
What are the immediate effects of the stress response?
- Increased heart rate & O2 intake
- Increased blood glucose levels
- Increased blood flow to muscles
- Increased alertness
- Inhibition of digestion, immune system
- Release of endorphins
- Dilation of pupils
120
Describe the consequences of Short-term versus long-term consequences of stress?
Beneficial in short-term or mild levels, but can cause major long-term problems if stress is chronic
121
What 5 health problems is chronic stress related to?
1. Heart disease
2. Diabetes
3. Ulcers
4. Growth problems
5. Compromised immune system
122
What is the relationship between cortisol & depression?
Cortisol elevated in 50% of depressed patients
123
Describe the rhythm in cortisol production?
- High in morning (7-9am)
| - Low at night (11pm-4am)
124
Describe the Dexamethasone suppression test?
Causes HPA negative feedback to turn off, so no cortical surge (not true in depressed patients)
125
What 2 disease's is depression a symptom of?
- Cushing's disease (high cortisol)
| - Addison's disease (low cortisol)
126
Describe the effect of the stress response on the immune system over time?
- 1st few mins: enhanced immune system
- After ~1hr: returns to normal
- Chronic stress: suppresses immune system
127
Why is cortisol described as being a key anti-stress hormone?
- It helps reduce inflammation during stress, also acts as immunosuppressent
- Various components of immune system influenced by cortisol
128
What was the Experiment at the Catholic University in Korea?
- Male & female undergraduate students all free of disease/illness
- Blood samples taken on day of exam & 4 weeks later, monitored for no. of specific immune cells
129
What were the results of the Experiment at Catholic University in Korea?
- Lowered Interferon gamma (IFN-γ), which is normally released by T lymphocytes & natural killer (NK) cells
- Examination Day IFN-γ: 190 pg/dl
- Four Weeks IFN-γ: 500 pg/dl
- Lowered T-helper 1 (Th1) cellular immunity
130
What are the conclusions of the Experiment at Catholic University in Korea?
- Although neuroendocrine status wasn't monitored, cytokine profiles were taken which are an indirect link to immune system
- Decrease in no. of macrophages, interferons, lymphocytes & natural killer (NK) cells
131
What was the NASA study?
- Relation between elevated stress hormones & reactivation of Epstein-Barr Virus (EBV) in astronauts
- Study effects of stress due to space flight on levels of neuroendocrine hormones & immune cells
132
Describe the method of the NASA study?
- Blood samples taken, 10 days before launch, landing day, 3 days after landing
- Urine samples for detecting hormones
133
What were the conclusions of the NASA study?
- Decrease in virus specific antibodies in all astronauts
- Reactivation of EBV
- Urinary cortisol & catecholamines elevated after flight
- Stresses lead to decreased virus specific T-cell immunity
134
Describe the classical mode of glucocorticoid action (transactivation)?
Cell producing a protein which has anti-inflammatory
effect, glucocorticoid receptor binding & driving more production of the anti-inflammatory which dampens down the ability to make an immune response
135
Describe a model for glucocorticoid action (transrepression)?
Cell produces a protein
which drives inflammation, the cortisol is coming in & binding to stop the production of that inflammatory protein (indirect) which reduces ability to make an immune response
136
What is the potency of Dexamethasone?
25-80
137
What is the half life in hrs (t1/2) of Dexamethasone?
36-54hrs
138
Give some examples of synthetic glucocorticoids?
- Hydrocortisone
- Cortisone acetate
- Prednisone
- Prednisolone
- Dexamethasone
139
Describe the immunosuppressive action of glucocorticoids?
- Suppress cell-mediated immunity
- Inhibit IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-alpha
- Suppress humoral immunity: B cells express less IL-2R & secrete less IL-2
- Down regulation of Fc receptors on macrophages
(reduced phagocytosis)
140
List the possible side effects of glucocorticoids?
- Immunosuppression
- Hyperglycemia, insulin resistance, impaired glucose tolerance
- Skin fragility, bruising
- Osteoporosis
- Weight gain
- Adrenal insufficiency
- Muscle breakdown
- Irregular menstruation
- Cushing’s syndrome
141
What does excess use of high dose steroids do?
Suppress CRH & ACTH
142
What does prolonged used of high dose steroids do?
Leads to adrenal atrophy, recovery can take months
143
Describe the steroid withdrawal after less than 1 week treatment?
- Usually ok to withdraw abruptly
| - 1 week recovery
144
Describe the steroid withdrawal after 6-10days treatment?
- Reduce to replacement
- Tape over 4 more days
- Recover in 4 weeks
145
Describe the steroid withdrawal after 11-30 days treatment?
- Reduce to twice replacement, then by 25% every 4 days
| - 3 months to recover
146
Describe the steroid withdrawal after >30days treatment?
- Reduce to twice replacement, then by 25% per week, then 0800h check with cortisone
- Recovery may take 1yr
147
What is type 1 diabetes (main type in juveniles)?
Destruction of insulin producing beta-cells in pancreas
148
Describe the 2 stages of type 1 diabetes?
- 1st stage: insulitis (lymphocyte invasion of pancreatic islets)
- 2nd stage: overt diabetes, massive death of islet B cells & loss of glucose homeostasis
149
Describe the autoimmune process involved in type 1 diabetes?
- Immune assault on beta-cells mostly T lymphocytes
- Naïve beta-reactive T cells meet antigen in pancreatic lymph nodes (PLN)
- Antigens delivered to PLN by dendritic cells
- Thus PLN is site where tolerance to pancreas is 1st broken down
150
What problems also links to type 1 diabetes?
- Alimentary problems
| - Enteroviruses (coxackie virus), gluten, coeliac disease
151
When does lymphocyte access to PLN occur?
During infancy
152
What does altering the status of the gut also alter?
Insulitis
153
What are the different types of pathological classifications?
- Inherited/Acquired
- Infections (viruses, bacteria etc)
- Inflammation (vasculitis, paraneoplastic, idiopathic, MS)
- Toxic (drugs, chemicals etc)
- Metabolic (DM, vitamin deficiency, thyroid problems etc)
- Degenerative
- Trauma
154
What are the 3 problems of relying on pathology?
1. Sampling error
2. Accessibility of tissue
3. Often tissue only available late in disease process (post-mortem)
155
What are "Dawson's fingers"?
- Pattern of plaques in the brains of people with multiple sclerosis
- Located around ventricles
156
Describe the pathology of Multiple Sclerosis?
- An inflammatory, demyelinating disease of the CNS
- Demyelinating lesions of MS, called plaques, appear as indurated areas
- Absence of inflammation at edge of chronic lesions
157
What are the 4 different classifications of Multiple Sclerosis?
1. Relapsing-remitting MS: ~85% of cases
2. Secondary progressive MS
3. Primary progressive MS
4. Progressive-relapsing MS
158
What can relapsing-remitting MS go on to develop into after many yrs?
Secondary progressive
159
Is Multiple Sclerosis related to genes or environment?
BOTH (polygenic disease)
160
Describe the relationship of vitamin D & MS?
- Prospective studies shows vitamin D deficiency prior to MS onset predisposes to increased risk of MS (geography & sunlight)
- In RRMS every 10ng/mL increase in vitamin D level there's a 34% decrease in rate of subsequent relapse
- Vitamin D supplementation & disease activity in RRMS
161
What can Vitamin D be used as?
Immunomodulator
162
What are virtually all subjects with Multiple Sclerosis (>99%) infected with?
EBV compared to only ~90% of control subjects
163
Describe the pathology of Alzheimer's disease?
- Neurofibrillary tangles
| - Amyloid plaques
164
Describe the pathology of Parkinson's disease?
Lewy body present in dopaminergic neurons leading to loss in substantial nigra
165
What causes peripheral neuropathy?
Axonal degeneration (diabetes, toxic, demyelination)
166
List the potential causes of peripheral neuropathy (common, acquired)?
- Diabetes
- Idiopathic
- Toxic (alcohol, drugs)
- Vitamin Deficiency (B12)
- Post-infectious (Guillain-Barre syndrome)
- Paraneoplastic
- Leprosy
- Amyloid, inflammation (e.g. vasculitis)
167
What is Charcot-Marie Tooth?
- Inherited conditions that damage peripheral nerves
- Also known as hereditary motor & sensory neuropathy (HMSN)
- Progressive
168
What are the consequences of Sural nerve biopsy?
- Loss sensation
| - 30% have neurpathic pain
169
What is slow twitch (I) fibres innervated by?
- Alpha 2 motor neurons
| - Smaller of the 2 α motor neurons
170
What is fast twitch (II) fibres innervated by?
- Alpha 1 motor neurons
- Larger of the 2 α motor neurons
(higher excitation threshold & faster conduction velocity)
171
What is the size principle?
Motor neurons recruited in order of size
172
Describe the motor unit recruitment (size principle)?
- 1st: Smallest alpha motor neurons (α2) slow twitch
| - Last: Largest alpha motor neurons (α1) belong to fast twitch
173
Describe the staining properties of slow twitch (type I)?
Myosin isoforms with low ATPase activity
174
Describe the staining properties of fast twitch (type II)?
Myosin isoforms with high ATPase activity that promotes rapid breakdown of ATP for energy of high-speed muscle shortening
175
Describe the distribution of muscle fibre types?
- All muscle composed of slow & fast twitch fibres
- Most individuals possess between 45-55% slow twitch
- Mosaic pattern
176
Where would you do a muscle biopsy?
- Under LA
- Usually deltoid, quadriceps or tibias anterior (muscle & nerve)
- Done CPK & EMG 1st
177
List 5 different types of inherited muscle diseases?
1. Dystrophies (degen & regen)
2. Congential myopathies (no regen)
3. Mitochondrial
4. Metabolic
5. Myotonic
178
List 5 different types of acquired muscle diseases?
1. Inflammatory (polymyositis/dermato)
2. Toxic (alcohol, simvastatin)
3. Metabolic (Cushing’s)
4. Disuse atrophy
5. Rhabdomyolysis
179
What is Duchennes muscular dystrophy caused by?
Absence of dystrophin, a protein that helps keep muscle cells intact
180
What is the inheritance of Duchennes muscular dystrophy?
X-linked recessive
181
What is Psychosis?
Any disorder so severe that the victim loses contact with reality
182
List 5 different disorders which are associated with psychosis?
1. Schizophrenia
2. Bipolar disorder
3. Dissociative identity disorder (split personality)
4. Schizoaffective disorder
5. Persistent delusional disorders
183
How common is Schizophrenia?
1% of World population
184
When are the usual ages for diagnosis of Schizophrenia?
- Men early 20s
| - Women late 20s
185
Give 4 statistics for Schizophrenia disorder occurrence & its affects on people?
- 20% who have 1st episode recover
- 80% suffer either another acute episodes or more chronic condition
- 10% successfully commit suicide
- 19% diagnosed are employed
186
List the (positive & negative) symptoms of Schizophrenia?
- Pervasive thought disturbance
- Difficulty ignoring irrelevant stimuli (external/internal)
- Cognitive deficits
- Withdrawal from personal contact
- Delusions
- Hallucinations
- Emotional disorder
- Behavioural disruption
187
Describe the pattern of Schizophrenic symptoms?
- Episodic
| - Lack of insight
188
Describe what is needed to diagnose Schizophrenia?
- 2 Characteristic symptoms for significant time during 1 month
- OR, 2 Less specific symptoms & social/occupational dysfunction & duration of symptoms (1 month)
189
According to DSM-5 what are the 5 characteristics symptoms for diagnosing Schizophrenia?
1. Delusions
2. Hallucinations
3. Disorganised speech
4. Grossly disorganised or catatonic behaviour
5. Negative symptoms (reduced emotional expression)
190
According to ICD-10 what are the main characteristic symptoms for diagnosing Schizophrenia?
- Thought echo/ insertion/ withdrawal/ broadcasting
- Passivity, delusional perception
- Voices commenting or discussing
- Persistent bizarre delusions
191
According to DSM-5 & ICD-10 what exclusions are there for diagnosing Schizophrenia?
- Dominant mood symptoms
- Schizoaffective disorder
- Physiological effects of substance misuse (drug intoxication/ withdrawal)
- Organic causes
- Overt brain disease
192
What cognitive deficits are there in Schizophrenia? (executive functions)
- Sustained attention
- Planning
- Verbal & visuospatial working memory
- Language skills
- Explicit learning & memory
- Perceptual/ motor processing
193
Describe the delusional symptoms of Schizophrenia?
- Ideas of reference/ changes in salience
| - Delusional system
194
What type of hallucination occurs in Schizophrenia?
Auditory
195
Describe the behavioural disruption symptoms of Schizophrenia?
- Catatonic
| - Disorganised
196
What are the 6 subtypes for Schizophrenia?
| changed in DSM-5 to domains, gradients & dimensions
1. Cataonic
2. Disorganised (Hebephrenic)
3. Paranoid
4. Simple
5. Undifferentiated
6. Residual
197
What are the causes of Schizophrenia?
Deficits in ability to keep thoughts & actions on track:
- Genetics
- Physiological
- Anatomical
- Psychosocial
198
Describe the potential physiological causes of Schizophrenia?
- Dopamine hypothesis (classical antipsychotic, overstimulation)
- Dopamine-serotonin interaction hypothesis (atypical antipsychotics)
- Acetylcholine?
- Glutamate?
- GABA?
199
Describe the anatomical reasons of Schizophrenia development?
- Reduction in global brain volume (hypoxia at birth)
- Neuronal displacement
- Abnormally sized neurones (in areas associated with corticostriatal-thalamic loop)
200
Describe the potential psychosocial causes of Schizophrenia?
- Social class
- Minority position
- Urban environment
- Family environment
- Cannabis use?
201
What is the Diathesis model for Schizophrenia?
Vulnerability - Stress
202
What are the 2 types of drug therapies for Schizophrenia?
1. Classical antipsychotics
| 2. Atypical antipsychotics
203
List the 3 possible psychological interventions for Schizophrenia?
1. Family intervention
2. Cognitive behaviour therapy
3. Social-skill training
204
List the ways of early intervention & assessment of Schizophrenia according to NICE?
- Psychiatric
- Medical
- Physical
- Psychological
- Developmental
- Social
- Occupational & educational
- QOL
- Economic
205
What is the NICE recommended treatment for 1st episode of Schizophrenia?
Oral antipsychotic medication with psychological intervention (family intervention & individual CBT)
206
What does NICE say to "offer" for continuing treatment & care for Schizophrenic patients?
- CBT to promote recovery (esp. persistent symptoms/ remission)
- Family intervention
- Consider depot/long-acting antipsychotic medication if patient prefers it after acute episode/to avoid covert non-adherence as a clinical priority
- Monitor physical health regularly, esp. potential side effects
207
Give 3 % statistics for the dependency outcome of Schizophrenic patients?
1. Independent- 30%
2. Relatively dependent- 50%
3. Highly dependent- 20%
208
What does activation of nuclear receptors induce?
New protein synthesis which produce physiological effects
209
Where is especially is some of the T4 converted to T3 (thyroid hormones)?
In kidney & liver
210
Describe actions of T3 (thyroid hormone) on the body's growth system?
- Increase soft tissue growth
| - Increase bone maturation
211
Describe the action of T3 (thyroid hormone) on the body's Central nervous system?
Increase maturation of CNS
212
Describe actions of T3 (thyroid hormone) on the body's Basal metabolic rate (BMR)?
- Increase Na+/K+-ATPase
- Increase O2 consumption
- Increase heat production
- Increase BMR
213
Describe actions of T3 (thyroid hormone) on the body's Metabolism?
- Increase glucose absorption
- Increase glycogenolysis
- Increase gluconeogenesis
- Increase lipolysis
- Increase protein synthesis & degradation
214
Describe actions of T3 (thyroid hormone) on the body's cardiovascular system?
- Increase inotropic
- Increase chronotropic
- Increase cardiac output
215
What are the 2 common manifestations of hyperthyroidism?
1. Diffuse toxic goitre
| 2. Toxic nodular goitre
216
Describe a diffuse toxic goitre?
- Autoimmune disorder
| - Antibodies to TSH receptor stimulate thyroxine secretion
217
What is a toxic nodular goitre caused by?
Benign neoplasm/adenoma
218
What are the 6 causes of hyperthyroidism?
1. Graves disease (LATS/TSI)
2. Overtreatment with thyroxine
3. Thyroid/pituitary adenoma (rare)
4. Transient neonatal thyrotoxicosis (mother with Graves disease)
5. Inflammation of thyroid/thyroiditis
6. Excess iodine in diet (very high- hypothyroidism)
219
What are the investigations to assess hyperthyroidism?
- Measure blood TSH, free T3 & T4 levels
- Test for anti-thyroid antibodies (esp. TSH
receptors antibodies)
- Radionucleotide thyroid scan (123I- or 99mTcO4 -uptake) viewed by a gamma camera
220
What are the 3 treatment modalities for thyroid disorders?
1. Radioactive iodine
2. Anti-thyroid drugs
3. Surgery
221
What are the negatives for the current 3 treatment modalities for thyroid disorders?
- None is optimal
- None interrupts the autoimmune process
- Each has a drawbacks
222
How is radioactive iodine given to treat diseases of the thyroid (hyperthyroidism)?
- Radioiodine (131I) given orally & selectively taken up by thyroid
- Given as single dose & lasts about 2 months (Not during pregnancy/ lactation)
223
What does oral treatment of Radioiodine (131I) for hyperthyroidism do?
- Damages cells
- Emits short-range β radiation & affects only follicle cells
- Hypothyroidism will eventually occur (replacement therapy)
224
What 4 potential drugs can you use to treat hyperthyroidism?
1. Thioureylenes (thioamides), Carbimazole (methimazole) & propylthiouracil
2. Iodine
3. Beta-blockers (propranolol)
4. Calcium supplements
225
What is the function of Thioureylenes (thioamides), Carbimazole (methimazole) & propylthiouracil drugs for hyperthyroidism?
- Decrease synthesis of thyroid hormones
- Inhibit thyroperoxidase so reducing the iodination of thyroglobulin
- Acts over 3-4 weeks
226
What is the function of iodine drug for hyperthyroidism?
- Given orally in high doses & converted to iodide
- Transiently
reduces thyroid hormone secretion & vascularity of gland
227
What is the function of calcium supplement drugs for hyperthyroidism?
Maintenance of normal bone density because parathyroid hormone demineralises the bone
228
What is the thiocarbamide group in thioamides essential for?
Antithyroid activity
229
What does hypothyroidism lead to in children?
Cretinism
230
What is hypothyroidism also known as?
Myxedema
231
Describe the process of Myxedema in hypothyroidism/ hyperthyroidism?
Accumulation of increased amounts of hyaluronic acid & chondroitin sulphate in the dermis of both lesioned & normal skin, causing swelling/puffiness of subcutaneous tissue
232
What 4 things can potentially cause decreased thyroid hormone levels?
1. Low T4
2. Possibly low T3 too
3. Raised TSH (test with protirelin)
4. Possibly various anti-thyroid antibodies
233
What are the 6 potential etiologies for congenital hypothyroidism?
1. Hypoplasia (agenesis/dysgenesis)
2. Familial enzyme defects (dyshormonogenesis)
3. Iodine deficiency (endemic cretinism)
4. Intake of goitrogens during pregnancy
5. Pituitary defects
6. Idiopathic
234
Describe the effects of newborns with congenital hypothyroidism?
- May have few/no clinical manifestations of thyroid deficiency
- Longer the condition goes undetected the lower the IQ
235
What are the 6 potential aetiologies for acquired hypothyroidism?
1. Iodine deficiency
2. Auto-immune thyroiditis
3. Thyroidectomy or RAI therapy
4. TSH or TRH deficiency
5. Medications (iodide & cobalt)
6. Idiopathic
236
What is the most common cause of hypothyroidism?
Hashimoto's disease
237
Describe Hashimoto's disease?
- Autoimmune lymphocytic thyroiditis
- Females > Males
- Runs in families
238
What are the 3 different anti-thyroid antibodies involved in Hashimoto's disease?
1. Thyroglobulin Ab
2. Microsomal Ab/Thyroid peroxidase (TPO) Ab
3. TSH-R Ab (blocking antibodies)
239
What are the 2 possible treatments for hypothyroidism?
1. Levothyroxine
| 2. Liothyronine
240
Describe Levothyroxine & what it's used for?
- Synthetic analogue of
thyroxine
- Has all the actions of endogenous thyroxine
- Standard T4 replacement therapy for hypothyroidism
241
Describe Liothyronine & what it's used for?
- Synthetic analogue of triiodothyronine
- Has all the actions of endogenous triiodothyronine
- Treatment of choice for myxedema coma
242
What is a Myxedema coma?
Extreme form of hypothyroidism compounded by some stressful state such as infection, myocardial infarction or stroke
243
In Graves disease what are the symptoms limited to?
Pretibial myxedema (only 1-5% of patients)
244
Why do we need statistics to interpret evidence?
Because of variability between people (side effects, effectiveness of treatment) & within people (BP, strength of left & right hands)
245
What are the 3 different ways of calculating risk?
1. Absolute risk reduction (ARR)
2. Relative risk (RR)
3. Number needed to treat (NNT)
246
What are the 2 types of Numerical data?
1. Continuous ie. height, BP
| 2. Discrete ie. no. of children in family, no. of hand nodes
247
What are the 2 types of Categorical data?
1. Ordinal ie. social class, pain severity
| 2. Nominal ie. marital status, blood group
248
What 3 different types of data are used for calculating an average (central tendency)?
1. Mean
2. Median
3. Mode
249
What are the 2 different types of data used to show variability?
1. Standard deviation
| 2. Inter-quartile range
250
Describe what the mean uses?
All data but can be influenced by outliers
251
Describe what the median uses?
Not influenced by outliers, but doesn't use all data (less informative)
252
What are the 3 types of graph distribution for data (mean, median, mode)?
1. Negatively skewed
2. Normal (no skew)
3. Positively skewed
253
What is the equation to calculate risk?
Number with disease/ Total number at risk
254
What is the equation to calculate Absolute Risk reduction (ARR)
Risk group 1 - Risk group 2
255
What is the equation to calculate Relative risk (risk ratio)?
Risk group 1/ Risk group 2
256
What is the equation to calculate number needed to treat (NNT)?
1/ARD proportion
257
What is relative risk independent of?
The original prevalence
258
Since relative risk can be misleading, what should you always state?
Baseline absolute risks as well as relative risks
259
When is the odds ratio used?
- Case-control studies
- Observational studies
- Regression models
260
What is the equation for odds ratio?
Cases or controls with exposure/ Cases or controls without exposure
261
What is the odds ratio if odds are equal in case & control group?
OR= 1
262
If events are rare, then what is odds ratio a good approximation to?
Relative risk (RR)
263
What is population in evidence?
Theoretical concept to describe the group of individuals of interest to the research question
264
What is the sample in evidence?
- Preferably random sample, that is representative of the population in which we are interested
- Usually smaller than population in which we are interested
265
What do we use the mean, relative risk & prevalence of the sample to estimate?
"True" mean/relative risk/proportion of the population
266
When do we have more confidence in results of a sample?
If the sample is LARGE
267
What is the standard error of the mean (SE)?
Measure the variability of the sample means
268
What does a large standard error of the mean (SE) indicate?
- Much variability in sample means
| - Many lie a long way from the population mean
269
What does a small standard error of the mean (SE) indicate?
Not much variability between the sample means
270
Why is standard error of the mean (SE) always SMALLER than standard deviation (SD)?
Because there is less variability between sample means than between individual values
271
What does larger samples lead to?
Smaller standard error of the mean (SE)
272
What does a confidence interval give?
A range of values, estimated from sample data, which is likely to include the, unknown, population parameter (mean)
273
What is a 95% confidence interval?
- Range of values within which we are 95% confident the true population mean lies
- Sample mean +/- 1.96*SE
274
What is the confidence interval good for?
Making decisions about whether observed differences are likely to be due to chance alone, or likely to be a true effect
275
What is a null hypothesis?
No significant difference between specified populations, any observed difference being due to sampling or experimental error.
276
What is an alternative hypothesis?
Statistical significance/ difference between two variables
277
Where/How does the pancreas develop?
As an out growth of the gut tube, closely associated with gall bladder development
278
What are the endocrine functions of the pancreas?
Islets of Langerhans produce hormones (glucagon, insulin, somatostatin, pancreatic polypeptide)
279
What is the weight of the endocrine pancreas?
Less than 2% of the total mass of the pancreas
280
What do the A (α, α2) cells of the endocrine pancreas synthesis?
Glucagon
281
What do the B (β) cells of the endocrine pancreas synthesis?
Insulin
282
What do the D (α1, γ, δ) cells of the endocrine pancreas synthesis?
Somatostatin
283
What are the exocrine functions of the pancreas?
Pancreatic acini produce pancreatic amylase etc.
284
Describe the anatomy of the Islet of Langerhans in the pancreas?
- α cells around the periphery
- δ & β cells at the centre
- Blood flows from the centre to the periphery
285
Describe the 4 steps of synthesis & processing of insulin?
1. Insulin mRNA translated as single chain precursor (preproinsulin) & removal of signal peptide during insertion into endoplasmic reticulum generates proinsulin
2. Proinsulin has amino-terminal B chain, carboxy-terminal A chain & connecting C peptide
3. Within endoplasmic reticulum, proinsulin exposed to endopeptidases which excise C peptide, generating mature insulin
4. Insulin & free C peptide packaged in Golgi into secretory granules which accumulate in cytoplasm
286
What chain reaction does absorption of food in the GI tract cause?
Increase blood glucose --> β cells stimulated --> Insulin release --> Physiological actions
287
What 6 factors potentiate β cell's producing insulin release once there is an increased blood glucose?
1. α cell producing Glucagon
2. Free fatty acids
3. GI tract hormones/ incretins/ GIP/ GLP-1/ CCK
4. Certain amino acids
5. Parasympathetic stimulation (Ach)
6. β adrenergic stimulation (Adrenaline)
288
What 3 factors inhibit β cell's producing insulin once there is an increased blood glucose?
1. α adrenergic stimulation (Noradrenaline)
2. δ cells producing somatostatin
3. Autocrine effects of insulin
289
Describe the 7 steps to the mechanism of insulin release from the pancreatic β cell?
1. Glucose enters cell via GLUT2 transporter (facilitated diffusion)
2. Glucose metabolism leads to increase [ATP]i or [ATP]i/[ADP]i
3. Increased [ATP]i &/or [ATP]i/[ADP]i inhibits an ATP-sensitive K+ channel
4. Causes Vm to become more positive (depolarisation)
5. Actives voltage-gated Ca2+ channel in plasma membrane
6. Ca2+ influx & increased [Ca2+]i which evokes Ca2+-induced Ca2+ release
7. Elevated [Ca2+]i leads to insulin exocytosis & release into blood
290
What insulin's action of increased protein synthesis effect?
Growth & maintenance
291
What chain reaction does absorption of a high protein meal in the GI tract OR starvation cause?
Decreased blood glucose --> α cell stimulation (because there is no insulin inhibition) --> Glucagon --> Physiological actions
292
What are the 3 physiological actions of insulin?
1. Increased protein synthesis (most tissues)
2. Increased glycogenesis (liver, muscle)
3. Increased lipogenesis (liver & adipose tissue)
293
What is the chain reaction for insulin increasing glycogenesis?
Increased glycogenesis --> Increased glucose transport into cells (muscle/adipose tissue) --> Decreased blood glucose
294
What 5 factors potentiate α cells producing glucagon?
1. GI tract hormones
2. Certain amino acids
3. Parasympathetic stimulation (Ach)
4. β adrenergic stimulation (Adrenaline)
5. α adrenergic stimulation (Noradrenaline)
295
What 2 factors inhibit α cells producing glucagon?
1. β cell producing insulin
| 2. δ cell producing somatostatin
296
Where do the physiological actions of Glucagon predominate?
In the liver
297
What is the physiological actions of glucagon with no insulin?
- Decrease lipogenesis
- Increased lipolysis
(increased fatty acids & glycerol)
298
What is the main physiological action of glucagon?
Increased glycogenolysis (via raising cAMP) --> Increased blood glucose
299
What is the physiological action of glucagon with cortisol?
Increased gluconeogenesis
300
How common is Diabetes Mellitus?
2-3% of the population although higher in 50-60 year olds (15-20%) & within some races (African & Native Americans)
301
What 2 things does Diabetes Mellitus result from?
1. Insulin deficiency (5-10%)
| 2. Insulin insensitivity (>90%)
302
How much blood glucose is defined as hyperglycaemia?
>10mM or 180mg%
303
Describe the 3 main signs of hyperglycaemia?
1. Glucosuria- tubular fluid exceeds renal threshold for re-absorption
2. Polyuria- osmotic diuresis due to glucose in tubular fluid
3. Polydipsia- dehydration increasing angiotensin II levels which act as dipsogen on thirst centres in brain
304
What is type 1 Diabetes Mellitus?
Insulin dependent diabetes mellitus (IDDM/ Juvenile-onset DM)
305
What is increased blood FFA & glycerol in Diabetes Mellitus due to?
Increased lipolysis in adipose tissue
306
What is ketoacidosis in Diabetes Mellitus due to?
Incomplete oxidation of fatty acids & ketogenic amino acids
307
Describe the cause of type 1 Diabetes Mellitus?
Destruction of pancreatic beta cell (autoimmune disease after viral attack esp. Coxsackie B virus)
308
Describe the treatment of type 1 Diabetes Mellitus?
- Insulin administration (IM injections of short/long acting formulations of recombinant human insulin)
- Restricted carbohydrate diet (<45% of total calorific intake)
309
What is type 2 Diabetes Mellitus?
Non insulin-dependent diabetes mellitus (NIDDM/ Maturity onset DM)
310
Describe the treatment for type 2 diabetes mellitus?
- Restricted diet (1000 callories per day)
- Sulphonyl ureas (increase beta cell response to glucose)
- Biguanides (stimulate glucose uptake in muscle)
- When uncontrolled: Insulin injection!
311
What is type 2 Diabetes Mellitus related to?
Obesity (relative inactivity & over eating)
312
What are the 6 acute effects of Diabetes Mellitus (insulin deficiency)?
1. Increased hepatic glucose output
2. Decreased glucose uptake by cells
3. Decreased triglyceride synthesis
4. Increased lipolysis
5. Decreased αα uptake by cells
6. Increased protein degradation
313
What does the acute effects of Diabetes Mellitus (insulin deficiency) eventually lead to if untreated?
Renal failure --> Death!!!
314
What 2 processes are increased during long term Diabetes Mellitus?
1. Fat metabolism
| 2. Blood glucose
315
What 2 things does loss of arterial compliance in long-term diabetes mellitus cause?
1. Diabetic atherosclerosis
| 2. Hypertension
316
What are the 3 common cardiovascular pathologies due to long-term diabetes Mellitus?
1. Angina
2. Cardiac arrhythmias
3. Renal disease
317
Describe the embryonic development of the thymus gland?
- Develops from 3rd pharyngeal pouch
| - Migrates inf to superior mediastinum & loses connection with larynx
318
What incase & colonise in the thymus gland?
Lymphoid thymocytes derived from bone marrow
319
What does the thymus control the development & "education" of?
T lymphocytes
