Pathogenesis of neurologic disease associated with lysosomal storage diseases

(A) Single gene is mutated
(B) Insufficient enzyme activity
(C) Storage of primary substrate

1. neuronal swelling
2. secondary or primary glycolipid substrate accumulation
   --> GM2 ganglioside storage in neurons -->

• neurite sprouting --> abnormal synapses
• meganeurites

(D) both 1 & 2 above lead to neural dysfunction

Read full entry

Liver: possible causes of fatty change

- toxins (hepatocyte dysfunction causes impaired lipoprotein secretion)
- diabetes mellitus (excessive fat mobilization)
- protein insufficiency (decreased synthesis of apoproteins, leading to lipoprotein insufficiency)
- excessive fat intake/ caloric intake (normal amounts of lipoprotein aren't sufficient to deal with excess fat)
- starvation (excessive fat mobilization + protein insufficiency)

All of the above eventually lead to accumulation of clear cytoplasmic vacuoles in hepatocytes.
Read full entry

How a normal liver becomes cirrhotic: 3 major components

1. SEVERE, DIFFUSE, HEPATIC FIBROSIS

• a post-necrotic and post-inflammatory response.
• hepatocyte injury causes release of IGF-1, which acts as a mitogen for stellate cells.
• Kupffer (and other) cells make TGF-beta, prompting stellate cells to turn into myofibroblasts
• fibroblasts and myofibroblasts proliferate. Collagen (types I, III, XVIII) and fibronectin are produced.
• because the myofibroblasts produce collagen and ECM in the space of Disse, the normal fenestrations in hepatic endothelium become closed.
• closure of fenestrations causes blood to be shunted through the liver and into the hepatic vein, functionally bypassing hepatocytes.
• eventually fibrosis will connect portal and central areas.

2. NODULAR REGENERATION

• a post-necrotic response.
• 75% of liver can be removed before liver dysfunction occurs
• liver can regenerate up to 80% of its mass and will function if the connective tissue framework remains intact

3. BILE DUCT HYPERPLASIA

• may be associated with necrosis, inflammation, toxins, blockage of bile ducts
• proliferation of bile duct epithelium is concentrated in portal areas.

Read full entry

Liver: patterns of necrosis

- multifocal random pattern is caused by infectious agents (viruses, protozoa, bacteria)
- massive pattern indicates toxic or nutritional problems
- zonal patterns fall into 3 anatomical categories:

• centrilobular (hypoxia, toxins)
• midzonal (rare)
• periportal (toxins)

Read full entry

Acute necrotizing pancreatitis: pathogenesis

1. initial insult may be dietary, toxic, hormonal
2. enzymes are stopped from being secreted!
3. "colocalization" of lysosomes and secretory zymogen granules
4. lysosomal hydrolases act on trypsinogen to form trypsin
5. once typsin is activated...
6. other zymogens are activated
7. leads to activation of lipase, amylase, elastase, protease, etc.
8. autodigestion (necrosis) of pancreas and surrounding tissues

• blood vessels --> thrombosis, hemorrhage, edema --> further necrosis b/c of ischemia
• fat necrosis + calcium --> fat saponification
• inflammation (secondary event) --> neutrophil enzymes can cause further necrosis --> fibrosis

Read full entry

Canine prostate: non-neoplastic lesions

- benign prostatic hyperplasia: proliferation of prostatic epithelium associated with testosterone
- squamous metaplasia: associated with excess estrogen (e.g. Sertoli cell tumor)
- cystic hyperplasia

• usually secondary to benign prostatic hyperplasia or squamous metaplasia
• caused by obstruction of ducts that carry prostatic secretions to urethra
• results in multiple fluid-filled cavities

- paraprostatic cysts

• fluid-filled cysts adjacent to prostate
• develop from abnormal tissue that remains from embryonic development

- bacterial infection (bacterial prostatitis)

• may ascend or descend the urethra (if descending, comes from urinary bladder)
• usually associated with pre-existing prostatic abnormality

- prostatic abscess

• progression of bacterial prostatitis with accumulation of pus and abscess formation.

Read full entry

Tell me about equine herpes virus 1

- an infectious agent that can induce abortion and stillbirth
- involves multifocal necrosis of lung, liver, lymphoid organs
- intranuclear viral inclusion bodies with chromatin margination are pathognomonic
- may also cause respiratory disease, fatal vasculitis, myelopathy secondary to vasculitis
- can also affect South American cammelids
Read full entry

Female gonadal stromal tumors

GRANULOSA CELL TUMOR
- common in mares, but rarely malignant.
- may be solid or may involve one or more cysts.
- animal exhibits failure to cycle, visible as anestrus.
- contralateral ovary undergoes atrophy.
- 40-50% produce androgens, (result: male behavior)
- 90% produce inhibin, causing

• regression of the contralateral ovary
• lack of progesterone that results in nymphomania.

- may occur in pregnant mares.
Read full entry

Abnormal gonads: hermaphrodites

- types: bilateral, unilateral, lateral.
- hypospadia: incomplete masculinization of the penis.
- confirm your diagnosis via karyotype, histopathology
- chimera: mosaic, XX (may have SRY), or unknown
- possible causes:

• congenital adrenal gland hyperplasia
• fetal exposure to sex hormones
• testicular feminization syndrome
• XY gonadal dysgenesis
• XY gonadal agenesis
• chromosomal abnormalities

- interruption of DAX-1 expression may lead to hypogonadotropic hypogonadism

- SOX 9 regulates SRY expression

Read full entry

Abnormal phenotypic gender: pseudohermaphrodites

Pseudohermapthrodites may result from problems with receptors, hormones or enzymes:

• persistent paramesonepthric (Mullerian) duct syndrome involves a receptor abnormality (dogs have Mullerian Inhibiting Substance). Undescended testes are attached to uterine horns, vasa deferentia are located in uterine wall. Bilateral oviducts, complete uterus with cervix, and cranial vagina are present.

• androgen insensitivity (testicular feminization) involves deficiency or abnormality of cytosol receptors for androgen. Complete or partial failure of androgen-dependent masculinization. Wolffian system does not develop or does not develop fully. Uterus, cervix and anterior vagina regress as they do normally.

• steroid 5-alpha-reductase deficiency means that dihydrotestosterone cannot be produced; therefore closure of urethra and scrotum do not occur; also, prostate and penis fail to develop.

• adrenogenital syndrome means that a female can't make adrenal cortical steroids due to enzyme deficiencies. This results in overproduction of adrenal androgens. The female duct system is modified toward the male.

Read full entry

Malformations in neonatal/ juvenile cats

Broad categories of causes:
- biological agents
- physical agents
- chemical agents
- genetic defects

Certain malformations may/ often result in death.
Read full entry

Kittens: necropsy is different than adults

- color of skeletal muscle
- presence of thymus
- scant adipose tissue
- prominence of thyroid glands, adrenal glands, mesenteric LNs
- thinner kidney cortex
- softer brain (high water content)
- limited ossification
- histologically evident hematopoesis in liver and spleen (for several weeks after birth)
- (possibly) unseparated eyelids
- (possibly) closed aural canals
- (possibly) prominent urachus (between umbilicus and urinary bladder)
- males have descended testes that can move in/out of scrotum until 5-7 mos.

In addition:
- frequent use of heat lamps may accelerate autolysis
- empty stomach/jejunum may indicate

• mom can't make milk
• mom neglecting baby
• baby is diseased

- full stomach may indicate death due to

• rapidly progressive illness
• trauma

- gas-filled stomach may indicate

• hypothermia (decreased gut motility led to fermentation of ingesta)
• aerophagia (swallowing air) due to pulmonary disease or agonal death

Read full entry

Toxic substance pneumonia revisited

What is atypical interstitial pneumonia of cattle?
- necrosis of type I pneumocytes
- edema, respiratory distress
- replacement of type I pneumocytes by type II pneumocytes
- septal fibrosis and eventually emphysema

How do cattle get atypical interstitial pneumonia?
- if they eat feed rich in L-tryptophan
- L-tryptophan is converted to 3-methyl indole in the rumen
- Clara cells convert 3-methyl indole to a cytotoxin, resulting in necrosis of type I pneumocytes

Certain plants can be pneumotoxic to cattle: for example, the sweet potato vine, which produces a mycotoxin called ipomeanol. Results are similar to atypical interstitial pneumonia.


There are toxic gases.
What type of toxic gases are we talking?

• nitrogen dioxide
• hydrogen sulfate (derived from bacterial growth on manure)
• ammonia (derived from bacterial growth on urine, manure; causes ciliostasis and loss of cilia, a.k.a. ciliocyophthoria)
• ozone (irritant)
• sulfur dioxide (irritant)
• carbon monoxide (not a pneumotoxin, but causes formation of carboxyhemoglobin, which results in hypoxia)
• volatile fluoropolymers (e.g. overheated Teflon; cause death by peracute pulmonary hemorrhage)

Read full entry

2 types of emphysema

- emphysema involves trapped air (either in alveoli or lymphatic vessels)
- alveolar emphysema has a bubble wrap appearance (bullae). It involves destruction of alveolar septa. It is uncommon in animals, but is common in humans due to chronic smoking or elastase induction.
- interstitial emphysema involves distended lymphatics between lobules. It is common in cattle with pneumonia; can occur due to gasping while dying. : (
Read full entry

COPD: an allergic phenomenon

- chronic obstructive pulmonary disease is a chronic bronchiolitis that involves airway constriction and expiratory effort. It involves:

• hyperplasia and hypertrophy of bronchiolar epithelium
• goblet cell metaplasia and increased airway secretions
• excessive mucus retention in airways

- another allergic phenomenon is extrinsic allergic alveolitis; it is uncommon in animals.
Read full entry

Pulmonary cytology

- tracheobronchial lavage, bronchoalveolar lavage can be used to recover mucus, cells and debris from the respiratory tract. Fluid is centrifuged, smeared onto a slide and examined. Components of normal washes:

• mucus. Inspissated mucus indicates poor ventilation of alveoli; granular mucus has been altered by neutrophil enzymes.
• epithelial cells. Some are present. Squamous epithelium coated with bacteria is from the oropharynx.
• leukocytes. Activated pulmonary alveolar macrophages are normal. More than 20% neutrophils is excessive. Eosinophils, lymphocytes and multinucleated giant cells indicate pathology.
• debris. Should be a small component. If excessive, may indicate aspiration pneumonia.

Read full entry

Neoplasms of the respiratory tract

- primary pulmonary neoplasms:

• uncommon in animals
• examples: bronchiolar-alveolar adenoma, carcinoma, carcinoid, pulmonary adenomatosis of sheep

- remember that granulomatous pneumonias can look like pulmonary neoplasms
Read full entry

Pneumonia, pneumonia and more pneumonia

- bronchopneumonia occurs when an animal inhales aerosols that then leave bacteria or particles in the airways.

• inflammatory exudates start in the airways and spill into the alveoli. Inflammation centers are on the bronchi and bronchioles.
• produces a cranioventral pattern of lung injury
• affected areas are consolidated, firm
• diagnosis made by gross exam

- interstitial pneumonia happens via hematogenous delivery of bacteria, viruses, allergens, toxins

• inflammation of insterstitium, alveolus
• type I cells are destroyed! type II cells proliferate
• alveolar septa become thickened
• diagnosis made by histological exam

- embolic pneumonia occurs when bacteria or septic emboli travel via the blood.

• can usually be diagnosed by gross exam

- granulomatous pneumonia can be due to varying agents, including fungi, mycobacteria, foreign body response, etc.

• nodular pattern
• chronic by definition
• grossly, similar to neoplasia

- bronchointerstitial pneumonia is caused by viruses; diagnosis must be confirmed by histological exam.

- aspiration (inhalation) pneumonia is a bronchopneumonia that can occur due to various reasons, including chemical or bacterial injury, sedation, anesthesia, gastric intubation, ingestion of petroleum products, or cleft palate.

• grossly, resembles bronchopneumonia
• histological proof: particles from diet in terminal airways (tertiary bronchi and bronchioles)

- toxic substance pneumonia can occur because type I pneumocytes have few defenses. Clara cells may produce toxic metabolites in certain circumstances.

- lipid "pneumonia" is probably caused by a mixture of surfactants and cell debris. Foamy macrophages and cholesterol crystals are visible in alveoli on histological exam. Grossly, white subpleural spots can be seen. Lipid pneumonia is an incidental finding.

Read full entry

Let's break down respiratory to make it less scary

Broad overview of the respiratory tract:
- form and function
- special anatomic considerations
- diseases

PLAN:
- skim through first 2 sections without taking notes
- read through diseases, taking brief notes
Read full entry

Openings

lesions characterized by parting or break in the skin without loss of epidermis.
examples: comedo, follicular cast, fissure, sinus

- comedo (blackhead) is keratin plug of infundibulum
- follicular cast is a superficial comedo that extends above the skin
- fissure is linear
- sinus is an inflammatory tract that exits externally
Read full entry