Upload File

“wars and elections are both too big and too small to matter in the long run. the daily...

  • Home
  • Documents
  • “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,
116
“Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops, into children’s bellies and their bright eyes. Good things don’t get lost. Here's what I've decided: the very least you can do in your life is to figure out what you hope for. And the most you can do is live inside that hope. Not admire it from a distance but live right inside it, under its roof. What I want is so simple I almost can't say it: elementary kindness. Enough to eat, enough to go around. The possibility that kids might one day grow up to be neither the destroyers nor the destroyed. That's about it. Right now I'm living in that hope, running down its hallway and touching the walls on both sides. I can't tell you how good it feels”

Upload: sherilyn-sandra-scott

Post on 16-Jan-2016

217 views

Category:

Documents


4 download

Report

Tags:

TRANSCRIPT

Page 1: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

“Wars and elections are both too big and too small to matter in the long run.  The daily work—that goes on, it adds up.  It goes into the ground, into crops, into children’s bellies and their bright eyes.  Good things don’t get lost.

Here's what I've decided: the very least you can do in your life is to figure out what you hope for. And the most you can do is live inside that hope. Not admire it from a distance but live right inside it, under its roof. What I want is so simple I almost can't say it: elementary kindness. Enough to eat, enough to go around. The possibility that kids might one day grow up to be neither the destroyers nor the destroyed. That's about it. Right now I'm living in that hope, running down its hallway and touching the walls on both sides. I can't tell you how good it feels”

From Barbara Kingsolver, “Animal Dreams”

Page 2: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Waverly Hills Tuberculosis Sanatorium. Louisville KT 1926

Built in 1911, expanded in 1926, closed in 1961

www.umdnj.edu/librweb

Despite Koch’s discovery, for 60 years the only treatment was isolation, “fresh air, and sunshine”

Page 3: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So it was time for another Nobel laureate!

Selman Waksman1888-1973

Page 4: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

He was working on bugs that live in dirt!

Selman Waksman1888-1973

Page 5: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Selman Waksman1888-1973

A childhood immigrant from theUkraine, through hard workHe became a professorOf microbiology and biochemistry at Rutgers

He was working on bugs that live in dirt!

Page 6: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Selman Waksman1888-1973

A childhood immigrant from theUkraine, through hard workHe became a professorOf microbiology and biochemistry at Rutgers

He coined the term antibiotic andDiscovered more than 20Antibiotics, including two whichAre widely used today.

Neomycin--check your medicine cabinet

He was working on bugs that live in dirt!

Page 7: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

StreptomycinStreptomyces griseus.

He was working on bugs that live in dirt!

Page 8: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

StreptomycinStreptomyces griseus.

Isolated on October 19, 1943 by Albert Schatz, a graduate student in Waksman’s lab

He was working on bugs that live in dirt!

http://en.wikipedia.org/wiki/October_19
http://en.wikipedia.org/wiki/1943
Page 9: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin

Isolated on October 19, 1943 by Albert Schatz, a graduate student in Waksman’s lab

He was working on bugs that live in dirt!

the-scientist.com

http://en.wikipedia.org/wiki/October_19
http://en.wikipedia.org/wiki/1943
Page 10: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin kills many bacteria, including

Mycobacterium Tuberculosis!

Bugs fight bugs

Page 11: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin kills many bacteria, including

Mycobacterium Tuberculosis!

Bugs fight bugs

But how?

Page 12: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The central dogma--anybody remember that?

Page 13: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The central dogma--anybody remember that?

DNA -> RNA -> Proteins

Page 14: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The central dogma--anybody remember that?

DNA -> RNA -> Proteins

Page 15: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

And we call that step?

DNA -> RNA -> Proteins

Page 16: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Translation!

DNA -> RNA -> Proteins

Page 17: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

www.palaeos.com

Bacteria do it too, and like us they use RIBOSOMES

Page 18: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lovely picture from Harry Noller

Let’s zoom in on the action

Page 19: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lovely picture from Harry Noller

The ribosome is an amazing machineThat unlike most in the cell runs on RNA!

Page 20: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lovely picture from Harry Noller

The ribosome is an amazing machineThat unlike most in the cell runs on RNA!

16S rRNA + proteins =30S or small subunit

Page 21: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

If we zoom in further…

Page 22: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lovely picture from Harry Noller

Luckily, our ribosomes are slightly differentand thus streptomycin affects them less

16S rRNA + proteins =30S subunit

Page 23: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin cannot be given orally, but must be administered by regular intramuscular injection.

An adverse effect of this drug is ototoxicity, i.e. It can result in temporary hearing loss.

http://en.wikipedia.org/wiki/Intramuscular_injection
http://en.wikipedia.org/wiki/Ototoxicity
Page 24: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin cannot be given orally, but must be administered by regular intramuscular injection.

An adverse effect of this drug is ototoxicity, i.e. It can result in temporary hearing loss.

Cool fact--this may be due to effect on Mitochondrial ribosomes!!!

http://en.wikipedia.org/wiki/Intramuscular_injection
http://en.wikipedia.org/wiki/Ototoxicity
Page 25: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

OK. So streptomycin kills bugs ina flask in the lab. What about inside a patient?

Page 26: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

First we have to make a lot of it.

In steps George Merck

of Merck and Co.

Page 27: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

First we have to make a lot of it.

In steps George Merck

of Merck and Co.

And we got the patent…

Page 28: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

First we have to make a lot of it.

In steps George Merck

of Merck and Co.

But we gave it back to Rutgers!

Page 29: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Now we need to try it on animals.Enter Dr. William H. Feldman and Dr. H. Corwin Hinshaw at the Mayo Clinic

Page 30: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Now we need to try it on animals.Enter Dr. William H. Feldman and Dr. H. Corwin Hinshaw at the Mayo Clinic

In two months they reported to Waksman that four tubercular guinea pigs receiving streptomycin "look exceedingly well."

We do, don’t we!

Page 31: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

OK, but how about people?Next Feldman and Hinshaw invent clinical trials

www.jameslindlibrary.org

Page 32: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

OK, but how about people?Next Feldman and Hinshaw invent clinical trials

Page 33: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

OK, but how about people?Next Feldman and Hinshaw invent clinical trials

This is really important!!

Page 34: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

OK, but how about people?

In August 1945 Hinshaw reported that thirty-three patients had been treated "and [we] continue to be quite optimistic."

Page 35: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Initially streptomycin appeared to be a miracle cure

Patients, including the first, “Patricia T”,Were returned to health from death’s door

Page 36: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Now the problem was scaling up

(Remember 5 million people a yearWere still dying of TB!)

By 1948 8 companies were making streptomycinBut their 80,000 pounds

Would only treat 1000 patients

Page 37: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Initially streptomycin appeared to be a miracle cure

BUT…..

Page 38: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

A second, much worse Problem was now on the horizon

By 1948 patients began to relapse!

For example the author George Orwell

Page 39: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

But a second, much worse problem was now on the horizon

In an MRC clinical trial, patients improved rapidlyBut within five years the death rate was the

Same as the untreated controls

Professor Hill of the MRC

Page 40: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

But a second, much worse problem was now on the horizon

In an MRC clinical trial, patients improved rapidlyBut within five years the death rate was the

Same as the untreated controls

Professor Hill of the MRC

Uh, oh.

Page 41: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

What was going wrong??

Page 42: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin resistant bacteriacould be cultured from these patients!

What was going wrong??

Page 43: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin resistant bacteriacould be cultured from these patients!

What was going wrong??

How couldThat happen?

Page 44: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Streptomycin resistant bacteriacould be cultured from these patients!

What was going wrong??

How couldThat happen?

Page 45: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Have you heardThe one aboutNatural selection?

Page 46: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

What was going wrong??

evolution.berkeley.edu

Page 47: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

And how did this happen?

evolution.berkeley.edu

Page 48: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

And how did this happen?

evolution.berkeley.edu

Page 49: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

And how did this happen?

evolution.berkeley.edu

Page 50: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

And how did this happen?

evolution.berkeley.edu

Page 51: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

And how did this happen?

Lovely picture from Harry Noller

16S rRNA + proteins =30S subunit

Remember me?

Page 52: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Occasional bacteria had variants in16sRNA or the ribosomal protein S12

Lovely picture from Harry Noller

16S rRNA + proteins =30S subunit

Page 53: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

These blocked binding of streptomycin to the ribosome and thus these bacteria

were resistant!

Lovely picture from Harry Noller

16S rRNA + proteins =30S subunit

Page 54: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Thanks and kudos to Gary Trudeau for hitting the nail on the head

Page 55: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,
Page 56: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,
Page 57: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So what now?

Page 58: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So what now?

Luckily, help was on the wayfrom

para-aminosalycilic acid (PAS)

Jörgen Lehmann

AND

Page 59: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lehmann started with a strange published factThe TB bug loves to eat aspirin (salicylic acid)

Page 60: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lehmann started with a strange published factThe TB bug loves to eat aspirin (salicylic acid)

Page 61: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lehmann started with a strange published factThe TB bug loves to eat aspirin (salicylic acid)

His hypothesis: Alter aspirin slightlyAnd the bugs will die trying to eat it

Page 62: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Lehmann moved quickly, from bacterial trials in December 1943To Guinea pig trials in January 1944To the first patient in March 1944 (before streptomycin!!)

Page 63: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Chest 1949;16;684-703

Lehmann J. Para-aminosalicylic acid in the treatment of tuberculosis. Lancet. 1946; 1:15-6.

Page 64: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So how does PAS work?

Page 65: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So how does PAS work?

50 years later we still don’t know for sure

Page 66: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So how does PAS work?

It is likely to act somewhere in the pathwayFor making nucleotides to make DNA

http://themedicalbiochemistrypage.org

Page 67: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So which is better:Streptomycin or PAS?

Page 68: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

So which is better:Streptomycin or PAS?

BOTH!

Page 69: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Remember this?

I fear no streptomycin

Page 70: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Remember this?

I fear no streptomycin

and PAS doesn’t touch me

Page 71: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

I fear no streptomycin

and PAS doesn’t touch me

But if the same patient is given both drugs…

Page 72: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Ahhhh……

No………

But if the same patient is given both drugs…

Page 73: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The two drug combination becameThe new standard

After this trial…..

Page 74: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

But the story is not over yet-- we neededAnother Nobel laureate

Page 75: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nobelprize.org

I was already the 1939 Nobel laureateFor discovering sulphanilamideThe first antibacterial drug

Gerhard Domagk

But the story is not over yet-- we neededAnother Nobel laureate

Page 76: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nobelprize.org

I was already the 1939 Nobel laureateFor discovering sulphanilamideThe first antibacterial drug

Gerhard Domagk

(though I was not allowed by the Nazisto accept the prize and I was held by the Gestapo for a week because of this honor)

But the story is not over yet-- we neededAnother Nobel laureate

Page 77: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nobelprize.org

Gerhard Domagk

But the story is not over yet-- we neededAnother Nobel laureate

I spent World War II in a bomb-damaged hospital labpursuing new chemical relatives ofsulphanilamide thatmight be effective against TB

Page 78: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Here’s what I discovered

Isoniazid

Page 79: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Here’s what I discovered

Isoniazid

First we need to know moreAbout mycobacteria

Page 80: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

All living cellsHave a plasma membrane

Page 81: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

All living cellsHave a plasma membrane

Gram positiveBacteria alsoHave a cell wall

Page 82: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

All living cellsHave a plasma membrane

Gram positiveBacteria alsoHave a cell wall

Mycobacteria have aVery complex cell wallServing as a barrier

http://web.uct.ac.za/depts/mmi/lsteyn/cellwall.html

Page 83: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

1. outer lipids2. mycolic acid3. polysaccharides (arabinogalactan)4. peptideglycan5. plasma membrane6. lipoarabinomannan (LAM)7. phosphatidylinositol mannoside8. cell wall skeleton

Wikipeda/mycobacterium

Just look at the parts list

Page 84: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

1. outer lipids2. mycolic acid3. polysaccharides (arabinogalactan)4. peptideglycan5. plasma membrane6. lipoarabinomannan (LAM)7. phosphatidylinositol mannoside8. cell wall skeleton

Wikipeda/mycobacterium

Just look at the parts list

Page 85: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Isoniazid is metabolized by the bacteriumTo isonicotinic acyl anion or radical

and inhibits the enzymethat makes

Page 86: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Isoniazid was added to the combination therapyand remains there today!

Page 87: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Isoniazid was added to the combination therapyand remains there today!

Streptomycin and PAS were removed fromfrontline therapy as new drugs

that were more effective orhad fewer side effects

came into the clinic

Page 88: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

National Institute of Allergy and Infectious Diseases (NIAID) 2007

Current first-line TB drugs and their dates of discovery

Page 89: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

NIAID (2007)

Page 90: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Let’s look at one of the new drugs in detail

rifampicin

Page 91: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

It binds the ß subunit of RNA polymerase

rifampicin

Check out a cool video view athttp://www.pingrysmartteam.com/rifampicin/rifampicin.htm

Cell. 2001 Mar 23;104(6):901-12

Page 92: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Binding does not block recruitment to the promotorBut inhibits transcription elongation after 2-3 nucleotides are madeby sterically blocking transcript elongation

Cell. 2001 Mar 23;104(6):901-12

Page 93: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Let’s take a closer look

Cell. 2001 Mar 23;104(6):901-12

Page 94: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Most mutations that confer rifampicin resistance changeResidues in the binding pocket

Page 95: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Our RNA polymerase is different enough that it is notinhibited by rifampicin

Cell. 2001 Mar 23;104(6):901-12

Page 96: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

CDC

First-line TB drugs

Left to right isoniazid, rifampin, pyrazinamide, & ethambutol Streptomycin (not shown) is given by injection

Page 97: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

First-line TB drugs

TBAlliance

4 drugs, 130 doses

Over 6-9 months!

Page 98: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

First-line TB drugs

TBAlliance

4 drugs, 130 doses!

http://www.mcvay.com/tb_treatment_in_the_western.html

Daily dose!

Page 99: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

First-line TB drugs

TBAlliance

Are also not compatible withAntiretroviral HIV therapy

(problem for 1/3 of HIV patients!)

Rifampin induces cytochrome p450s, Increasing metabolism of anti-HIV drugs

Page 100: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Remember the difference in TB rates world-wide but

CDC

Page 101: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The other major challengeIs multi-drug resistant TB

CDC

Page 102: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Remember this story???

Page 103: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

In other word MDR TB says

I fear none of theFirst line drugs!

Page 104: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

What drives drug resistance?

Page 105: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Incorrect, unsupervised, or incomplete treatment

Page 106: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The answer in the developed world:

Page 107: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

The answer in the developed world:

MORE DRUGS!

Page 108: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

NIAID (2007)

Page 109: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

NIAID (2007)

Page 110: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

New TB drugs under development

NIAID (2007)

Page 111: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nature 393, 537-544(11 June 1998)

And the future beckons

Page 112: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nature 393, 537-544(11 June 1998)

In 1998 the Sanger centre and the Pasteur InstituteDetermined the complete genome sequence

Of M. tuberculosis

Page 113: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nature 393, 537-544(11 June 1998)

4.4 million base pairs

About 4000 genes

Remarkable diversityOf genes involved in fatty acid

Synthesis and metabolism (>250 genes)

Page 114: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nature 393, 537-544(11 June 1998)

Remarkable diversityOf genes involved

in fatty acidSynthesis and

metabolism (>250 genes)

Page 115: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Nature 393, 537-544(11 June 1998)

The genome provides new targets for

drugs and vaccines

Page 116: “Wars and elections are both too big and too small to matter in the long run. The daily work—that goes on, it adds up. It goes into the ground, into crops,

Stats from WHO; slide from TBAlliance

But in the developing world…..


As the saying goes, “This too shall pass” Malaysia

THOUGHTS All too soon out goes the light

Beach Goes Blue...2 Rehoboth Beach-Dewey Beach Chamber of Commerce & Visitors Center 2017 Beach Goes Blue...Red & White, Too! E-Newsletter Beach Goes Blue...Red & White, Too! Fun On

Isocert Solutions: What Goes Into a Design Review

What Do You Think Goes Into Developing Games? Development

Your ad goes on the Internet, too. Pat: 785-475-2206 pages - all/obh... · Pat: Watch those unwanted items disappear! Your ad goes on the Internet, too. HeraldClassifieds (785) 475-2206

What Goes Into a Very Basic Survival Kit?

A DAVINE 11 GOES INTO 2021

STANSTED AIRPORT Structure Case Study byfaculty.arch.tamu.edu/media/cms_page_media/4433/Stansted Presentation.pdf · Waffle slab goes into column Goes down into foundation loads Loading

DescriptionThen she tasted the porridge from Mama Bear’s medium-sized bowl. “This porridge is too cold!” she whined. ... She goes into a strange house and eats food that isn’t

What goes into successful diversity and inclusion

What Goes into Marketing Intelligence Reports

These Go To Eleven: When the Law Goes Too Far

‘Into the Woods’ Oakland University goes

What Really Goes Into Creating Great Video Content Marketing

Our Government Goes Into Drygoods Business · Our Government Goes Into the Drygoods Business Uncle Sam Sets UpforHimself ¡n Nineteenth Street.Does a Flourishing Business E _____

What goes into making a funny dog video

This Is Improbable Too - Oneworld Publications€¦ · I do improbable research about improbable research. Some of what I find goes into my ‘Improbable Research’ column in the

What Do You Think Goes Into Developing Games?

Carbon Cycle. 0.2 Gtonne/year goes into solid earth 0.2 Gt/yr goes into atmosphere from outgassing Today 2012 approximately 10 Gt/yr are put into the

WHAT GOES INTO BUILDING A NEW HOSPITAL?

FEBRUARY 2010: Plymouth Music Zone Goes into Retirement

What goes into making your logo?

What Goes Into Building a Bluebird House

What Goes Into a Thesis? - biomet.umaryland.edu

What Happens When Green Marketing Goes Too Far – A Legal Perspective

What goes into making beef and why

What goes into developing a product innovation strategy?

What goes into making a Data Visualization?

The proposed home sharing ordinance goes too far. · 2016. 6. 14. · The proposed home sharing ordinance goes too far. 1 message Erin Buckley Tue,

And Tommy Goes, Too - University of Maine

So, What Goes Into A Voice Over Project? fileSo, What Goes Into A Voice Over Project? Voice Over Talent Mike Klassen

Introduction What goes into making a good weather forecast?

Pantawid Pamilya Goes Into Public

The larger end goes into the VGA port (pictured above) and the smaller one goes into the headphone jack