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1

Galen's four humor theory of disease

Blood
Black bile
Yellow bile
Phlegm
how all diseases come from inside you so it created a huge step backwards as it shifted an outward causality for diseases to an inward = less hygiene etc.

2

John Snow

London Cholera mapping

3

Crudelli & Klebs

identify bacillus rods

4

Alphonse Laveran

stepped away from slide and sees exflagellation stage, cooled blood

5

George sternburg

can't duplicate Crudelli & Krebs, same results in rabbits with spit

6

patrick manson

identifies mosquito vector for worm but only thought they took one blood meal and that dead mosquitos must release microbes in water

7

ronald ross

can't prove mosquito water, doesn't like ecologists; later discovers Anopheles mosquitos and prove mosquitos have malaria

8

Bignai & grassi

ask malaria victims about what they do to prevent, convinced of mosquito vector; get first credit

9

robert koch

creates koch's postulates and describes acquired immunity in malaria

10

domenico falleroni

collects mosquito eggs and notices 2 different types = 2 different mosquitos

11

Anopholism without malaria arguments

Malaria cases where there are not Anopheles mosquitos

12

Rome History

surrounded by pontine marshes and campagna = regular exposure and partial immunity; northern invaders die = malarial moat; houses faced inward. Atroparvus mosquito species keeps invading species out but it's a good vivax vector and bad falciparum vector. Cut oak forest down, mosquitos from Africa colonize and are good falciparum vectors; adapts to cold winters by moving indoors. Stable transmission is interrupted = loss of immunity = INC falciparum

13

Scotland History

sailed to Panama; slaughtered by malaria; bankrupted; England paid their debts and not independent anymore

14

Americas

import slaves with falciparum = INC mortality for whites = INC need for more slaves; Europeans bring malaria to vulnerable Native Americans; Punctipennis mosquito is dominant in New England and prefers animals, bad falciparum vector. People start using mill dams for power = start building dams to make mill ponds to power water wheels. Quadramaculatus mosquito is favored in this condition; war brings soldier with vivax home and lives close to mill dams = malaria spread; association of mill dam ponds with malaria; finally take dams down

15

Africa

malaria repels European invaders

16

Spanish

import slaves with falciparum causing spread to Panama

17

Bantu events

- Before Bantu: cold temps, wandering hunter/gatherers = irregular exposure and low population density; also forest floors have less mosquito habitat
- Sahara desert formed and Bantu moved south to equatorial Africa
- Bantu cut down jungle for farming = no other malaria prey = mosquitos colonize free puddles = anopheles gambiae rise
- Wandering nomads visit a village; not immune = death by malaria

18

Anopheles gambiae

Feeds almost exclusively on humans, most reliable malaria vector

19

Which malaria has the longest incubation period?

P. malariae

20

Which malaria uses duffy antigens to adhere to RBCs

P. vivax

21

Which malaria infects 80x more than vivax?

P. falciparum

22

Which malaria is in monkeys

P. knowlesi

23

One sentence definition for Malaria:

Infection by protozoan parasites (plasmodium) that is transmitted by mosquitos causing fever, anemia and death.

24

What are the two hosts malaria uses?

Humans and female anopheles mosquitoes

25

Definitive v Secondary host

Definitive host: host in which parasite reaches maturity and reproduces sexually (mosquitos)
Secondary/intermediate host: host in which the parasite only resides for a short period of time in an immature form (humans)

26

Describe the sporogenic cycle

Sporogenic cycle: in mosquitos; gametocytes activate in colder temp of mosquito and create ookinete; ookinetes multiply asexually and form oocytes that make 1000s of sporozoites

27

Describe the exo-erythrocytic cycle

Exo-erythrocytic cycle: in humans, outside RBC; sporozoites injected into humans and travel to liver via bloodstream; migrate through several liver cells before settling the parasitophorous vacuole; each vacuole generates many merozoites that are transported to bloodstream via merosomes
○ Falciparum 5-6 days
○ Vivax 8 days
○ Ovale 9 days
○ Knowlesi 8-9 days
Malariae 13 days

28

Describe the Erythrocytic cycle

Erythrocytic cycle: in humans inside RBC: merozoites recognize RBCs, attach to RBC surface proteins and use membrane to create parasitophorous vacuole. The Merozoites feed on hemoglobin and alter RBC membrane to be more permeable; each merozoite makes 8-12 new ones that infect more RBCs
○ Occurs every 24 hours in knowlesi
○ Every 48 hours in falciparum, vivax and ovale
Every 72 hours in malariae

29

What else happens to merozoites?

Some merozoites develop gametocytes that lie dormant in bloodstream

30

which malarial stage is responsible for recurring malaria?

Hypnozoites

31

Which malarial stage would you block with a vaccine to prevent infection?

Sporozoites

32

Sustained fever

temperature does not fluctuate more than 1 degree/24 hours; graph shows 2/3 at constant temp then decrease

33

Remittent fever

fluctuation of 2 degrees per hour; graph shows consistent and almost equal spikes and dips

34

Intermittent fever

normal temp except for a few hours per day; graph has random spikes and dips

35

Relapsing

high temp more than 3x in 6 months, at least a week apart, lasting a few hours to a few weeks. Fevers separated by symptom-free intervals; graph shows long period of high fever, long period of low fever, repeat

36

Fever

elevated body temp regulated by hypothalamus. Damage can occur directly to cells, locally as inflammation or systemic as gut bacterial translocation

37

Falciparum fever

tertian

38

Vivax/Ovale fever

tertian

39

Malariae fever

quartan

40

Knowlesi fever

quotidian

41

What are pyrogens and examples of exogenous and endogenous?

Pyrogens: heat producing substances
Exogenous like staph aureus toxin. Endogenous like cytokines

42

How does your body generate heat or reduce heat loss?

Shiver to produce heat
Shunting of peripheral blood to core to reduce heat loss
Vasoconstriction to reduce heat loss

43

How do we know malaria exerted evolutionary pressures?

We made adaptations to survive it

44

Which malaria is most ancenstral?

P. malariae

45

Which malaria is most modern?

P. falciparum

46

List blood adaptations and if they affect RBC function

Ovalocytosis: oval shaped RBC
Hemoglobin E: deforms Hb and slows vivax in body
RBC without duffy antigens: does not affect RBC function
Thalassaemia: deforms Hb and slows vivax
Sickle cell: reduces cell invasion = high survival rate from falciparum

47

How long does it take for you to lose acquired immunity

> 6 months = lost resistance

48

Innate v Acquired immunity

Innate: sickle cell trait against falciparum
Acquired: continuous exposure

49

Incubation periods

Faciparum: 9-14 days
Vivax: 12-18 days - uses duffy antigens
Ovale: 12-18 days
Malariae: 18-40 days - oldest model, longest incubation
Knowlesi: 11-12 days

50

What is premunition?

Host response that protects you against high numbers of parasite and illness that does not eliminate infection and is only partially effective

51

Relapse v Recrudescense

- Relapse: recurrence of infection from activation of hypnozoites - only from vivax and ovale; blood was cleared of malaria
- Recrudescence: infection recurring from persistent blood stages of malaria; symptomatically better but still have parasite in blood - all malaria; usually happens if treatment is incomplete
** in falciparum and malariae, parasites are not completely eliminated after recovery

52

Thick v Thin slide

Thick film: drop of blood on glass slide to examine larger volume of blood and shows the presence of parasite.
Thin film: drop is spread across the slide and is useful for identification of species

53

Advantages to malaria RDTs

Quick, no subjective component, no time delay, can do it at bedside

54

Symptoms of Uncomplicated malaria

Shaking and chills
High fever - paroxysmal
Excessive sweating
Extreme fatigue and sleep
May recur at regular intervals
Enlarged spleen, liver
Jaundice
Diarrhea/vomiting
Anemia - usually mild
Abdominal pain
Normal WBC
Low platelets
No vital organ dysfunction

55

Symptoms of Severe Malaria

Severe anemia
Renal failure
Pulmonary edema or ARDS
Hypoglycemia
Cerebral malaria; coma, seizures, neurologic manifestations
Circulatory collapse or shock
Enlarged spleen, liver
Miscarriage, low birth rates
Micro-hemorrhages in eye
Death

56

Neurologic consequences of severe malaria

Delirium: misperception of sensory stimuli; vivid hallucinations
Coma: unresponsiveness & cannot be aroused
Obtundation: less than full alertness
Stupor: deep sleep/unresponsiveness taking a lot to be aroused
Prostration: on the ground and cant get up

57

Specific consequences:
Anemia
Edema
Hypoglycemia
Low birth weight
Hypotension

Anemia: liver is slaughtering RBCs
Edema: INC alveolar permeability = fluid loss into lungs
Hypoglycemia: parasite consuming your glucose, not renewing
Low birth weight: due to DEC in nutrition
Hypotension: organs aren't getting enough blood

58

Common complications in pregnancy

Loss of blood and clogging of small placental vessels
Anemia INC maternal mortality
Low birth weight due to DEC in nutrition = INC risk infant death
Prematurity
INC risk of severe malaria

59

Has there been good or bad progress in eliminating malaria?

Good

60

What are major threats in controlling malaria?

INC travel
Plasmodium drug resistance
Unstable political/social will
INC environmental disturbances
Insecticide resistance
Cross-border Malaria
Poorly trained man power

61

What makes Vivax difficult to control?

- Unique biology - hypnozoites in the liver
- Asymptomatic in semi-immune populations
- Responds differently to anti-malarials than falciparum
- Poorly funded research
- Mixed infections with falciparum

62

Outbreak V endemic

Outbreaks: typically involves a village or group of villages
Endemic: entire district or ecotype

63

3 main categories of disease spread

1. Spread by direct contact between susceptibles
2. Spread by insect vectors
3. Water/soil/food borne

64

Miasma theory

Miasma: bad smoke or mist that changed the air/atmosphere. Theory that miasmas got worse in hot climates, worse near swamps, stagnant water and decaying things. Draining swamps helped. This lead to sanitary reforms which was good but not causing malaria

65

Leo Howard & Lewis Hackett

local ecology of malaria, not just one solution

66

Merozoite
Hypnozoite
Gametocyte
Sporozoite

Merozoite invasive form that attack RBC; generated in vacuoles
Hypnozoite in vivax and ovale, remain dormant in liver
Gametocyte made by merozoites in humans; mosquito take blood meal and they mature in mosquito gut to make ookinetes that make new sporozoites; also survive in human and mosquito
Sporozoite motile infective form; born in mosquito and also live in human

67

What causes end organ damage?

ischemia

68

Duffy-Free RBCs

Does not affect RBC function; Vivax can't find it

69

Hemoglobin E

Deforms Hb & slows vivax
Hetero: no symptoms
Homo: mild anemia & enlarged spleen

70

Thalessemia

Deforms Hb & slows vivax

71

Ovalocytosis

RBC oval shaped and makes invasion difficult; may be asymptomatic, anemic, jaundice or gallstones

72

Sickle Cell

Homo: death
Hetero: 90% reduction of death
Sickling of RBC = reduce cell invasion

73

Best vector for falciparum

Anopheles gambiae female

74

3 phases to intervene epidemic

Phase 1: early detection
- Weekly surveillance at sentinel sites; detection and control within 2 weeks
Phase 2: rapid increase
- Rapid increase in new cases
- Need to track spatial and temporal development; outbreak signature
Use epidemic wave to trace over time and space
Phase 3: Post epidemic period
- Transmission falls to usual low levels
- Short term impacts: economic negatives, behavior changes, devastated populations
- long term impacts: economic, political health resources are low; positive like good political change, improved sanitation and control

75

Intrinsic v Extrinsic factors that affect burden of disease

Intrinsic factors: human (herd immunity), parasite (virulence), vector (mosquito species complex)
Extrinsic factors: environmental, control, socioeconomic (war, natural disaster, climate)

76

Malaria dominates where

P. Malariae mostly throughout Africa
P. Vivax Central America, North Africa, Middle East, India, South America, SE Asia
P. Ovalae West Africa
P. Falciparum Africa, Haiti, Papua New Guinea, South America, SE Asia
Knowlesi - SE Asia, mostly around borders

77

Environmental, human-related and biological factors for predicting malaria

Environmental factors: altitude, temperature, precipitation
Human related factors: land use, livestock, insecticide, socioeconomic status, gender, treatment, access
Biological factors: breeding sites, insecticide resistance, immunity, age

78

Endemic, epidemic and decadal timescale prediction

Endemic areas: potential prediction of seasonal onset
Epidemic areas: prediction of outbreak
Decadal timescales: potential shift of epidemic areas to higher altitudes

79

Timeline for Eradication

1 Preparatory phase
2 Attack phase - interrupt transmission: Vector control measures; Surveillance of disease
3 Consolidation phase - not as much efforts as attack phase: Mopping up remaining foci of infections
4 Maintenance Phase; 3 consecutive years without transmission

80

Elimination v Eradication

Eradication: cessation of malaria parasite transmission and elimination of human reservoir - by extermination of infectious agent
Elimination: reduction to zero incidence of a specific disease in defined area

81

Control v Extinction

Control: reduction of mortality and disease incidence until no longer a major public health problem
Extinction: no longer exists in nature or lab