4. Endocrine Pathology II Flashcards
Hypothalamus
• Main controller of pituitary secretions.
• Hypothalamic regulatory hormones:
• Releasing hormones (RH):
• Stimulate synthesis and secretion of hormones from ____.
• Inhibiting hormones (IH):
• Prevent synthesis and secretion of hormones
from the ____.
anterior lobe of the pituitary (adenohypophysis)
adenohypophysis
• Hypothalamic hormone TRH (thyrotropin releasing hormone) - hormone is going to activate pituitary to release the first hormone ____
○ TRH travels to anterior pituitary and gland responds by releasing TSH
○ TSH hormone will act on thyroid gland (endocrine target organ) which will produce
second hormone
○ Second hormone in this case is ____ we saw this morning
• CRH stimulates release of ACTH by pituitary, hormone acts at level of ____ glands to induce secretion of glucocorticoids
• Main regulatory mechanism is ____ feedback!
○ Hormone 2 acts through negative feedback mechanism to inhibit adenohypophysis to drop secretion of hormone 1 and inhibit hypothalamus to inhibit secretion of releasing hormone
• Example: if hormone 2 is Thyroxine and T3, thyroid hormones will act in negative feedback mechanism to inhibit adenohypophysis so drop in synthesis of ____ that will have another negative feedback mechanism to prevent release of TRH
TSH
T3 and T4
suprarenal
negative
TSH
• Prolactin: secreted in response to secretion of hypothalamus known as ____ (prolactin releasing
factor) but remember this is a hormone!
○ Prolactin releasing hormone (PHF) acts on ____ to release prolactin
○ Prolactin is 1st hormone but WILL NOT act directly on gland
○ Prolactin stimulates growth and development of ____ during pregnancy
○ In this particular case, regulatory mechanisms shown here on left side of slide, prolactin acts through negative feedback mechanism to inhibit secretion of ____ by
hypothalamus therefore downregulating its own secretion
○ It can also act in a positive feedback mechanism to stimulate synthesis of
hypothalamic inhibitor factor known as ____ or prolactin-inhibiting hormone
• Now we know PIH is actually ____; PIH and dopamine = same molecule!
• What this means is that high levels of prolactin will increase secretion of PIH in hypothalamus that will also inhibit secretion of ____ = double feedback
mechanism
PRH
ant pit
mammary glands
PRF
PIH
dopamine
prolactin
• Another example is shown by secretion of growth hormone
○ Hypothalamus releases releasing factor and inhibiting factor
• Inhibitor factor - GH-IH also known as ____
• More commonly referred to as somatostatin
• Releasing factor - GH-RH
○ Same kind of system
• RH released by hypothalamus is released and stimulates synthesis of ____ that can act on some tissues but most importantly in liver, receptors for GH that induce synthesis of different family of hormones known as somatomedins
• Somatomedins are known as insulin like GF specifically ____ or ____
• Also have dual circuitry
• Actual effect of GH in many tissues (not all) is mediated by ____, not
growth hormones itself
• Effect of GH on muscle and bone is actually mediated by ____ but not by growth
hormone directly
• Circulatory similar to prolactin - negative feedback of releasing hormone and
positive feedback activation or stimulation of inhibiting hormone resulting in lower levels of GH in response to higher levels of somatomedins
somatostatin GH IGF-1 somatomedin-C1 GH IGF
Posterior Pituitary Gland (Neurohypophysis)
ADH
Stimulates ____ resorption by the renal tubules.
Oxytocin
Stimulates ____ of the uterus during birth and secretion of ____ from breasts during nursing.
water
contractions
milk
Anterior pituitary gland (adenohypophysis)
GH
Controls ____ and growth.
Prolactin
Controls ____ development and milk production.
Thyrotropin (TSH)
Stimulates growth of thyroid and production of ____.
Adrenocorticotropin (ACTH)
Stimulates growth of adrenal ____ and production of ____ hormones (glucocorticoids, androgens and mineralocorticoids).
Lutenizing hormone (LH) Controls production and release of \_\_\_\_ and progesterone by ovary and of \_\_\_\_ by testis.
Follicle-stimulate hormone (FSH)
Stimulates growth of ____ in ovary and of ____ in testes
metabolism breast thyroxine cortex cortical estrogens testosterone graafian follicles seminiferous tubules
Pituitary Gland Hormones: Growth Hormone
• Regulation and control of secretion of growth hormone (GH):
○ Start at level of ____ where there is GH releasing hormone released by hypothalamus and will act at level of anterior pituitary specifically at ____ cells that will produce growth hormone that circulates at blood stream and one example where it will act is at liver where there are specific hormones for GH
○ GH stimulates liver to synthesize second hormone like ____ and IGF-1
○ Same regulatory feedback circuits and inhibitory factor at level of hypothalamus
(____) which is inhibiting factor
○ What IGF regulates:
• Growth of ____ bones in length by acting at level of ____ plates (will become epiphyseal plates
hypothalamus acidophil somatomedin somatostatin long epiphyseal
Pituitary gland hormones: GH
Remember from last year, cells responsible for growth of bone are osteoblasts and they have receptors for IGF-1 for somatomedin-C so response to increased levels of IGF-1, osteoblast will react by producing components of matrix of the bone including:
• ____
• Many other proteins
• Facilitating deposition of ____ mineral
• Increased levels of IGF will produce increase levels in ____ during period of bone growth
collagen
hydroxyapatite
bone
Pituitary gland hormones: prolactin
Also wants to highlight prolactin:
• Prolactin is synthesized and secreted by anterior pituitary by same acidophil cells in response to ____ (prolactin releasing factor) and in minor way responds to ____ (thyrotropin releasing
hormone) but more important is PRF
• Prolactin has direct effect on ____ tissue only after giving ____ when process of lactation is about to begin
○ Prolactin produces resting mammary gland into active form meaning increase in ____ of mammary glands, cell differentiation and then secretion of components in milk
PRH TSH mammary gland birth complexity
Pineal gland
- Lies in ____ portion of roof of third ventricle.
- Contains ____.
- Synthesizes ____:
- Derives from ____.
- Sets ____ rhythms.
posterior pinealocytes melatonin tryptophan circadian
IMPORTANT POINTS (summarized): • What melatonin is derived from \_\_\_\_ • Produced in \_\_\_\_ • Melatonin helps to reset internal \_\_\_\_ ○ In absence of melatonin, internal clock of organs (all cells have internal clock) all of those clocks will begin to drift however by rhythm of inhibition of secretion of melatonin - those clocks are reset every \_\_\_\_ hours so entire body works in more coordinated way
tryptophan
dark
clock
24
Thyroid Gland
- Located along the ____ of the neck.
- Thyroid hormones regulate metabolism:
- ____ Effect: Increased energy consumption → increased heat generation.
- Amino acid-derived hormones: • ____ (T3).
- ____ (T4).
- Peptide hormone:
- ____ metabolism.
midline calorigenic triiodothyronine thyroxine calcitonin:calcium
Thyroid hormones
• After iodination and protonation of thyroglobulin (last slide) we have thyroid hormone that reaches cell
• Thyroid hormones can cross plasma membrane and two places of action”
○ ____
○ ____
○ Receptors for thyroid hormones at level of mitochondria
○ Activation of receptors and binding hormone to mitochondrial receptors increases ____
production - increases rate ____ takes place
• ATP production or activation of oxidative phosphorylation chain with all ____ reactions
produces heat so these binding of thyroid hormones to mitochondria and activation of mito metabolism increases generation of ____!
○ Part of calorigenic effect
• Another mechanism that thyroid hormones function on target cells is by binding receptor forming complex that acts as ____
○ Specific genes responsive for transcription factor so certain genes will be induced and transcribed in response to binding of thyroid hormone
• Nuclear function together with ____ function comprises full target cell response
• Some of the genes that will be increased in transcription and translation in thyroid hormones
are involved in mitochondrial metabolism
○ End effect is increase in heat generation in maintenance of internal body temperature
nucleus
mitochondria
ATP
ox phos
refox
heat
TF
mitochondrial
Thyroid gland: thyroid hormones
In terms of regulation of these mechanisms carried out by thyroid hormone, we can imagine disruption in homeostasis of body
• In normal conditions:
○ Body at normal temperature
○ Normal thyroid hormone concentrations
• Imagine for some reason our body temperature ____ (i.e. trying to catch a train at 4F as Segade was) aka homeostasis disturbed:
○ Body temperature comes down, what thyroid does is to activate neural reflex to induce hypothalamus to release ____
○ TRH acts on ____ so adenohypophysis releases ____ which acts on thyroid gland so thyroid produces ____ thyroid hormones
○ Thyroid hormones will reach target cells, they will increase production of ____
○ Normal ____ has been restored
drops TRH adenohypophysis TSH T3 and T4 heat homeostasis
Thyroid gland: calcitonin
In addition to the two better known thyroid hormones, thyroid also produces peptide hormone known as ____:
• We have thyroid follicle, most of cells produce thyroid hormones but small population of cells know as ____ cells in follicle that produce this peptide hormone
○ Since it is ____ hormone, secreted by secretion pathway
○ Calcitonin receptor is on ____ (cell responsible for modifying bone)
• Osteoclast has receptor for calcitonin so upon binding of receptor for osteoclast, will respond by becoming ____
• Osteoclasts form these cavities in bone (Howship’s ____) and show ____ border to indicate active cell
○ Upon binding of calcitonin to receptor, osteoclast loses ____ border indicating that the osteoclast is inactive
• Calcitonin is produced in physiologic conditions sensing levels of circulating calcium is too ____
• Way to drop levels of Ca2+ in blood is to stop ____ of bone
• Osteoclasts solubilizes bone mobilizing Ca2+ ions but this is one mechanism where
body tries to return high Calcium in body to normal levels
calcitonin
C
peptide osteoclast inactive lacunae ruffled ruffled high resorption
Parathyroid glands
- Embedded in ____ surface of the thyroid gland.
- Secrete peptide hormone parathyroid hormone (PTH).
- Effects of PTH: Regulation of plasma [____+].
- Osteoclast ____:
- ↑ release of Ca2+ from bone,
- Osteoblast ____:
- ↓ Ca2+ deposition in bone
- ↑ reabsorption of ____+ at the kidney, reducing loss.
- Stimulation of secretion of ____ by the kidney.
- Effects ____ or enhance PTH.
- Enhances ____+, PO43- absorption by digestive tract.
posterior
Ca2
stimulation inhibition Ca2 calcitriol complement Ca2
Osteoblast/osteoclast cross-talk: coupling
• This is osteoblast-osteoclast cross talk
• “this is one of my favorite slides of D1 - Segade”
○ Should remember that osteoclast lineage is induced to differentiate mature into active osteoclast through interactions with osteoblast
○ ____ is master regulator of osteoclast differentiation
○ Indicated by arrow is osteoblast has receptor for ____
○ What PTH does is to increase production of 2 important molecules:
• ____
• M-CSF ligand
○ Osteoclast lineage is part of monocyte macrophage lineage
• To induce differentiation of immature of monocyte into ____ (1st step of differentiation), need interaction of ____ ligand produced by osteoblast with receptor on osteoclast lineage
• This induces differentiation of osteoclast to macrophage and then to osteoclast ____
• Intimate precursor interaction with osteoblast and osteoclast
• Receptor produced known as RANK that is receptor for activation of ____
• Interaction induces final stages of osteoclas
Increased levels of PTH in response to low levels of calcium in circulation will increase circulation of ____ and expression of ____
• Therefore what osteoblast is doing is differentiating more osteoclasts, attach to bone and solubilize bone matrix thus releasing ____ ion
osteoblast
PTH
RANKL
macrophage M-CSF precursor NFkB RANKL M-CSF calcium
Parathyroid glands: PTH
Imagine calcium levels in blood ____
• Induces PT gland to secrete PTH
• Through all mechanisms before, release of Ca from bone, enhance reabsorption in ____, stimulation of calcitriol (enhanced calcium absorption of GI tract) - all mechanisms together increase levels of calcium in blood therefore homeostasis in blood
• Opposite mechanism on slide - calcium levels are too high
○ Thyroid gland C cells produce ____
• Will have decrease in calcium levels and homeostasis is restored again
drop
kidneys
calcitonin
Adrenal (Suprarenal) Glands
• Lie along superior border of each kidney.
- Subdivided into:
- Adrenal cortex:
- Mineralocorticoids:
- ____.
- Glucocorticoids:
- ____.
- Androgens:
- ____.
- Adrenal medulla:
- ____.
- Norepinephrine.
aldosterone
cortisol
testosterone
epinephrine
Adrenal (Suprarenal) Glands: Hormones from the Suprarenal Cortex
Cortisol
Stimulates ____ and fatty acid mobilization.
Aldosterone
Regulates the metabolism of electrolytes: ↑ renal ____+ reabsorption and ↑ ____+ urinary loss
Androgens
Stimulate the development of ____ sexual characteristics.
gluconeogenesis
Na+
K+
male
Examples of regulation of secretion of steroid hormones:
• Cortisol:
○ ____ - releases CRH which is corticotropin releasing hormone
○ CRH stimulated to be secreted by hypothalamus by all these conditions:
• Low ____ levels
• ____
○ CRH induces on ____ to increase secretion by ____ cells (not acidophil cells) and
release ____
• This means this will act at level of adrenal gland to induce secretion of variety of steroidal hormones
• Among these = cortisol that have targets downstream to regulate ____ and have feedback mechanism to regulate release of ____ (negative feedback mechanism)
hypothalamus
cortisol
stress
pituitary basophil ACTH gluconeogensis CRH
Adrenal (Suprarenal) Glands: Hormones from the Suprarenal Medulla
Epinephrine (adrenaline)
Increases: ____, blood pressure, ____, sweat secretion.
Decreases: ____ functions.
Norepinephrine (noradrenaline)
Induces ____.
heart rate
respiration
digestive
vasoconstriction
Endocrine pancreas
- Exocrine / Endocrine Gland
- Endocrine pancreas:
- “Clusters” of cells called ____.
- Comprise only 1% of entire pancreas.
• Cell types and secreted hormones:
• Alpha cells – ____.
• Beta cells – ____.
• Delta cells – ____, somatostatin (inhibits
secretion of HCl by stomach parietal cells).
• F cells – ____ (inhibits secretion
of somatostatin and pancreatic enzymes).
islets of langerhans glucagon insulin gastrin pancreatic polypeptide
Endocrine Pancreas: Insulin
- Insulin effects:
- Increased glucose ____ by muscle and adipose tissues.
- Increased glucose ____ and ATP formation.
- Stimulation of ____ formation.
- Stimulation of ____ absorption and protein synthesis.
- Stimulation of ____ formation in adipose tissue.
• Insulin Deficiency:
• Diabetes Mellitus – High blood sugar, impaired glucose ____, dependence on
____ for energy, glycosuria.
• Overproduction:
• ____ (physician-caused)/Tumor – Low blood sugar.
uptake utilization glycogen AA triglyceride
utilization
lipids
iatrogenic
Endocrine Pancreas: Glucagon
- Glucagon:
- Stimulation of glycogen ____ in skeletal muscle and liver tissue.
- Stimulation of ____ breakdown in adipose tissue.
- Stimulation of ____ in the liver.
breakdown
triglyceride
gluconeogenesis
Endocrine pancreas
Summary of actions of both glucagon and insulin when normal glucose homeostasis is changed
• Either when increase in glucose levels therefore activation of secretion of ____ by pancreas to
decrease glucose concentration in blood to restore homeostasis
• Or during periods of fasting where decline of glucose levels induce pancreas to release ____
○ Due to mechanisms previously discussed, blood glucose concentration rises and glucose blood levels are restored
insulin
glucagon
Sex Organs (Gonads): Ovary
• Regulate the ____ monthly sexual cycle:
• Ovulation.
• Reorganization of uterine endometrium.
• Dependent on the gonadotropic hormones ____ and LH, secreted by the ____
- Steroid Hormones:
- Estrogens:
- ____ (β-estradiol)
- Progestins:
- ____
- Androgens:
- ____.
- Non-steroidal hormones:
- ____.
- Activin.
- ____.
female
FSH
anterior pituitary
estradiol
progesterone
androstenedione
relaxin
inhibin
Sex Organs (Gonads): Ovary
Estrogens
Stimulate development of the ____ (ovum) and the maintenance of female sexual characteristics.
Progesterone
Prepares the wall of the ____ to receive the fertilized egg.
Relaxin
Relaxation of ____ ligaments and softening of the ____ to prepare for childbirth.
Activin
Induces biosynthesis and secretion of ____.
Inhibin
Decreases synthesis of ____ and inhibits its secretion.
egg uterus pelvic cervix FSH FSH
Sex Organs (Gonads): Ovary
Estrogen
- Stimulates ____ maturation
- Develops and maintains ____ organs and behavior
- Stimulates ____ and myometrium development
Progesterone
- stimulates ____ development
- stimulates development of ____ during pregnancy
follicle
female
endometrium
endometrium
mammary glands
Quick look at female monthly cycle:
• Different levels of different hormones throughout the cycle:
○ Divided by ovulation stage, we can distinguish two phases in cycle:
• Early stages that correspond to ____ phase characterized by synthesis of ____ (lower gran in green as synthesis of one of the estrogens = estrodiol)
• Alter phase is ____ phase with both synthesis of ____ and ____
follicular
estrogens
luteal
estrogens
progesterone
In upper part of panel (yellow and blue lines) - big changes in pituitary hormones (FSH and LH)
• At beginning of cycle, the pituitary ____ molecule is going to stimulate maturation of these follicles, several of them that will give rise to mature follicle from which the mature ovum will eventually be released
• FSH stimulates first maturation of follicles
• Follicular cells maturate
• Start secreting ____ (see increase level of circulating estrogen)
• In third stage, cells in follicle (third panel), higher expression of ____ receptors that are for other pituitary hormone (luteinizing hormone) - cells are very sensitive to increase of LH in pituitary
○ Sudden increase of ____ induces ovulation - release of mature egg out of follicle
FSH
estrogen
LH
LH
After ovulation, persistent stimulation by ____, functional change in the left over corpus luteum derived from follicle known as lutenization
• At this stage, we see highest levels of ____
If no fertilization, cycle stops here because corpus luteum regresses, decays and then levels of both ____ and ____ (estrogen and progesterone) drop quickly
LH
progesterone
progesterone
estradiol
Sex organs (gonads): ovary
Control of both development of follicle by combination of both pituitary hormones of ____ and ____
• HAVE IN MIND THIS GRAPH BECAUSE SIMILAR GRAPH WILL BE SHOWN LATER IN REGULATION
OF MALE SEX HORMONE PRODUCTION BY EXACTLY SAME TWO MOLECULES
FSH
LH
LEFT:
• Initial stages of follicular phase at level of anterior pituitary you have secretion of ____ and LH
• Target of two hormones is two follicles in ovaries
• In early stages of follicular stage, follicles will start producing low levels of estrogen known as ____
- At low levels of estrogen, estrogen has surprising effect - because it is actually inhibitory both at level of ____ and level of ____
- At hypothalamus, low levels of estrogen will inhibit ____ thus keeping the levels of FSH and LH relatively low
- At the same time, estrogen is preventing uterus from fully developing an ____ - prevents proliferation of endometrium
FSH
estradiol
hypothalamus
endometrium
GnRH
uterus
RIGHT:
• When we reach ovulation stage, things change completely
• Hypothalamus still release ____ and anterior pituitary is still releasing FSH and LH
• In previous slides, during ovulation stage, FSH and LH increase dramatically!
• Anterior pituitary hormones stimulating follicles will have 2 effects
○ High levels of estrogens made by follicles and actually are activating of ____ ensuring high production of two pituitary hormones
○ High levels of estrogen at the same time are causing ____ to fully develop/thicken
• END RESULT = PROCESS OF ____
GnRH
hypothalamus
endometrium
ovulation
THIRD PHASE = LUTEAL PHASE
• Pituitary hormone specifically ____, act on corpus luteum (left over after ovulation and
transformation of follicle to corpus luteum that produces progesterone)
• Corpus luteum produces ____ AND ____
○ In combination, these hormones through negative feedback mechanism will inhibit ____ and hypothalamus
○ Will inhibit production of GnRH and inhibition of production of ____ and LH
In uterus:
• High levels of combination of estradiol and progesterone, will induce ____ of blood
vessels (arteries) in endometrium leading to cell ____, death of tissue and menstruation
LH progesterone estradiol anterior pit GnRH constriction death
Sex Organs (Gonads): Testis • Androgens: • \_\_\_\_ hormones. • Produced by \_\_\_\_ cells. • Main hormone: \_\_\_\_.
- Inhibin:
- Secreted by the ____ cells.
- ____ hormone.
steroid
testicular interstitial (leydig)
testosterone
testicular sertoli (sustentacular) protein
Sex Organs (Gonads): Testis
Andogrens: testosterone
Induces production of ____. Stimulates development of ____ secondary sexual organs and characteristics.
Inhibin
Supports ____ and physical maturation of ____.
sperm
male
differentiation
sperm
Sex organs (gonads): testis
In males, pituitary gland produces same two pituitary hormones that had important role in regulating female monthly cycle
• Pituitary in males also produce ____ and LH
• In males, target cells and therefore effects are different
○ LH regulates secretion of ____ in combination of FSH and ensures full ____ of sperm cells via spermatogenesis
FSH
testosteorne
differentiation
Circulatory in production of male sex hormones:
• Hypothalamus releasing same GnRH seen in females - act on anterior pituitary and in turn resends in secreting ____ and LH
○ FSH will act over ____ cells that help spermatogenesis process
○ LH acts on ____ cells that produce testosterone
THIS IS WHERE IT IS DIFFERENT FROM FEMALE SEX ORGAN REGULATION
• You see hormones produced by testes (inhibin and testosterone) have ____ effects when acting on anterior pituitary and hypothalamus
• TYPICAL NEGATIVE FEEDBACK MECAHNISM from Leydig cells onto the ____
• It is also important to understand that these are purely inhibitory
FSH
sertoli
leydig
inhibitory
sertoli
Endocrine Tissues in Other Organs: GI Tract
- Stomach:
- Gastrin – involved in the release of ____, and contraction; ____ secretion.
- Ghrelin – ____ mediator.
- Duodenum:
- ____.
- ____.
HCl
bile
hunger/satiety
secretin
cholecystokinin
Endocrine Tissues in Other Organs: Kidney and Heart
• Kidney: • Calcitriol – \_\_\_\_+ homeostasis. • Renin – \_\_\_\_+ homeostasis. • Erythropoietin – induction of \_\_\_\_ production.
• Heart:
• Atrial natriuretic factor –
inhibits ____+ reabsorption, renin release, ____ secretion.
Ca Na RBC Na aldosterone
Endocrine tissues in other organs: skin
• Here we consider even skin as endocrine tissue
• Mentioned this morning that one type of hormone put on list is Vitamin D
○ As you know, vitamin D derives from ____ through first stage involving action of UV light on skin to form intermediary known as ____ that is converted into cholecalciferol
○ Do not have to know all details but be aware that in ____ is first steps for important calcium regulation hormone calcitriol begins
○ Skin can be considered endocrine system
• Calciferol is then transported to liver where it is converted into another intermediary = ____
• This intermediary then travels to kidney and becomes more interesting
○ When calcium is low, enzyme known as ____which converts 25- hydroxycholecalfierol to 1,25-hydroxycholecalfierol (adds one H) and only is stimulated when calcium is low which is known as calcitriol
○ When calcium is high however, different mechanism activated producing inactive form of molecule (____) that has NO FUNCTION in regulating calcium levels
cholesterol
7-dehydrocholesterol
skin
25-hydroxycholecalciferol
1alpha-hydroxylase
24,25-hydroxycalcicalciferol
Endocrine tissues in other organs: skin
ACTIVE = ____ IS IMPORTANT ONE
○ ____ leaves kidney, enters circulation, bound to carrier protein (vitamin D carrier protein) and reaches target cell
○ Target cells of calcitriol are in ____
○ In small intestine, will induce calcium binding protein whose net effect, IMPORTANT TO
KNOW MORE THAN THE DETAILS:
• expression of protein increases transport of Ca2+ from GI into ____ and expression of protein increases transport of Ca2+ from GI into circulation and increases absorption of ____
○ In response to ____ calcium levels, renal enzyme (1alpha-hydroxylase) creates active form of Vitamin D3 that acts at level of enterocytes at level of GI tract that increases reabsorption of ____+ which returns homeostatic levels of calcium
This mechanism acts in combination with ____ to maintain homeostatic levels
1,25-hydroxycholecalciferol calcitriol small intestine circulation Ca2+ low Ca PTH
Do you know what cholecalciferol is used for in addition to vitamin precursor in humans but in other animals specifically rodents? It is a ____
- Segade found a mouse in his kitchen, went to grocery store, this looks good, mice love it called decon
- He looked at composition and it only had cholecalciferol which is vitamin D
- He went online, apparently mice are very sensitive to high levels of cholecalciferol
- Rant about the mice he found in his house
poison
