“If We Break Up, I Want Closure. None Of This Bitter High School Mentality That Usually Follows After

I’m so happy for you!

people who can graciously hide that they don’t like people are so terrifying. last year while working on tech for a play i asked my friend how he became friends with another guy on the crew and he got quiet, looked straight into my soul and said “he’s not my friend. i fucking hate him.” i lost 5 years of my life

Pregnancy - physiology

Hormones

hCG - human chorionic gonadotropin - present in blood and urine, produced by blastocyst and placenta

Low levels of hCG could mean miscarriage, ectopic pregnancy, miscalculation of dates

High levels = molar pregnancy (cells that normally form a baby dysfunction and form cysts instead), multiple pregnancy (twins etc), miscalculation of dates

Progesterone increases fat deposition in early weeks and stimulates appetite

Increased oestrogen from corpus luteum promotes mammary gland development (breasts enlarge)

And inhibits ovulation via negative feedback [OES decreases GnRH release by hypothalamus –> linhibition of FHS and LH –> no ovulation]

Relaxin (secreted by corpus luteum) softens connective tissue in preparation for labour - not specific, all joints can be affected

Peaks in early and late pregnancy

Physical changes

Blood pressure

As early as 4 weeks into pregnancy 

plasma volume increase

caused by the affects of oestrogen and progesterone on the kidneys

OES and Prg cause vasodilation 

less resistance = less pressure

Heart rate increases by 25% to compensate

stroke volume increases 

increased overall cardiac output by 50% in third trimester

Direct action of enlarged uterus:

compresses the descending aorta and inferior vena cava 

decreased venous return - less blood in means less blood out, less blood in ventricle –> reduced pressure on walls –> reduced force to exit –> reduced placental perfusion

increased aortic pressure

increased heart rate

[shouldn’t sleep on back for this reason]

Outcomes:

Fall in blood pressure (can cause collapse if serious)

Can cause foetal hypoxia even without mother symptoms

Haematological changes

red cell mass increase by 20% (renal - increased erythropoietin production in response to detection of blood oxygenation and sodium/water balance)

Plasma volume increases more than RBC count does, causing the impression of decreased haemoglobin (anaemia)

Increased tendency to clot (hypercoagulable)

due to increase in clotting factors and plasma fibrinogen

platelet production increase (however count drops due to increase in activity and consumption) - function remains normal]

WBC count may increase due to an increase in granulocytes

Respiratory changes

Increased chest diameter, diaphragmatic expression and elevation

dyspnoea common (difficulty breathing)

breathing becomes more costal (mouth) than abdominal 

mainly mediated by progesterone levels (cause bronchial and smooth muscle relaxation and hypersensitivity to CO2)

Changes to the urinary system

cardiac output increase –> increase in renal plasma flow and glomerular filtration

increase in urea, creatinine, urate and biocarbonate clearance 

with progesterone, renin and aldosterone up water retention increases

can lead to urinary stasis and increased risk of UTI

Any drugs given that are excreted renally must be given in much higher quantities consequently

Gastrointestinal changes

Appetite increase + cravings 

Gastric reflux sphincter relaxation (increased indigestion, also due to increased intra-gastric pressure (expanding uterus)) 

gallbladder dilated 

GI motility decreased and transit time slower 

albumin and protein decrease 

cholesterol twice normal value

Muskuloskeletal 

Calcium reuptake into bloodstream results in mild decalcification of bones 

relaxin softens joints (pubic symphysis + alters gait (waddling))

abdominal muscles stretch to elastic limit 

stretch marks (stria gravidarum) caused by rupture of elastic fibres and small blood vessels 

Reproductive changes

Massive increase in mass

Placenta growth (nutrition, excretion, immunity, endocrine) 

Parental blood supply 

Iconic Bellarke lines

To get you through these tough times, until Bellarke is an official ship.

1. Bellamy: If I’m on that list, you’re on that list. Write it down or I will.

2. Bellamy: Clarke, If I don’t see you again-

Clarke: No, You will

3. Bellamy: We can’t lose Clarke! We can’t lose her.

4. Clarke: You’ve got such a big heart Bellamy. People follow you, you inspire them because of this (Touches his heart). But the only way we’re gonna get through this is if you use this too (touches his head).

Bellamy: I got you for that.

5. Clarke: The Heart and the Head.

Bellamy: The Heart and the head

6. Bellamy: I was so mad at you for leaving. I don’t want to feel that way anymore.

7. Bellamy: Besides, I could use a break from keeping you alive.

Clarke: Thank you for keeping me alive.

Bellamy: Well, you don’t make it easy.

8. Diyoza: 283 lives for one. She must be pretty important to you.

Bellamy: She is.

9. Jaha: She’s lucky to have you. You keep her centred.

Bellamy: You got it backwards.

10. Bellamy: Together.

Me, thinking about high school:

becoming an adult cheat sheet!!!

learn how to coupon

how to get free therapy

clean bathroom tips

what to do when you can’t pay your bills

learn time management skillz

recipes that take 30 minutes or less

see if you’re paying too much for your cell phone bill

create a resume

how to make a doctor’s appointment

organize your closet

find the right career

a list of stress relievers

how to pick a major

how to take care of yourself when you’re sick

things to bring to a doctor’s appointment

what the hell is a mortgage?

buying a used car

how to pick a health insurance plan

read the news

leave your childhood traumas behind

how to quit smoking

a list of hotlines in a crisis

what to expect from your first gynecologist appointment

what to do if you get pulled over by a cop

things to keep in your car in case of an emergency

Mind blown 😂

tag yourself: note takers edition

Takes digital notes: tries to keep up with notetaking but eventually falls behind after 5 lectures, drinks coffee only to stay awake, tries the aesthetic of drinking hot tea while taking notes but fails, wakes up early once in a century and thinks they’ve reached their peak, wants a better organisation system but is too tired, worries about studyspo for 2 mins before saying fuck it

Takes handwritten notes: have really nice handwriting but they don’t realise it themselves, headers!! are!! everything!!, have a love-hate relationship with taking notes, studying only when they feel like it, only writes key points as notes because everything else is too much, drifts off a lot while notetaking to daydream

Doesn’t take notes: wears hoodies like 90% of the time, tries really hard to take care of themselves but it’s hard™, hair in a bun because hairstyles?? too much work, yells “fuck the system” as they study more than anyone else, studies straight from books and Knows what to study, can’t study for more than 45 mins at a time, is productive nonetheless, kinda exhausted but still carrying on

Takes notes only in class: take! notes! in! class! save! your! time! fuckers!, in a constant state of chaos but they’ll never admit, have a great relationship with the professors, raises eyebrows at everything it’s a Brand, likes lunch dates a lot, hates people who talk during lectures, wants a vacation already

Is still rotating between handwriting and typed notes: “did we have any homework” at the beginning of every lecture, is really friendly but tired of everything, likes laughing at stupid jokes, hates studying but is still doing it anyway, Major Chaos™, everyone loves them but they don’t have a lot of close friends, will fight for their friends to death, the mood: they’re just being their ball of anxiety, let them live thnx

If you're tired, read this. Please.

Hey, amigo.

It’s hard, isn’t it?

I know. Sometimes, it’s painful too.

Sometimes you really wanna give up, throw the books, hide in a corner and never take any action again.

I understand. I really do.

But I’m not here to collaborate on the pity party. I’m not going to join in on the groaning challenge, or complain about how hard it is.

First, get this though. It is hard. I won’t lie. It is worth groaning upon. Maybe one or two pity parties are affordable too.

Yet, there’s a pact we’ve make together, and I’d like to remind you of it, before we talk further. New here? We call it the Shush Pact.

Don’t do it. Don’t complain. Don’t whine. Don’t give in so easily. Don’t.

Go ahead. Make the pact. Now.

Go on! Do it.

Tell yourself, today’s hard. Tiring. But, I won’t give in to this. Nor will I complain and moan about it, and waste my energy. Not today, Amelia! Today’s not that day.

Done?

Sure?

Okay. Let’s go.

If you’re tired.

If you’re tired, exhausted of the hustle, and almost at your breaking point, I want you to remember how MUCH this means to you.

I don’t know what’s driving you nuts. Maybe it’s a math problem you just can’t crack. The presentation due next week that isn’t up to the mark. Maybe it’s 3 gigantic books you have to read up on before your next theology class. Perhaps your business has come at a standstill, and you can’t get it to grow. Or maybe you hate your job, and have finally, bravely, taken the step to work the 6 hours after you come home on building the art portfolio of your dreams, because in your heart, you’ve always been an artist. Maybe you’re juggling three jobs and working late nights to save enough money to catch the dream bus.

I don’t know. But I do know that it means a lot to you.

I know how passionate you’re about this, and how much it means to you.

And yet, you’re tired.

You’re tired of it!

You’re tired of studying so much. You’re tired of DMing every business in town, to have none reply back. You’re tired of working so much, handling so much, and you feel like you haven’t had a break since you were a kid. You’re tired of the pressure, you’re tired of the hustle and you just… wanna quit.

Don’t.

Please.

It’s hard to be positive in this dark, numb time and you’re starting to work mechanically, questioning your existence with every hour, but I have to make you understand! You’re worth this! You’re so worthy of this, my love.

Please don’t quit.

Don’t give up. It’s hard, but seal those lips, and trust your gut. I know you can make it. You’ve worked so hard for this! You’ve struggled so much, invested in so many weeks of work, and right now, at your breaking point, I want you to realise that you’re worthy. Of getting that grade, that degree, finding a job you love, your crazy ambitions of opening a flower shop… everything! All of it!

You deserve the world.

Listen to me. Open your ear and listen: you’re tired, yes. But here’s the truth. You’re not done yet.

You’ve got so much to prove to yourself. So many identities to identify yourself with. Exams to slay, jobs to get, money to make, dreams to build, people to meet and love to spread.

Listen. There’s more to this. There’s more to YOU.

Don’t give up now.

Not today.

You’re not done yet.

Tiredness will pass, and I want you to just try pushing through this. Just try. You’ll see you’re so capable of winning and it’ll blow your mind when you look back and realise the strength you truly possessed because you were able to push through.

Winning is your blood. It’s your oxygen.

Tiredness is a toxic. A poison. You’re not tired, you just think you are. When the human brain says it’s done, it’s actually got 70% more to give.

Don’t forget. Your legacy awaits. If this truly means everything to you, if you’ve already put in hundreds of hours of work into this, PUSH THROUGH! You’ve got to, because your future self deserves a better life! Don’t let them tell you that you need a break. A Hawaii vacation. They’ll say you’re getting nowhere and urge you to take a break.

You and me, we both know you don’t need one. You just needed a reminder of your capabilities.

And I’ve given you that now.

Just remember, you’re not done yet.

So fuck tiredness.

Go win.

Anti-cancer drugs - DNA targeting

Include alkylating agents, intercalating agents, and chain cutters.

Alkylating agents

Highly electrophilic species, looking for nucleophilic sites to attack, and forming covalent bonds to bases in DNA 

Prevent replication and transcription 

Toxic side effects (e.g. alkylation of proteins) 

Bind in the major groove of DNA

Both types cross-link DNA by covalently bonding to nitrogen of base pairs.

Binding of nucleic acid bases results in miscoding and distortion. 

Distortion of DNA prevents excision by HMG proteins – permanent damage. 

Transcription and replication prevented, tumour growth slows. 

Two electrophilic sites on an anticancer drug can cause interstrand and intrastrand cross-linking.

Preference for 1,2-GG or 1,2-GC linkage sites, with interstrand or intrastrand linkage, is dictated by drug chemical structure 

Other linkage adducts are possible. Eg 1,3-GCG, 1,2-GA. 

Monofunctional adducts are also possible 

Chlormethine (a nitrogen mustard)

 Chlormethine is highly reactive, toxic side effects. 

Lead compound for many less toxic mustard derivatives. 

Methyl (CH3 ) group has positive inductive effect – promotes loss of chloride – see mechanism 

Less toxic chlormethine analogues:

Melphalan:  e- withdrawing ring lowers Nu strength of N, less reactive drug, less side effects, less toxic. Mimics PhAla, carried into cells by transport proteins. 

Uracil mustard:  Uracil ring is e-withdrawing, less reactive alkylating agent. Mimics a nucleic acid base, concentrates in fast growing cells.

Cyclophosphamide:  Most commonly used alkylating agent, Non-toxic, orally active prodrug. Acrolein associated with toxicity.

Busulfan: Causes interstrand cross-linking. Sulphonate group withdraws electrons, adjacent carbon subject to Nu attack by DNA bases. 

Dacarbazine – A diazine:  Prodrug activated by oxidation in liver, decomposes to form methyldiazonium ion. Alkylates guanine groups 

INTERCALATING AGENTS

 Aminoacridines eg Proflavine

Antibiotics - Dactinomycin

Extra binding to sugar phosphate backbone by cyclic peptide 

Intercalates via minor groove of DNA double helix 

Prevents unwinding of DNA double helix 

Blocks transcription, blocks DNA-dependent RNA polymerase 

Anthracyclines eg Doxorubicin (adriamycin) 

 Extra binding to sugar phosphate backbone by NH3 Planar rings and Anthracyclines eg Doxorubicin (adriamycin) 

Intercalates via major groove of DNA double helix 

 A topoisomerase poison - blocks action of topoisomerase II by stabilising DNA-enzyme complex 

CHAIN CUTTERS 

Calicheamicin g1 I antitumour agent 

 Nucleophilic attack on trisulphide chain starts a rearrangement process. 

This interacts with DNA to generate a DNA diradical, which reacts with oxygen, resulting in chain cutting.

Bleomycins (BLM)

Highly active head, neck, testicular cancer (Hodgkin lymphoma) 

Single and double-strand cleavage of DNA with several reduced metal ions and O2 , Fe(II) highest in vivo activity. 

Three regions - 

bithiazole DNA binding domain (DBD) locks BLM into the minor groove, 

carbohydrate domain (CHD) H-bonds BLM to sugar phosphate of DNA 

metal binding domain (MBD) bonds to Fe(II)    

Mechanism

A reaction with hydrogen peroxide gives Fe(III) and hydroxyl radicals which abstract H atoms and cut the DNA chain. 

Fe2+ + H2O2 Fe3+ + OH. + OH− Fenton mechanism 

Lungs and skin have low levels of BLM hydrolase - higher sensitivity and toxicity. Pneumonitis occurs in about 10% of patients, progresses to pulmonary fibrosis. Over-expressed in malignant cells, resistance to bleomycin    

Summary of Anti-Tumour Specificity for DNA 

Major groove alkylators 

GG interstrand - N-mustards, nitrosoureas. 

GG intrastrand - methanesulphonates. 

GC-interstrand - nitrosoureas, triazines. 

Minor groove intercalators 

GG interstrand – anthracyclines. 

GC-interstrand – actinomycins, acridines. 

Minor groove chain cutters 

GC or GT intrastrand – bleomycins