Health and Disease Week 22 Flashcards
(198 cards)
1
Q
What is the upper respiratory tract made up of?
A
nasal cavity, pharynx, larynx
2
Q
What are the main functions of the upper respiratory tract?
A
- humidifies and warms air
- defence
- sensory
- speech
3
Q
What is the lower respiratory tract made up of?
A
trachea, bronchi, lungs
4
Q
What are the main functions of the lower respiratory tract?
A
gas exchange, defence, controlling metabolic rate
5
Q
Which structures in the lower respiratory tract have cartilage?
A
the walls of the trachea and bronchi
6
Q
What are the bronchi and bronchioles surrounded by?
A
smooth muscle to keep them open
7
Q
What are the 2 zones of the lower respiratory tract?
A
- conducting zone
- respiratory zone
8
Q
define the conducting zone
A
the part of the respiratory system that warms, moistens and filters air as it moves into the lungs
9
Q
Where does the conducting zone include?
A
trachea, bronchi, bronchioles, terminal bronchioles
10
Q
What is the function of the conducting zone?
A
- pathway for airflow
- defence against pathogens and particulates
- warms and moistens air
11
Q
Where does the respiratory zone include?
A
respiratory bronchioles, alveolar ducts and alveolar sacs
12
Q
What is the function of the respiratory zone?
A
gas exchange
13
Q
define airway resistance
A
the resistance to the flow of air through the respiratory tract during inhalation and expiration
14
Q
What is the airway resistance largely affected by?
A
the diameter of the airway
15
Q
How does the radius of the airway affect airway resistance?
A
as radius decrease, resistance increases
16
Q
Do single or multiple airways provide more resistance?
A
single - so single large to medium sized airways provide more resistance to flow than numerous small airways
17
Q
Which zone provides the largest resistance to airflow?
A
the conducting zone bronchioles
18
Q
Why is the little resistance in the alveoli despite small diameter?
A
number of divisions is so high
19
Q
What is the equation for airway resistance?
A
airway resistance = 1 / conduction
20
Q
What is asthma?
A
when someone has intermittent episodes where the airway smooth muscle contracts, increasing airway resistance
21
Q
What makes the smooth muscle hyper-responsive in asthma?
A
chronic inflammation - as this causes strong contraction
22
Q
What are the causes of inflammation that cause asthma?
A
- allergies
- viral infections
- exercise particularly in cold, dry air
- tobacco smoke
- environmental pollutants
23
Q
What are examples of classes or drugs that are medications for asthma?
A
- anti-inflammatory drugs
- bronchodilators
24
Q
What do anti-inflammatory drugs do? What are examples?
A
reduce chronic inflammation - for example, beclomethasone, steroids
25
What do bronchodilators do? What are examples?
relax the airways and increase the diameter - for example, Salbutamol is a short-acting beta-2 adrenoceptor agonist
26
What parts of the respiratory zone do asthma medicines act on?
bronchi to bronchioles to increase their radius and decrease resistance to airflow
27
How does chronic inflammation lead to asthma?
1. causes a thickening of the airway walls
2. this reduces airflow and prevents mucus drainage
3. more mucus can increase the likelihood of infection, scarring and thickening of walls
4. can lead to collapse of airways if the walls begin to stick together
28
What type of cells make up the bronchi epithelium?
1. ciliated cells
2. goblet cells
3. glandular cells
29
What type of cells make up the epithelium of the bronchioles?
1. ciliated cells
2. non-ciliated cells
3. goblet cells
4. club cells
30
What type of cells make up the alveoli epithelium?
1. squamous cells
2. cuboidal cells
31
What 2 layers does a normal mucus film have?
1. the sol layer
2. the gel layer
32
What does the superficial gel layer contain?
chemicals, antibodies, immune cells
33
What adaptations do epithelial surface from the pharynx to the respiratory bronchioles have?
1. cilia
2. club cells - secrete substances such as surfactant proteins
3. goblet cells and glands
4. tissue-resident phagocytes
34
What causes 'smokers cough'?
smoking decreases the number of cilia and how active they are, so it is harder for cilia to get rid of mucus
35
What is another name for alveolar epithelial cells?
pneumocytes
36
What are the 2 types of pneumocytes?
type I cells and type II cells
37
What are the features of type I pneumocytes?
- squamous epithelial cells
- involved in gas exchange
- fused to capillary
38
What are the features of type II pneumocytes?
- cuboidal
- secretory, so secrete surfactant to prevent alveoli collapsing
- precursors for type I cells
39
Where is surfactant produced?
by the type II alveolar epithelial cells
40
What is the alveolar surfactant made up of?
lipids (mostly phospholipids) and proteins
41
What does surfactant do?
reduces surface tension of the alveoli and prevents them collapsing
42
What is it called when the alveoli collapse?
atelectasis
43
What is instilled into babies with Infant Respiratory Distress Syndrome when born premature? Why?
Beractant (Bovine) or Pumactant (synthetic, lipid only) as their lungs cannot produce surfactant
44
What is lung epithelium maturation stimulated by in premature babies?
corticosteroids
45
How do the lungs empty at birth?
there is a surge in corticosteroids and catecholamines to rapidly empty the lungs of fluid
46
What are the two circulatory systems supplying blood to the lungs?
1. pulmonary circulation
2. bronchial circulation
47
Where does pulmonary circulation flow from and to?
the pulmonary artery flows from the right ventricle to the lungs from the body
48
What are the features of blood arriving from the right ventricle?
low oxygen, high flow, low pressure
49
How does pulmonary circulation return blood to the body?
to the left of the heat via the pulmonary vein which eventually recirculates around the body via the aorta
50
How does blood from bronchial circulation arrive at the lungs?
it comes from the aorta
51
What are features of the blood arriving at the lungs from bronchial circulation?
high pressure, supplies oxygen and nutrients to keep the tissues alive
52
define ventilation
the movement of air from the environment into the lungs
53
How is ventilation controlled?
automatic and controlled by the CNS
54
How is breathing controlled by neurones?
the smooth muscles and the glands that make up the respiratory system are controlled mainly by the parasympathetic division of the autonomic nervous system
55
How are respiratory muscles innervated?
1. somatic motor nerves
2. autonomic nerves
3. sensory output
56
How do somatic motor nerves innervate respiratory muscles?
via the Phrenic nerve, somatic motor nerves innervate the SKELETAL muscles in the thorax such as the diaphragm
57
What do the autonomic nerves supply?
smooth muscles and secretory cells
58
Where do the autonomic nerves that control respiratory muscle innervation branch from?
the vagus nerve
59
Which neurotransmitters control respiratory smooth muscle innervation?
acetylcholine (excitatory/contraction) and nitric oxide (inhibitory/relaxation)
60
How are respiratory glands innervated?
by acetylcholine
61
Which neurotransmitters and receptors work in the sympathetic NS of smooth muscle and glands?
acetylcholine -> nicotinic receptor -> noreadrenaline -> adrenoceptor
62
Which neurotransmitters and receptors work in the parasympathetic NS of smooth muscle and glands?
acetylcholine -> nicotinic receptor -> acetylcholine -> muscarinic receptor
63
How do you know how to treat a pulmonary disease?
depends on what causes it e.g. inflammation, contractions, microbes etc
64
What are 2 classes of bronchodilators?
beta-agonists and muscarinic antagonists
65
What is an example of a beta-agonist? What does it treat?
Salbutamol - asthma and COPD
66
What is an example of a muscarinic antagonist? What does it treat?
Ipratropium - COPD
67
What is a class of drug that is anti-inflammatory?
glucocorticoids
68
What is an example of a glucocorticoid? What does it treat?
Budesonide - asthma, COPD
69
What is a drug class that is antimicrobial?
antibiotics
70
What is an example of an antibiotic used to treat respiratory disease?
Tobramycin - Cystic fibrosis
71
How do sensory afferent impulses reach the brain to impact the lungs?
they travel via the vagus nerve to the medullary centre
72
What are the 2 main types of myelinated stretch receptors in airway smooth muscle?
1. slowly adapting stretch receptors (SAR)
2. rapidly adapting stretch receptors (RAR)
73
What are 2 examples of reflexes elicited by SARs?
shortened inspiration and Hering-Breuer reflex
74
What is the Hering-Breuer reflex?
a protective mechanism that prevents over-inflation of the lungs by inhibiting inspiration and promoting expiration when lung stretch receptors are activated, mediated through the vagus nerve
75
What are the RARs stimulated by?
sudden, sustained irriation
76
What type of reflexes do RARs elicit?
cough, bronchoconstriction, mucus secretion
77
What are the main unmyelinated fibres in the sensory afferent pathways in the lungs?
pulmonary and bronchial C fibres
78
What is the main role of the C fibres?
detecting harmful substances and initiating protective reflexes
79
define exogenous
of external origin
80
define endogenous
of internal origin
81
What are examples of exogenous and endogenous stimuli that activate C fibre receptors?
endogenous - inflammatory agents that are generated by the body
exogenous - noxious (toxic) agents in the air
82
What are examples of protective reflexes that are initiated by C fibres?
reflex bronchoconstriction and mucus secretion
83
What are the steps of a cough reflex?
1. stimulation of irritant receptors
2. sensory nerves convey signal to medulla
3. motor nerves signal to skeletal muscles
4. glottis closes
5. abdominal and internal intercostal muscles contract rapidly
6. interpulmonary pressure rises
7. glottis opens
8. cough
84
What is the structure of the pleural membrane (membrane surrounding the lungs)?
it is a double membrane with pleural space between them
85
What is the pleural space filled with?
serous fluid
86
What is the function of serous fluid in the lungs?
lubricant to allow smooth contraction and relaxation
87
What happens when the diaphragm and external intercostal muscle contract?
1. increased lung volume
2. internal pressure falls
3. air moves into lungs
88
What helps expiration?
elastic recoil
89
What are 4 metabolic functions of the lungs?
1. regulation of blood pressure and hormones
2. inactivation of some hormones
3. clot prevention
4. detoxification
90
How are the lungs involved in blood pressure regulation?
1. lung endothelial cells contain angiotensin converting enzyme (ACE), which changes angiotensin I to Angiotensin II, activating it
2. bradykinin and serotonin are also affected by ACE
91
How do the lungs have a role in inactivating some hormones?
1. break down Prostaglandins E1, E2 and F2 alpha (inflammatory mediators)
2. and norepinephrine (a stress hormone that affects blood pressure)
92
How do the lungs have a function in clot prevention?
the lungs break down small clots in the circulation and prevent them travelling to the brain and causing strokes
93
What type of epithelial cells make up the trachea and bronchi?
ciliated columnar epithelial cells and goblet cells which secrete mucus
94
Which type of cells make up the epithelium of the bronchioles?
cuboidal epithelial cells and club cells instead of goblet cells which secrete defensive mediators
95
What is the primary purpose of the respiratory system?
gas exchange
96
What are other purposes of the respiratory system?
- regulation of acid-base stats by controlling CO2
- activation and deactivation of circulating mediatoes
- speech
97
What does PaO2 stand for?
partial pressure of arterial oxygen
98
What does PaCO2 stand for?
partial pressure of arteries CO2
99
What is the main controller of respiration?
the brainstem in the medulla
100
What is the medulla also known as?
the primary respiratory control centre
101
What is the main function of the respiratory centre in the medulla?
to send signals to the muscles that control ventilation
102
How do nerve impulses generated in the medulla cause contraction?
1. impulses travel through dorsal root into spinal cord
2. goes to motor neurones that induce contraction of respiratory muscles
103
Which type of cells send signals back to the medulla to stop inspiration when the lungs are full?
mechanoreceptors
104
What do chemoreceptors do?
sense O2, CO2 and pH levels in the blood and send input to the medulla which modified the rate and depth of breathing
105
Where is breathing controlled voluntarily?
in the cerebral cortex - but it is eventually overridden
106
What are the 2 types of mechanisms that regulate breathing?
1. neuronal control
2. chemical control
107
Where is neuronal control of respiration done?
the medulla
108
Where is chemical control of respiration done by?
the central and peripheral chemoreceptors
109
Which 2 respiratory centres exist in the medulla?
1. inspiratory centre
2. expiratory centre
110
What is the role of the inspiration centre?
it automatically generates impulses in rhythmic waves which travel to the respiratory muscles
111
Where do the respiratory centres also receive inputs from?
the periphery (vagus nerve) and the pons (from the pneumotaxic centre)
112
What do impulses from these places do?
begin to decreases the inspiration centre and there is a decrease in impulses to the respiratory muscles, to cause expiration - inspiration centre then becomes active again
113
What does the dorsal respiratory group control?
inspiration ONLY
114
What does the ventral respiratory group control?
BOTH inspiration and expiration
115
What are the 2 respiratory centres in the pons which work with the inspiration centre to produce a normal rhythm of breathing?
1. Apneustic centre
2. Pneumotaxic centre
116
What does the apneustic centre do?
it prolongs inhalation and is then interrupted by impulses from the pneumotaxic centre which contributes to exhalation
117
What does the pneumotaxic centre do?
inhibits the apneustic centre and controls rate of breathing
118
What will happen if you cut between the cortex and the pons?
- stops input from the cortex
- you will have a loss of voluntary control over breathing
119
What will happen if you cut between the medulla and the pons?
- you separate the pneumotaxic centre from the medullary centre
- you will have loss of feedback regulation from the pons
- breathing is more irregular but continues
120
What will happen if you cut between the medulla and the spinal cord?
- breathing stops
- there is no neuronal input from the midbrain brain
121
How does the cerebral cortex send signal to control breathing voluntarily?
sends impulses directly to the respiratory motor neurones
122
What do chemoreceptors do?
detect changes in blood gases and pH
123
Where are the chemoreceptors located?
in the carotid arteries, aortic bodies and medulla
124
What is a decrease in oxygen in the blood detected by?
peripheral chemoreceptors in the carotid and aortic bodies
125
What do the carotid and aortic bodies do when blood oxygen decreases?
generate sensory impulses and send them along the glossopharyngeal and vagus nerves to the medulla - this increase respiratory depth or rate
126
Why is too much CO2 in the body an issue?
too much lowers the pH when it reacts with water
127
Where are the central chemoreceptors located?
in the medulla - medulla reponds by increasing expiration
128
What do the chemoreceptors in the carotid and aortic bodies and medulla detect?
carotid and aortic bodies - decrease of oxygen
medulla - increase in CO2 or decrease in pH
129
Does blood CO2 or pH have a bigger influence on ventilation? Why?
- H+ and HCO3- do not easily cross the blood-brain barrier as charged
- CO2 does cross it
- CO2 dissociates in the cerebrospinal fluid
- blood CO2 has bigger effect than pH
130
What happens when O2 levels fall in peripheral control of respiration?
1. a fall in O2 stimulated the glomus cells in the carotid and aortic bodies
2. glomus cells close K+ channels causing depolarisation
3. dopamine is also released from glomus cells, which stimulates the afferent fibres which send a nerve impulse to the medulla
131
What are the features of haemoglobin?
- a tetramer
- has 4 oxygen-binding haem groups
- 2 alpha subunits and 2 beta subunits
- haem molecules each contain a single iron atom
132
What is unique about oxygen binding?
the binding of one oxygen molecule to haemoglobin increases the affinity for the next molecule of oxygen to bind
133
How does oxygen diffuse into the tissues?
1. blood gets oxygenated by the lungs
2. when reaching peripheral tissues, the PO2 in the capillaries are about 95 mmHg and PO2 in interstitial fluid is about 40 mmHg
3. the large pressure difference causes oxygen to diffuse rapidly from the capillary
4. oxygen is used in the mitochondria and PO2 drops to about 40 mmHg
134
What are the steps of oxygen release in the tissues?
1. when metabolic rate increases, so does carbon dioxide waste production
2. the pH of the blood decreases
3. this promotes the dissociation of oxygen from haemoglobin
135
What is myoglobin?
an iron and oxygen binding protein found in skeletal and cardiac muscle
136
What are features of myoglobin?
- higher affinity for oxygen than haemoglobin
- does NOT have cooperative binding
- binds with a single oxygen moelcules
- affinity is NOT affected by pH or CO2 - so it can capture oxygen released by haemoglobin
137
Why is pH important in blood?
as blood pH falls, the blood becomes more acidic and oxygen will not bind to haemoglobin, which is very important for tissue delivery
138
What are the 3 ways CO2 is transported?
1. as HCO3-
2. as dissolved CO2 in plasma
3. as carbaminohaemoglobin (HbCO2)
139
Which enzyme converts carbonic acid into H+ and HCO3-?
carbonic anhydrase
140
How is an increase in CO2 detected?
1. CO2 production increases
2. the CO2 in the cerebrospinal fluid increase and dissociates
3. H+ is detected by central chemoreceptors in the medulla
141
How is the charge maintained inside red blood cells?
newly synthesised bicarbonate ions are transported out of the red blood cells into the plasma in exchange for a chloride ion - CHLORIDE SHIFT
142
What type of cell is the alveolus wall formed from?
very thin, unciliated squamous epithelial cells - mostly type I with a few type II
143
What is the Haldane effect?
when oxygenation of blood in the lungs displaces CO2 from haemoglobin increasing removal of CO2
144
What does oxygenated blood have a reduced affinity for?
CO2
145
What does the Haldane effect describe?
the ability of haemoglobin to carry increased amounts of CO2 in the deoxygenated state as opposed to the oxygenated state
146
What are the 3 main physiological responses to low inspiration of oxygen (for example at high altitude)?
1. increased ventilation (not sustained)
2. pulmonary vascoconstriction (rapid and sustained)
3. increased haemotocrit
147
What is increased ventilation driven by?
peripheral chemoreceptors
148
What is the aim of pulmonary vasoconstriction?
1. push blood away from poorly ventilated areas to alveoli with higher oxygen content
2. as the alveoli with higher oxygen content will provide a higher oxygen gradient, and oxygen can move into the blood
149
How is haemotocrit increased?
1. decreased oxygen levels activate the transcription factor HIF (hypoxic inducible factor)
2. HIF regulates the transription of the gene to make erythropoietin
3. erythropoietin is produced by the kidneys and it stimulates the bone marrow to make red blood cells
4. this increases haemotocrit
150
What are the 2 types of altitude sickness?
1. acute mountain sickness
2. chronic mountain sickness
151
What are the causes of acute mountain sickness?
lowlanders moving rapidly to altitude over 2500m
152
What are the symptoms of acute mountain sickness?
- flu-like symptoms
- breathlessness
- hypoxic pulmonary vasconstriction
- pulmonary and cerebral oedema
153
What is cerebral oedema?
when fluid leakage causes swelling in the brain - can lead to coma
154
What are the physiological changes caused by chronic mountain sickness?
1. low PO2 that cannot be matched by ventilation
2. increased erythropoietin production in kidneys
3. too high haemotocrit
4. increased load on right side of heart
155
What does too high haematocrit lead to?
excessive levels of red blood cells lead to viscous blood and may cause blood clots, strokes and heart attack
156
What does increased load on the right side of the heart lead to?
1. more viscous blood increases pulmonary artery pressure
2. right side of the heart has to work harder to pump blood around
3. over time this may lead to right-sided heart failure
157
What is a treatment used from chronic mountain sickness?
acetazolamide
158
What does acetazolamide do?
1. inhibits carbonic anhyrase
2. this reduces HCO3- production, leading to mild acidosis
3. acidosis stimulates more ventilation and inhibits kidney EPO production
4. prevents excessive RBC production
159
What are the adaptations of Tibetans?
they can maintain a sustained increase in ventilation
160
What is an adaptation of Andeans?
they have higher haematocrit - this could be due to mutations in the HIF signalling pathway
161
What is the main different between Tibetans and Andeans?
1. Tibetans are hypoxemic compared with Andeans
2. this means they have lower oxygen levels in the blood at altitude
162
How do high altitude populations have adapted muscles and tissues?
their tissues and muscles are adapted to better use oxygen
1. they have increased muscle capillaries
2. high myoglobin levels
3. myoglobin gene polymorphism
163
Why are higher myoglobin levels important?
it is a protein that binds oxygen and stores it for later, so more is available when oxygen is low
164
What does the myoglobin gene polymorphism cause?
allows myoglobin to store oxygen more efficiently
165
Why do East Africans have more genetic diversity than Tibetans or Andeans?
the highland population were established much earlier
166
Why are East Africans so good at endurance sports?
they have access to high altitude training to improve their endurance by increasing RBC numbers, contributing to their success in long-distance running
167
What is the most important buffer in the body?
the HCO3-/CO2 system
168
How do chemoreceptors and the lungs maintain CO2 levels?
by ventilation
169
How do the kidneys maintain HCO3- levels?
by filtering or generating HCO3- and secreting H+
170
What type of enzyme is carbonic anhydrase?
a zinc metalloenzyme
171
What are the 2 main types of carbonic anhydrase?
1. cytosolic-located CA
2. membrane-located CA
172
What is the equation for pH in the body?
pH = 6.1 + log (HCO3- / 0.03 x PCO2)
173
What does this equation show?
that changes in HCO3- or CO2 levels changes the pH
174
In which 3 ways is CO2 transported from tissues?
1. dissolved in plasma and red blood cells
2. carbaminohaemoglobin
3. forms carbonic anhydrase then H+ and HCO3-
175
How is CO2 transported to the lungs?
1. loss of CO2 from alveoli causes the equilibrium position to move and more CO2 is generated when HCO3- combines with H+
2. loss of CO2 from blood causes the dissociation of Hb to release more CO2
3. CO2 is expired
176
How are H+ ions transported between the tissues and blood?
1. oxyhaemoglobin loses oxygen into tissues and CO2 enters blood to form HCO3- and H+
2. deoxyhaemoglobin is generated at the tissues
3. deoxyhaemoglobin has a higher affintiy for H+ than oxyhaemoglobin so it binds most of the H+ generated
177
How is H+ transported between the blood and lungs?
1. blood flows through the lungs
2. deoxyhaemoglobin binds to oxygen to form oxyhaemoglobin
3. H+ reacts with HCO3- to generate CO2 and H2O
4. CO2 is expired
178
Where are the peripheral chemoreceptors found?
- in the neck in the carotid bodies
- in the thorax at the arch of the aorta - aortic bodies
179
Where are the central chemoreceptors found?
in the medulla
180
What does H+ activate?
only really peripheral chemoreceptors as it cannot quickly pass the blood brain barrier
181
How do the kidneys regulate bicarbonate levels?
1. reabsorption of filtered HCO3-
2. production of new HCO3-
182
Where is HCO3- reabsorbed in the kidneys?
1. proximal convoluted tubule
2. loop of Henle
3. collecting duct
183
What else can the collecting duct do with HCO3-?
secrete HCO3-
184
What is the equation for renal HCO3- excretion?
(HCO3- filtered + HCO3- secreted) - HCO3- reabsorbed
185
Where is intracellular renal carbonic anhydrase found?
inside red blood cells and the kidney epithelial cells lining the tubules
186
Where is extracellular renal carbonic anhydrase found?
in the brush border surface of epithelial cells in the kidneys
187
How is filtered HCO3- rebabsorbed?
1. HCO3- is filtered by the kidneys
2. HCO3- combines with H+ to form carbonic acid then CO2 and H2O in the tubule
3. HCO3- formed in the tubule cells is reabsorbed into the blood - so this replace that filtered
188
How are bicarbonate levels increased?
1.H+ formed in the tubule cells combines with phosphate instead of HCO3- to preserve HCO3-
2. the product is excreted by the kidneys
3. HCO3- produced in the tubule cells is reabsorbed into blood
4. net gain of HCO3-
189
How are HCO3- levels increased by glutamine metabolism?
1. glutamine is metabolised to ammonia and HCO3- in tubule cells
2. ammonia is excreted into tubules then urine
3. HCO3- is rebabsorbed into blood
4. net gain of HCO3-
190
What happens when the body is in acidosis?
1. pH is too low - too much H+
2. the kidney will excreted H+ into urine and reabsorb more HCO3-
191
Which type of kidney cell functions in acidosis?
Type A intercalated cells in the collecting duct
192
What happens in alkalosis?
1. pH is too high - too little H+
2. the kidney excretes K+ and HCO3-
3. H+ is reabsorbed into the blood
193
Which type of kidney cells function in alkalosis?
type B intercalated cells in the collecting ducts
194
What does respiratory acidosis lead to?
hypoventilation
195
What does respiratory alkalosis lead to?
hyPERventilation
196
What is the renal response to acidosis?
1. sufficient H+ is secreted to reabsorb the filtered HCO3-
2. more H+ is secreted into tubules and combines with the filtered HCO3- in the plasma
3. tubular glutamine metabolism and ammonium secretion is increased to increase bicarbonate in the plasma
4. newer HCO3- is added to the blood and plasma HCO3- is increased
197
What is the renal response to alkalosis?
1. the amount of H+ secretion is not enough to reabsorb all the filtered bicarbonate
2. excess bicarbonate is excreted in urine
3. decreased tubular glutamine metabolism and ammonium excretion
4. so HCO3- in plasma is decreased
198
