Joints of the Foot

Joints of the Foot

There are 26 bones in the foot; all but five are involved in at least two joints.
* Hind foot
* Midfoot
* Forefoot
* foot biomechanics1

Subtalar joint: where the talus rests on and articulates with the calcaneus. This is a synovial joint with a weak capsule supported by medial, lateral, posterior & interosseous talocalcaneal ligaments.

* The interosseous talocalcaneal ligament (very strong) lies in the tarsal sinus (separates the anterior & posterior talocalcaneal joints).
* Anatomical subtalar joint- functionally a single synovial joint between the slightly concave articular surface of the talus and the convex posterior articular surface of the calcaneus.

Important Intertarsal joints:
1. Subtalar (talocalcaneal) joint
2. Transverse tarsal joint (calcaneocuboid & talonavicular)

* The main movement at these joints are foot eversion & inversion, eversion is augmented by extension of the toes (especially the lateral toes), inversion is augmented by toe flexion especially the 1st &2nd toes.

Transverse tarsal joints – a compound joint
1. Talonavicular part of the talocalcanealnavicular joint

2. Calcaneocuboid joint

* These 2 separate joints are aligned transversely. At this joint the forefoot & midfoot rotate as a unit on the hind foot around an AP axis. This augments inversion/eversion of the foot.
* Anatomical amputations of the foot are made through this joint.


1. Intertarsal joints:
These bones are so tightly opposed by ligaments that little movement occurs between them

2. Tarsometatarsal joints:
Plane type synovial joints involved in gliding/sliding type movements

3. Metatarsophalangeal joints
Flexion/extension in the foot occurs at the metatarsalphalangeal joints & the interphalangeal joints

4. Interphalangeal joints
Each has plantar, medial & lateral collateral ligaments, dorsal extensor aponeuroses act as dorsal ligaments.

All the joints proximal to the metatarsalphalangeal joints are united by dorsal & plantar ligaments.

All the bones of the metatarsals and interphalangeal joints are united by lateral & medial collateral ligaments.

Major ligaments of the Plantar foot
Plantar calcaneonavicular (Spring) ligament

* Fills a wedge shaped gap between the talar shelf & inferior margin of the posterior articular surface of the navicular. This ligament supports the head of the talus and plays an important role in the transfer of weight from the talus & maintaining the longitudinal arch.

Long Plantar Ligament
* Traverses from the plantar surface of the calcaneus to the groove on the cuboid. Some fibers extend to the base of the metatarsals (forming a tunnel for the tendon of the fibularis longus. This ligament is important in maintaining the longitudinal arch.

Plantar calcaneocuboid (short plantar) ligament:
* Located deep to the long plantar ligament, it runs from the anterior part of the inferior surface calcaneus to the inferior surface of the cuboid. It is located on a plane between the plantar calcaneonavicular (spring) ligament and the long plantar ligament. It is also involved in maintenance of the longitudinal arch.

Arches of the Foot
* The ligamentous bony arrangement of the foot allows considerable flexibility/deformation with weight bearing contact. The arches distribute the weight of the foot (pedal platform) acting both as shock absorbers & spring boards during ambulation of all types.
* Weight distribution is between the calcaneus and sesamoid bones at the 1st metatarsal and head of the 2nd metatarsal; weight is shared laterally with the heads of metatarsals 3-5. Elastic arches between weight bearing points compress with loading and recoil with unloading.
* Lateral Longitudinal arch
* Medial Longitudinal arch
* Transverse Arch

All three work as a unit in weight bearing

* Medial Longitudinal Arch higher and more prominent than the lateral arch.
* Consists of the calcaneus, talus, navicular, 3 cuneiforms and 3 metatarsals
* Talar head is the keystone of the medial longitudinal arch
* The medial arch is supported by the Tibialis anterior ligament as it attaches to the 1st metatarsal and medial cuneiform. Also the tib posterior & FHL.
* The tendon of the fibularis longus passes from lateral to medial and also supports the medial longitudinal arch.
* Lateral Longitudinal Arch is much flatter and consists of the calcaneus, cuboid & lateral metatarsals.
* The medial arch is involved in weight bearing while the lateral arch is involved in balance
* Transverse arch: cuboid, cuneiforms and bases of the metatarsals. This forms the medial & lateral parts of the longitudinal arches which serve as pillars fro the transverse arch.
* The tendon of the fibularis longus & tibialis posterior crossing the sole of the foot obliquely help maintain the curve of the transverse arch.
* The Arches of the foot are maintained by both passive & dynamic supports.

Passive factors
1. Shape of the united bones (especially the transverse arch).

2. 4 layers of fibrous tissue
o 1. Plantar aponeurosis
o 2. Long plantar ligament
o 3. Short plantar ligament
o 4. Spring ligament

Dynamic Support
1. Active (reflexive) bracing action of the intrinsic muscles of the foot support the longitudinal arches.
2. Active & tonic contraction of muscles & tendons extending into the foot:
Longitudinal arch
flexor hallicus longus
flexor digitorum longus
Transverse arch
fibularis longus
tibialis posterior &anterior
3. Plantar ligaments & aponeurosis bear the greatest stress and are most important in maintaining the arches.

Pes Planis (flat feet)
Prior to 3 years of age it is normal to have flat feet due to a fat pad. After the age of 3 this fat pad disappears.

Pes planis can be classified as:

* Flexible: the arch is normal when unloaded however with loading the arch is lost. this is the most common type. It is due to inadequate passive arch support (weak, loose ligaments).
* Rigid type, the arch is absent regardless of loading, this may be due to a congenital deformity.

* Acquired “fallen arches” is due to a tibialis posterior dysfunction due to trauma, denervation and/or degeneration. The plantar calcaneal ligament fails allowing the head of the talus to rotate inferomedially creating a prominence on the medial aspect of the mid-hind foot junction. This is often referred to as over pronation.

Talipes equinovarus (Club foot)
* Club Foot
* A congenital deformity males/females 2/1 Foot inverted, ankle plantarflexed and forefoot abducted. The abnormality is related to short, tight muscles, tendons and ligaments.

* Orthopedic Subtalar joint: anatomical subtalar joint + talocalcaneal part of the talocalcaneonavicular joint (these straddle the interosseous talocalcaneal ligament
* The main movement at this subtalar joint is inversion/eversion.

Joints of the Foot.ppt

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Opioid Analgesics & Antagonists

Opioid Analgesics & Antagonists

* Pain management

Opioid Analgesics & Antagonists

* Severe or chronic malignant pain opioids are the drugs of choice.
* Opioids are natural or synthetic compounds that produce morphine-like effects; opiates are drugs obtained from the juice of the opium poppy.
* All drugs in this category act through binding to specific opioid receptors in the CNS to mimic the effects of endogenous agents (endorphins & enkephalins) that eliminate many of the symptoms of a pain syndrome.
* Their anxiolytic and euphoric effects have led to their abuse.

Opioid Receptors

* Opioids interact stereospecifically with protein receptors on the membranes of certain cells in the CNS, on nerve terminals in the periphery and on cells of the gastrointestinal tract and the anatomic regions.
* The major effects of opioids are mediated through three receptor families: μ, κ and δ.
* Analgesic properties are mediated mainly via μ receptors and κ receptors of the dorsal horn of the spinal cord.
* Enkephalins interact more selectively with the δ receptors in the periphery.
* All three families are G-protein coupled receptors and inhibit adenylate cyclase.
* They are also involved in postsynaptic hyperpolarization (increasing K+ efflux) or reducing presynaptic Ca++ influx; this inhibits neuronal activity.

Receptor distribution

High densities of opioid receptors have been identified on peripheral nerve fibers, immune cells and five general areas of the CNS:

1. Brainstem: mediating respiration, cough, nausea & vomiting, maintenance of BP, papillary diameter and control of stomach secretion.

2. Medial thalamus: mediating poorly localized deep pain

3. Spinal cord: receptors located in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli.

Receptor distribution

4. Hypothalamus: mediating neuroendocrine secretion.

5. Limbic system: the greatest concentration of receptors are located in the amygdale, these receptors play a major role in emotional behavior & response and little analgesic effect.

Receptor distribution

6. Periphery: Peripheral nerve fibers bind opioids, they inhibit Ca+2 dependent release of excitatory, pro-inflammatory substances (substance P) from nerve endings

7. Immune cells: the role of these receptors in analgesia is undetermined.

Opioid Agonists

* The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, morphine and less potent codeine. These drugs show a high affinity for the μ receptor and less affinity for the κ and δ receptors.

Morphine


Mechanism of Action:

* Opioids exert their major effects through interaction with central & peripheral opioid receptors, binding results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release.
* Morphine acts at the κ receptors in lamina I & II of the substantia gelatinosa of the cord and decreases the release of substance P, it also inhibits the release of excitatory transmitters from nociceptive nerve terminals centrally and in the cord.

Actions:

Analgesia:

* Opioids cause pain relief by both raising the pain threshold at the spinal cord level and altering the central perception of pain. Awareness of pain remains but it loses its unpleasant character.

Euphoria:

* Opioids produce a sense of contentment and well being, this may be

related to stimulation of the central tegmental tract.

Respiration:

* Opioids cause respiratory depression by decreasing the sensitivity of central respiratory neurons to CO2. This occurs at therapeutic doses and as dose increases respiratory arrest will occur.

Suppression of cough reflex

* Antitussive properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex.

Actions:

Miosis:

* This results from stimulation of μ and κ receptors located in the Edinger-Westphal nucleus of CN III, this is resistant to tolerance, pin point pupils remain after most other opioid effects have developed tolerance.

Emesis:

* Opioids directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting.

GI tract:

* Opioids relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle. Constipation is also resistant to tolerance. Biliary spasm is exacerbated by increasing biliary tone with sphincter of Oddi spasm.

Cardiovascular:

* At large doses morphine produces hypotension & bradycardia.

Actions:

Histamine release:

* Morphine causes mast cell degranulation with the release of histamine causing urticaria, itching, diaphoresis and vasodilation. In asthmatics it may precipitate bronchospasm.

Hormonal Actions:

* Morphine inhibits the release of GnRH, CRH and deceases the release of LH, FSH & ACTH and β-endorphin. Testosterone and cortisol levels decrease. Prolactin and GH release are increased via suppression of dopamine levels centrally. ADH release is also diminished.

Therapeutic Uses

* Analgesia: Few drugs are as effective as morphine for the relief of pain.
* Treatment of diarrhea
* Anti-tussive: codeine and dextromethorphan are congeners with greater antitussive effects.
* Pulmonary edema: IV morphine dramatically relieves the dyspnea associated with pulmonary edema due to LV failure.

Pharmacokinetics

1. Administration: Morphine is poorly absorbed orally; codeine is a much more effective oral analgesic. Both undergo extensive first pass metabolism in the liver. Inhalation is an effective route but has found favor only with non-medicinal administration.

2. Distribution: Morphine readily enters all body tissues except the brain; morphine is the least lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS much more quickly).

3. Metabolism: Conjugated in the liver, morphine–6-glucuronide is a much more potent analgesic; however morphine-3-glucuronide is less analgesic. Both are excreted in the urine with small amounts excreted in the bile. Hepatic & renal dysfunction both prolong the normal 4-6 hour duration of action when administered systemically.

Adverse effects

* Severe respiratory depression can occur and is the mechanism of dearth in most opiate overdose. Vomiting, dysphoria and allergic reactions are also common adverse effects.
* Caution must be exercised when opiates are used in those with liver or renal failure.

Tolerance & Physical Dependence

Repeated use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation. Tolerance does not develop to miosis and constipation. Physical & psychological dependence readily occur with morphine and other opiates. Withdrawal induces a syndrome associated with autonomic, motor and psychological responses that are incapacitating, rarely are these life threatening.

Meperidine

* Meperidine (Demerol) is a synthetic opioid structurally unrelated to morphine.
* Mechanism: It binds to μ receptors with some binding at κ receptors.
* Actions: It causes respiratory depression similar to morphine but has no significant cardiovascular effect when given orally. IV administration produces a decrease in PVR resulting in increased peripheral blood flow. It causes papillary dilation via an atropine –like effect.

Meperidine

* Therapeutic uses: Severe acute pain, it lacks anti-tussive activity and produces less smooth muscle contraction/spasm than morphine.
* Pharmacokinetics: It is well absorbed form the GI tract; it is most often given IM. It has a shorter duration of action than morphine (2-4 hours). It is demethylated in the liver and excreted in the urine.
* Adverse effects: With large repeated doses normeperidine (demethylated meperidine) accumulates causing anxiety, muscle tremors and convulsions. It causes papillary dilation (vs. miosis with morphine) in large doses. There is cross-tolerance with other opioids.

Methadone

* This is a synthetic orally effective opioid that is equipotent to morphine but induces less euphoria and has a longer duration of action.
* Mechanism of action: Methadone binds to the μ receptor.
* Actions: Methadone is well absorbed orally and is an equipotent analgesic to morphine. It causes miosis, respiratory depression, biliary spasm and constipation just like morphine.

* Therapeutic uses: It is used for controlled withdrawal from heroin & morphine. Methadone is it self addictive but the withdrawal syndrome is somewhat milder but more protracted than with other opioids.
* Pharmacokinetics: Readily absorbed orally it is highly protein bound so remains in tissues for a prolonged period. It is transformed in the liver and excreted by the urine as mostly inactive metabolites.
* Adverse effects: similar to morphine particularly the risk of addiction

Fentanyl

* Chemically related to merperidine fentanyl has 100 times the analgesic potency of morphine. It has a rapid onset of action and a short duration (15-30 minutes. It can be used IV, epidurally or intrathecally. Transmucosal and transdermal preparations are available. Fentanyl is metabolized to an inactive metabolite by the cytochrome p4503A4 system. Drug metabolites are eliminated through the urine. Like morphine fentanyl causes miosis (vs. mydriasis). A particular risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa.
* Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl.

Heroin


* Heroin is produced by the diacetylation of morphine which results in a three fold increase in its potency. The acetylation allows it to cross the BBB much more rapidly yielding a more pronounced euphoria. It may be used IV or smoked, both allow for rapid distribution, heroin is metabolized to morphine. There is no medical indication for its use in the US.

Moderate Agonists

Codeine

* This is a much less potent analgesic than morphine, it produces less euphoria and has much lower abuse potential and rarely produces physical dependence.
* It is an effective oral analgesic. It does possess significant antitussive effects at subanalgesic doses.
* Codeine is often formulated with either acetaminophen, aspirin of ibuprofen; care but be exerted when these are used with over the counter analgesic to avoid overdose with the non-opioid agent.
* A synthetic congener of codeine dextromethorphan lacks analgesic properties is an effective antitussive available without prescription.

Moderate Agonists

Oxycodone

* This is a semisynthetic derivative of morphine that is orally active; it too is formulated with over-the-counter analgesics. It is metabolized in the liver and excreted via the kidney. Controlled release forms of oxycontin requiring once or twice a day dosing are effective for chronic pain. Crushing these pills disrupts the sustained release mechanism resulting in acute intoxication consistent with opiate overdose.

Moderate Agonists

Hydrocodone is a semi-synthetic opioid derived from two of the naturally occurring opiates, codeine and thebaine. Hydrocodone is an orally active narcotic analgesic and antitussive. It is commonly available in tablet, capsule, and syrup form and is often compounded with other analgesics like acetminophen or ibuprofen

Moderate Agonists

Propoxyphene

* This is a derivative of methadone, it is used for mild to moderate pain; it has ~1/2 the potency of codeine.
* It is often formulated with another over-the-counter analgesic. The combination has greater effect than either drug alone.
* Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression. Opioid antagonists can reverse the pulmonary and CNS effects but not the cardiotoxixity.

Mixed Agonist-Antagonist and Partial Agonists

Buprenorphine

* This agent is a partial agonist at μ receptors producing morphine-like effects in naïve users but precipitating withdrawal in morphine dependents.
* It is metabolized in the liver and excreted in the urine and bile. This agent may be taken sublingually or parenteral and possess a long duration of action.
* Adverse effects respiratory depression not reversible by naloxone, hypotension and nausea.
* Its main use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone. It is available outside of the specialized clinic allowed to dispense methadone for opiate withdrawal.

Antagonists

Opioid antagonists bind with high affinity to the μ, κ & δ receptors but fail to transducer. In normal individuals these agents produce no effect but in those with opiates present they induce an acute withdrawal syndrome.

A. Naloxone

* This agent is used to reverse the coma and respiratory depression associated wit opioid overdose. It competes at all receptors with much greater avidity than agonists. IV administration produces a reversal of CNS & respiratory depression within ~30 seconds. It has a relatively short T1/2 (60-100 minutes) so reversal will often abate requiring repeat administration. Binding affinity is 10X greater at the μ receptor than κ; this may explain how naloxone reverses respiratory depression but not analgesia (resulting from agonism of the κ- receptors in the spinal cord).

B. Naltrexone

* This agent has similar actions as naloxone but it is an oral agent with a much longer duration of action, a single dose is able to antagonize the effects of heroin for up to 48 hours.

Opioid Analgesics & Antagonists.ppt

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PicornaVirus- Characteristics

PicornaVirus- Characteristics
* pico = small, rna =RNA Viruses
+ icosahedral 30 nm
o naked nucleocapsid = Nonenveloped
o plus strand(+) RNA m-RNA
+ single stranded and capped for infectivity and packaging
+ this genome is infectious(should it be introduced into a cell)
o vertices of capsid creates canyon-like depressions which contain the VAP’s, VAP -1, VAP -2, VAP -3
+ most VAP bind to intracellular adhesion molecule -1(ICAM-1) expressed on epithelial cells, fibroblasts, and endothelial cells

PicornaViruses - Pathogens
* Four genera in this Family cause most Human disease
o Enterovirus enteroviruses
# stable at pH 3(acidic conditions), in detergents, sewage, etc
# replicate at temperature> 33 C
o Rhinovirus rhinoviruses
# sensitive and unstable at pH 3 (acidic conditions)
# replicates best at temperatures =33 C
* thus, confining them to the upper respiratory tract
o Hepatovirus
o Aphthovirus

PicornaViruses – Virus Cycle
* Adsorption the susceptible cells
+ appropriate receptors determine host range
+ ICAM - 1 or similar cellular receptors bind VAP’s
* Penetration
+ internalized by endocytosis
+ sometimes by viropexis thru small channels in the cytoplasmic membrane which removes the capsid
* Uncoating
+ genome released by acidic conditions in the endosome
+ capsid removed by passage thru channels in the membrane

PicornaVirus – Replication
* Viruses replicate in the cytoplasm
+ genome binds directly to ribosomes where in functions as m-RNA
+ viral polyprotein is synthesized in 10 -15 minutes
# polyprotein in cleaved into viral products
* cleavage proteases
* viral RNA dependent RNA polymerase
* misc proteins which inhibit cellular functions
+ negative strand(+) template produced by viral RNA polymerase
# these templates then generate new plus stranded RNA
PicornaVirus – Virus Cycle
* Maturation/Assembly
+ structural proteins VP0, VP1, VP3 ect are cleaved from the polyprotein by the viral induced protease
+ structural protein component assembly, then genome is inserted to complete maturation
* Release
+ virions are released by cell lysis

PicornaVirus - Pathogenesis
* Enteroviruses
o most enteroviruses are cytolytic
o they cause direct damage to the cell by preventing cellular m-RNA from binding to the ribosomes
o also viral m-RNA competes with cellular m-RNA for ribosomal binding sites
o symptoms vary with the tissue trophism of the enterovirus
o most enteroviruses cause viremia
* Rhinoviruses
o bind to ICAM-1 receptors on respiratory epithelial cells
o produce a slow cytolytic effect; not via cellular m-RNA mechanism
o temperature and pH restrict viruses to the upper respiratory tract
o no viremia occurs in Rhinovirus infections
o most Rhinovirus replication occurs in the nose
o infected cells secrete bradykinin and histamine which cause “runny nose”
# these cytokines also enhance the expression of ICAM-1receptors and may cause the virus to spread to adjacent cells

Picornaviridae - Enteroviruses
* Polio Viruses
* Coxackie Viruses
* Echo Viruses
* Entero Viruses

Rhinovirus – Clinical Disease
* Acute Rhinitis = Common Cold
+ nasal obstruction accompanied by sneezing, rhinorrhea (runny nose), mild pharyngitis, headache, and malaise
+ without secondary bacterial infection, rhinovirus infections seldom are accompanied by fever
+ symptoms peak in 3-7 days, but may last up to 3 weeks
# 500 - 1000 infectious virions per milliters of nasal secretion
+ virally infected cells secrete interferon which limits the progression of infection , but also contributes somewhat to symptoms
+ nasal secretory IgA, and serum IgG also contribute to recovery, but produce minimal long term protection due to serotype variation(type specific immunity)
+ cell-mediated immunity plays very little role in controlling rhinoviruses

Enterovirus – Clinical Disease
* Poliomyelitis polio
o symptoms range from asymptomatic (in the oropharynx and gut) to mild febrile illness(fever, headache, sore throat, malaise, to aseptic meningitis (headache, and pain in neck and back), to paralysis( destruction of anterior horn cells and motor cortex cells), to death(destruction of medullary center and cranial nerves)
o Paralytic polio is generally to result of lower motor neuron damage and leading to a flaccid paralysis of the lower extremity
o Bulbar polio – causes damage to the respiratory centers in the medulla

Poliomyelitis - Pathogenesis
* initial virus replication is in lymphoid tissues of tonsils and pharynx
o virus is swallowed (resists acid and bile) and replicates in the lymphoid cells of the Peyers patches
# primary viremia takes the viruses to CNS, anterior horn cells and brain motor cortex - producing paralysis of the extremities
* virus may cross the blood brain barrier into CNS
* or virus may move via peripheral nerves to the CNS
o if virus spreads to other areas of the CNS, like medulla and cranial nerve, then bulbar paralysis of respiration, pharynx, vocal cords, etc
# if virus is shed back to the blood from the CNS, this is secondary viremia
+ pathogenically polio viruses are neurotrphic (narrow trophism)
+ humoral antibody is required for recovery and prevention

PicornaViruses – Other Clinical Diseases
* Herpangia = fever, sore throat with painful swallowing, anorexia and vomiting
o vesicular ulcerated lesion on the soft palate and uvula
o etiological agent is Coxsackie virus A, an enterovirus
o virus is shed from the lesions, respiratory droplets and in the feces(fecal-oral)
* Hand-Foot-Mouth Disease vesicular exanthem
o vesicular lesions on the hands, feet, mouth, tongue accompanied by mild fever
+ Coxsackie virus A16
+ etiological agent is virus is shed/transmitted from lesions and is also shed in the feces(fecal-oral)
* Pleurodynia acute onset of fever and unilateral lowthoracic, pleuritic chest pain which may be excruciating = “devils grip”
o somtimes abdominal pain and vomiting; muscles very tender on affected side
+ etiological agent is Coxsackie virus B
* Myocarditis/Pericarditis acute febrile illness with sudden onset of heart faliure giving symptoms of myocardial infarction
o etiological agent is Coxsackie virus B
o occurs at all ages, but most like threatening in neonates
* Aseptic Meningitis acute febrile illness accompanied by headache, pain in neck and back including nuchal rigidity(signs of meningeal irritation)
+ etiological agent is Coxsackie viruses A, B and Echoviruses
+ may also lead to polio-like paralysis
* Respiratory Tract Diseae common cold (rhinitis)
+ Coxsackie viruses A21/A24; Echoviruses 11/20
* Acute Hemorrhagic Conjunctivitis
+ Enterovirus 70 and CoxsackieVirus A24
* Diabetes insulin-dependent
+ Coxsackie B virus destruction of the Islets of Langerhans
* Hepatitis A Infectious Hepatitis
o Hepatovirus

PicornaVirus - Diagnosis
* Enteroviruses
o Laboratory
+ Clinical Chemistry
# cerebrospinal fluid from CNS disease reveals
* lymphocytic pleocytosis (25 - 500 cell/ml)
# CSF glucose and protein
* glucose normal or slightly depressed
* protein normal or slightly elevated
+ Serology
# detection of specific viral antibody in IgM fraction
# four fold increase in IgG from acute to convelescence
o Culture performed only for epidemiological confirmation
# polioviruses from pharynx or feces
# coxsackie or echoviruses from throat or feces
* monkey kidney tissue culture
* human embryo kidney tissue culture
# culture virus is specifically identified with antibody assays

PicornaViruses - Diagnosis
* Rhinoviruses
o mostly based upon symptoms
o laboratory identification of Rhinoviruses uses
+ serology no antigen in common with all Rhinoviruses
# must find antibody to specific serotype
+ culture human diploid fibroblasts at 33 C

Picornavirus - Epidemiology
Enteroviruses
o enteroviruses are exclusively human pathogens = human reservoir
o modes of transmission
+ Polioviruses
# p-p, indirect, fecal-oral
+ coxsackie and echoviruses
# p-p, aerosol droplets, and fecal-oral
* Rhinoviruses
o account for more than one-half of all upper respiratory tract infections defined and the “common cold”
o transmitted by respiratory droplets (aerosol), contact, and fomites
# hands are a major vector; 40 - 90 % people with colds
o Non-enveloped viruses are stable and survive on hands and fomites for hours

Enterovirus - Polio Control
* control of polio has centered around stimulation artificial active immunity via vaccines
o to shift the ratio of susceptible/immunes.
* Two Polio Vaccines
o Salk Vaccine - three strains of inactive polio viruses(IPV)
o Sabin Vaccine -three strain of active attenuated viruses(TVOPV)
# attenuated viruses are supposed to grow only in the oropharynx or intestinal tract, but not in nerve cells. In absence of reversion, this is the case and system responds immunologically
* Polio will be the next communicable disease to be eradicated
o Changes in Polio immunization guidelines – 1998
+ Use only inactive (Salk) vaccine
+ To reduce reversion of attenuated strains

ParamyxoViruses - Characteisteristics
* single-stranded, negative sense RNA viruses
o helical(spherical) nucleocapsid surround by envelope (150 - 300nm)
+ envelope glycoproteins
# F(fusion) protein - promotes fusion of virus with host cell
* all viruses in this group caused cell-cell fusion of infected cells forming synctytia and giant cells
# VAP - Hemagglutinin-Neuraminidase Paramyxovirus/Mumps
* Hemagglutinin Morbillivirus
* G protein RSV
o various enzymes/proteins carried in virion
+ L protein is the RNA dependent RNA polymerase
+ P protein facilitates RNA synthesis

Paramyxovirinae – Human Pathogens
* Respirovirus = Parainfluenza
* Rubulavirus = Mumps
* Morbilliviruse = Measles
* Pneumovirus = Respiratory Syncytial Disease

ParamyxoVirus- Viral Cycle
* Adsorption
+ VAP’s(HN, H, or G) bind virion envelope to cell surface receptors(sialic acid)
* Penetration
+ F protein promotes fusion of the virion envelope with host cell membrane
# this same protein is expressed on virally infected cells and causes them the fuse forming syncytia(multinucleated giant cells)
* Replication occurs in the cytoplasm of host cells
+ a positive sense(+) template is madefrom the negative-sense(-) RNA
# catalyzed by the virion based RNA dependent RNA polymerase
+ the positive sense(+) RNA serves as the m-RNA for a protein synthesis and as the template for replication of the new negative-sense(-) RNA
* Maturation/Assembly
+ new negative-sense genomes interact with the other viral proteins both structural and non-structural(L, NP, P,) to forms nucleocapsids
+ virions then associate with host cell membrane via virus encoded matrix(M) protein
* Release
+ Nucleocapsids bud from host cell membrane and acquire their envelope with its glycoproteins ( F/HN)

ParamyxoViruses – Clinical Disease
* Measles also called Rubeola
o serious febrile disease with symptoms of high fever and cough, coryza, conjunctivitis(three C’s) and photophobia
+ incubation period = 7 - 13 days
+ within 2 days of prodromal fever lesion known as “Kopliks” appear on the mucous membranes especially the buccal mucosa. = diagnosis
* within 12 - 24 hrs after Kopliks appear the exanthem appears
o maculopapular rash starting below the ears and spreading over the entire body - lesions often run together = confluence
+ patient is sickest and fever is highest the day rash appears
o classic childhood exanthem caused by Morbillivirus
o pathogenesis
+ virus spreads from initial site of infection in lymphocytes and blood (viremia)
+ in the tissues, the virus shows a major propensity to causedcell fusion resulting the giant cell formation
+ virus can pass from cell to cell and escapes detection by antibody
+ infection usually results in cell lysis
+ rash is due to T-cells attacking the virus infected endothelial cells lining the small blood vessels

ParamyxoViruses – Clinical Disease
* Mumps
o febrile illness characterized by parotitis( acute benign swelling of the salivary glands
+ incubation period = 7 - 14 days
+ glands become infected during incubation period when virus multiplies in respiratory epithelial cells and spreads via Stenson duct or by viremia (or both) to the salivary glands
+ the viremia carries the virus to tissues throughout the body( testes,ovary,pancreass, thyroid, etc.) and especially the the CNS
+ CNS involvement occurs in approx 50% of patients and forms the basis for aseptic meningitis
o etiological agent is Rubulavirus

ParamyxoViruses - Diagnosis
* Measles
o symptoms - the clinical symptoms are so distinct that laboratory comfirmation is seldom necessary
o laboratory virus may be found in respiratory secretion, urine, blood, and sometimes in brain tissue
+ antigen detection =immunofluorence of pharyngeal cells
+ antibody response = IgM when rash appear; four fold increase in IgG
+ cytopathology multinucleated giant cells with cytoplasmic inclusion bodies seen in respiratory cells and urine sediment
+ culture virus grows in human or monkey primary cell cultures
* Mumps
o symptoms although often asymptomatic
o laboratory virus found in salvia, urine, pharynx, Stensens duct, and cerebrospinal fluid
# serological detection of mumps specific IgM
# or fourfold increase in mumps specific IgG
o cytopathology multinucleated giant cells in monkey kidney cell cultures
+ also infected cells “hemadsorb” guinea pig erythroctyes

Paramyxoviruses – Disease Complications
Measles Complications

o pneumonia accounts for 60% of deaths from measles
o Subacutesclerosing panencephalitis virus becomes a “slow virus” in the brain and appears as an extremely severe neurological sequalae
* Mumps
o Aseptic meningitis
o Ochitis
o Pancreatitis

ParamyxoViruses - Epidemiology
* Measles
o human reservoir virus is spread in respiratory secretion before symptoms(incubation carrier) and several days after symptoms appear(3 - 4 days after the apppearenc of the rash)
o measles is highly contagious via p - p, direct, respiratory droplets
# 85 % of susceptibles in an exposed group (household) become infected by one single symptomatic individual
* Mumps
o human reservoir both symptomatic and asymptomatic
o highly communicable before immunization 90% of U.S. population was exposed before age 15
o p-p, direct, respiratory droplet transmission; some direct contact
# incubations carriers are infectious 7 days before symptoms

ParamyxoViruses – Clinical Disease
* Parainfluenza
o mild cold-like infection of the upper respiratory tract with symptoms of fever, coryza, pharyngitis, and mild bronchitis = common cold
o may progress to a more severe bronchiolitis and pneumonia
+ generally more serious in children in whom in progresses to laryngotracheobronchitis ( also known a “Croup”)
# Croup is due to subglottal swelling which closes the airway
# Croup ranks second only to RSV as the most severe lower respiratory tract infection in infants and children
o two serotypes of Respirovirus Viruses ( types 1&3)
o viruses remain localized in the respiratory tract; there is no viremia
o Cell-mediated immunity is responsible for cellular damage as well as recovery
o Antibody, esp IgA is protective and prevents additional infection for a short time; but re-infections are common throughout life

ParamyxoViruses – Clinical Disease
* Respiratory Syncytial Disease
o respiratory tract infections ranging from the common cold to pneumonia
+ rhinorrhea is a prominent symptom in older children and adults
+ bronchiolitis is a more severe manifestation in infants
# cell-mediated immunity causes necrosis of the bronchi and bronchioles with the formation of “plug” of mucus, fibrin. This obstructs the narrow airways in young infants leading to suffocation
# this traps air and decreases ventilation
# very fatal in premature infants
o caused by the Pneumovirus (also called RSV) single serotype

ParamyxoViruses - Diagnosis
* Parainfluenza Croup in children in very diagnostic; otherwise symptoms cannot be distinguished from the “common cold”
+ virus and virally infected cells are present in nasal washings and respiratory secretions; and can be detected by cytopathology or immunofluorence antigen detection methods
+ specific antibody (IgM) can be found using hemadsorption or hemmagglutination test
* Respiratory Syncytial Disease
+ cannot be grown in cell culture
+ most labaratory diagnosis is done on nasal washings and respiratory secretions using immunofluorescenc or enzyme immunoassay
+ serological finding of fourfold increases in IgG provides confirmation

ParamyxoViruses - Epidemiology
* Parainfluenza
+ human reservoir -viruses are ubiquitous and infection is very common
+ p-p, direct, respiratory droplets transmission; some direct contact
+ reinfection throughout life is common since immunity is short lived
+ some serotypes are seasonal
# parainfluenza 1, 2 (major agent of croup) in the autumn
# parainfluenza 3 occurs throughout the year
* Respiratory Syncytial Diseae
+ human reservoir very common in young children
# 65 - 98% of children in day-care setting are infected by age 3
# infects everyone by age 4
# 25 - 33% of cases in children involve the lower respiratory tract
+ RSV infections almost always occur in the winter and epidemic occur every year; unlike influenza which sometimes skips a year
+ highly contagious with an incubation period of 4 -5 days
+ most common cause of fatal acute respiratory tract disease in children under the age of 2

ParamyxoViruses - Immunity
Measles

o T-cells contribute to symptoms, but also are thebasis of resolution and recovery ; antibody (B-cells) forms the basis of prevention and protection
+ antibody does not contribute to complete recovery because the virus moves from cell to cell(direct extension
o antibody based immunity is “ lifetime”; does not often reoccur in same person
+ only one serotype of Morbilli(measles) virus
* Mumps
o same as with measles
o only one serotype of Mumps virus
o antibody based immunity is “lifetime”; does not often reoccur
* Parainfluenza
o Protective immunity following infection is short lived
+ Only IgM antibody response which has not memory
o Therefore, reinfections throughout life are common
* Respiratory Syncytial Disease
o same as with Parainfluenza; no natural passive immunity

ParamyxoViruses - Control
* Measles
+ active attenuated measles virus; one antigen in the polyvalent MMR
+ inactive vaccine did not provide protection and complicated natural disease
* Mumps
+ active attenuated mumps virus; one antigen in the polyvalent MMR
* Parainfluenza
+ no vaccine available
+ immune system support is only treatment and protection
* RSV
+ no vaccine available
+ passive immunization is sometimes used in premature infants
+ treated with Ribavirin

OrthomyxoViruses - Characteristics
* pleomorphic, enveloped, negative -sense RNA having a segmented genome
+ 7 - 8 individual strands of RNA
# nucleoprotein(NP) and transcriptase associated with each strand
+ envelope has two glycopreteins
# hemaggluttinin(HA) - projects as spikes and promotes adsorption
* genetic mutation (instability) producing antigenic variation
# neuraminidase(NA) - projects as spikes and promotes adsorption and release
+ matrix proteins line the virion and compose the capsid
o transcription and replication of influenza viruses occurs in the nucleus
o assembly occurs in the cytoplasm; close association with membrane
o release is by budding through the cytoplasmic membrane
o viruses are prone to genetic variation via mutation(recombination)
# antigenic drift
# antigenic shift
OrthomyxoViruses – Viral Cycle
* Adsorption
+ Hemagglutin (HA) is the viral attachment protein
# Binds the virion to the sialic acid component of epithelial cell receptors
# The viral component that causes hemagglutination of chicken and guinea pig red blood cells
# Is antigenic: antibody against it is protective(neutralizing)
* mutations in the virus genome cause changes in the HA and are responsible for antigenic shift and drift in type A viruses
+ Neuraminidase(NA) facilitates adsorption by hydrolyzing the sialic acid (neuramic acid) in respiratory mucous and thus exposing the sialic acid receptors to which the HA binds
o Penetration
+ Virion is taken into host cell by endocytosis
# The virus is released from the endosome when the fusion-promoting portion of the HA fuses the viral envelope with the endosomal membane
# Acidification of the Matrix and NP also uncoat the virus during release from the endosome; genome is this taken into cell nucleus

OrthomyxoViruses – Viral Cycle
* Replication
+ virions carry three variants of RNA dependent RNA polymerase
# during transcription of the viral RNA segments the polymerases used the cellular m-RNA in the nucleus as a primer; this removes the methylated cap form the cellular m-RNA so that it cannot bind to the ribosomes; resulting in cessation of cellular protein synthesis(translation)
+ positive sense(+) templates are produced for each RNA segment
# these templates are then used to polymerize new negative sense RNA
+ m-RNA formed in the nucleus is translated in to a spectrum of viral proteins by the ribosomes in the cytoplasm
# among the proteins synthesized are the HA and NA glycoproteins which are processes by the endoplasmic reticulum and the golgi and then incorporated into the host cell membrane

OrthomyxoViruses – Viral Cycle
* Maturation/Assembly
+ the negative sense replicas are transported to the cytoplasm where they associate with new polymerase and NP molecules
+ these segment are held together by matrix protein(M2) which then bind it to the cell membrane via matrix protein(M1)
+ since the mature virion must have 8 different RNA segments, only a few virions mature; the others are defective but antigenic
o Release
+ The complete and defective virions bud from the host cell membrane
+ The envelope with its HA and NA glycoproteins is acquired during this process
+ The cycle take about 8 hours
OrthomyxoViruses – Clinical Disease
* Influenza
+ a prodrome of malaise and headache(lasting a few hours) leads to abrupt onset of fever, servere myalgia, and usually a nonproductive cough
# the viruses infect the cells of the upper respiratory tract
* the infection first affects the mucous-secreting cells, and ciliated epithelial cells plus other cells the respiratory epithelium
+ these changes in the upper respiratory barrier, allow the virus to move into the lower respiratory tract and infect the bronchial and alveolar epithelium
+ virally infected cells binds opportunistic bacteria; setting the stage for secondary bacterial pneumonia
+ ultimately the mucosal surfaces throughout the respiratory tree become inflamed; causing submucosal edema, hyaline membrane disease, and necrosis of alveolar walls
+ incubation period of 1 - 4 days; acute illness last approx 3 days; but the cough may last more than a week
+ influenza is more severe in young children and the elderly
+ complications are bacterial pneumonia and Reye’s syndrome
# Reyes syndrome is an acute encephalitis that affects children who have acute febrile illness; and is promoted by salicylates

OrthomyxoViruses - Diagnosis
* symptoms especially when community epidemics occur laboratory distinguishes influenza from other respiratory viruses
+ respiratory secretion
# cultured non-specific cytopathology; hemadsorption; hemagglutionation
+ serology
# hemagglutinatin-inhibition
+ Antigen detection
# Detection of Types A and B envelope glycoproteins
OrthomyxoViruses - Epidemiology
* Reservoir Human and Animal Strains
o Source In the U.S. infected human
# In Asia/Orient both infected humans and infected animals
o Antigenic Changes
+ Antigenic Drift Influenza types A and B exhibit slights changes in the HA and NA antigens due to mutution; perhaps some reassortment
# has only minor affect on the susceptibility of a population
# occurs every two to three years
+ Antigenic Shift Only occurs in Influenza Type A viruses; mostly due to reassortement of genes between human and animal strains
# results in complete changes in HA and NA antigens
# affects the susceptibility status of a population significantly
# occurs every 8 - 10 years Fig 56-5
o Mode of Transmission
+ person-to-person, direct, respiratory droplets acute phase
# incubation carriers

OrthomyxoViruses - Epidemiology
* Pandemic resulting from Antigenic Shift
+ 1918 HswH1 orignal swine flu
+ 1947 A/FM/47/H1N1
+ 1957 A/Singapore/57/H2N2
+ 1968 A/HongKong/68/H3N2
+ 1977 A/USSR/77/H1N1
+ 1979 A/Bangkok/79/H3N2
+ 1989 A/Beijing/89/H3N2
+ 1991 A/Texas/91/H1N1

OrthomyxoViruses - Control
* Interrupt transmission this is almost possible to accomplish
* Immunization
+ Inactivated(formalized) vaccine is produced each year and contains the three or four most recent antigenic strains which have affected the world
# intact virus
# splitt virus
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