• Sprengel’s – unilateral elevation of scapula; actually, failure of scapula to descend.
• Omovertebral bone – often seen with sprengel’s. Often associates Klippel-Feil syndrome, blocked vertebra, webbed neck
• Rhomboid fossa – a muscular impression on X-ray. No clinical consequence.
• Hemivertebra – only neatly triangular when drawn.
• Scrambled spine, also a structural scoliosis.
• Butterfly vertebra – missing primary ossification centers in the body, apparently migrating to the levels above and below.
• Intrathoracic rib – unlikely to produce any complications.
• Synostosis of rib (bifid rib, or costal synostosis). Failure to separate.
• Elongation of L5 TP, considered a physiologic variant most likely calcification of iliolumbar ligament.
• Spina bifida in the lumbar vertebra seems to associate with increased disc pathology.
• Reversed thoracic kyphosis or thoracic lordosis: recommendable to perform thoracic cage mensuration. If linked with a heart murmur, then straight back syndrome. If there is a heart murmur it is likely a result of floppy valve syndrome. High percentage have pathology requiring valve replacement.
• Costochondral ossification – physiologic calcification – everything (serum and tissue calcium) is normal.
• Thoracolumbar transitional ribs.
• Notochordal persistency resulting in cupid’s bow.
• Winking owl sign – metastasis (most common) or congenital. Sclerosis of the contralateral indicates congenital because it takes a long time to sclerose.
• There is an apparent correlation between spina bifida and DJD.
• Springboard divers, interior lineman, gymnasts are at high risk for acquired splondylolysis.
• If flexion/extension demonstrate 3% or more translation you confirm unstable listhesis; less than 3% does not rule in or out anything.
• Oppenheimer’s ossicles – nonunion of growth centers.
• Lordotic sacrum
• Injection granulomas [from arthritic injections in the gluteus] called dystrophic calcification (regularly seen in patients).
• Pseudotumor of the pelvis – results from observation of the growth plate between the ischial and pubic rami.
• Fabella – sesamoid-like bone in lateral gastroc often confused with synovial chondroplasia.
• Rockerbottom foot – missing tarsal bones
• Bipartate sesamoid bones.
• Tarsal coalition – bony bars in the tarsals.
• Pseudotumor of the humerus – lucency that results from the attachment of rotators – it disappears on baby-arm X-ray
• Supracondylar process – found on the humerus and points toward the elbow joint (normal variant). Often confused with osteochondroma – points away from the joint, found anywhere on the body, and has a chondral cap.
• Maudline’s deformity – ulnar deviation of wrist
• Ulna minus – short ulna. Non united growth centre of ulnar styloid process.
• Radius minus.
• Synostosis – failure of the bones to separate.

A problem that occurs during or after a trip does not necessarily need to have a causal connection with that trip. Articular symptoms occur frequently in tourists. The first question is whether these complaints are due trauma, strain, arthritis or arthrosis. Arthritis is accompanied by inflammatory symptoms. Arthrosis is a degenerative condition of the joints which occurs all over the world. It usually involves primary idiopathic arthrosis, though some cases are secondary (trauma, infection, …). If the condition is arthritis, a distinction should be made between a monoarthritis and a polyarthritis. Furthermore, it is important to know whether it involves an acute problem or a chronic disease. A few articular abnormalities unconnected with travel are also mentioned here, such as those that can be seen in adopted children.

• Reactive arthritis is sometimes a problem in tourists, because of the frequency of intestinal infections (Campylobacter, Yersinia, Salmonella, Shigella). The lesions appear several days to weeks after an acute infection. Presence of HLA-B27 increases the risk of post-infectious arthritis 50-fold. Reactive arthritis can also occur in inflammatory intestinal diseases and in genital Chlamydia trachomatis infections. The ankles and knees are more often affected than other joints.

• Rat bite fever (Haverhill fever) is accompanied by skin rash, fever and a migratory artritis. The patient might not spontaneously tell the doctor that a bite from a rodent (rat or other) occurred. When transmissions occurs via contaminated milk, there will be no skin ulcer.

• Filariosis. Arthritis secondary to infection with Wuchereria bancrofti usually affects the knee or an ankle joint. Inflammation of the joint can be secondary to rupture of dilated lymph vessels. Microfilariae can be detected in the blood. Mansonella perstans filariosis occasionally causes articular problems.

• Dracunculiasis (Guinea worm) can be accompanied by severe inflammation of joints, with eosinophilia. Detection of the adult worm in a concomitant skin ulcer orientates the diagnosis. There are no microfilariae in the blood or tissues.

• Coccidiomycosis can be accompanied by severe joint pain (desert rheumatism). Culture of the fungus is usually necessary for the diagnosis.

• Acute bacterial infection of a joint is occasionally seen. Septic arthritis can result in permanent damage to the joints. Staphylococcus aureus is notorious for this. Infection with Neisseria meningitidis or Neisseria gonorrhoeae can be accompanied by acute septic arthritis or by development of an immue complex arthritis that may exhibit a migratory character.

• Viral. Many acute articular inflammations are secondary to a viral infection (rubella, rubeola, mumps, hepatitis B, Chikungunya, parvovirus B19 [erythema infectiosum], lymphocytic choriomeningitis virus). The arthritis is usually self-limiting. Ross River Virus is an arbovirosis confined to Australia. Chronic arthralgia may follow acute infection. Similar symptoms can follow infection with Barmah Forest virus. There are a number of other (rare) arboviruses which cause arthralgia (see chapter arboviruses).

• In the trauma group, it is important to check if their might be any foreign body, such as a broken off sea urchin spine near a joint.

• Acute rheumatic fever. Migrating arthritis of the major joints is an essential sign in this disease, which is frequent in tropical countries. It can occur several weeks after a throat infection with Lancefield group A streptococci, e.g. Streptococcus pyogenes. Subcutaneous noduli appear a few weeks after fever, carditis and sudden arthritis. Both erythema marginatum and noduli are rare (cfr Jones' criteria).

• Familial Mediterranean Fever. The disease was for a long time of unknown origin, but mutations have recently been identified in the gene coding for the protein marenostrine. Certain population groups such as Armenians and children of consanguineous marriages run a high risk of being affected. Attacks of acute abdominal pain as well as pleuritis and pericarditis occur. There is a considerable risk of amyloidosis as a complication. DNA-analysis can confirm the clinical suspicion in more than 70% of the cases (anno early 2004). Colchicine is used for prevention.

• Reiter syndrome can occur after unprotected sexual intercourse and is characterised by urethritis, conjunctivitis/iritis and arthralgia. A culture or better PCR should be carried out (detection of Chlamydia trachomatis and Neisseria gonorrhoea). PCR for Chlamydia trachomatis can also be performed on urine.

• Miscellaneous. Gout and pseudogout (calcium pyrophosphate) are cosmopolitan diseases. Autoimmune diseases, such as sarcoidosis, systemic lupus erythematosus and rheumatoid arthritis, including the juvenile form (Still’s disease). Henoch-Schönlein purpura is usually identified by the associated symptoms (abdominal pain, cutaneous rash, renal abnormalities). Do not forget tuberculosis and leprosy in cases of osteomyelitis.

• Caisson disease (the bends) due to rapid decompression after scuba diving can initially result in itching and a marbled or mottled appearance of the skin. These symptoms can precede more serious problems (abdominal pain, transverse myelitis, lung embolism due to nitrogen gas). Aseptic bone necrosis is a later complication.

• Infectious. Chronic arthritis due to tuberculosis is not unusual in the tropics. It is more likely to occur in the hip joint. Brucellosis with bone lesions can resemble tuberculosis. Buruli ulcer disease, leprosy and fungal infections can mutilate joints.

• Lyme disease caused by Borrelia burgdorgeri can follow tick-bite in individuals in Europe or America, but is apparently non-existent in the tropics.

• Whipple’s disease (infection with Tropheryma whipplei) is very rare. Insufficient data are available on its incidence in the tropics. In addition to polyarthritis, it is characterised by fever, chronic diarrhoea due to malabsorption, anaemia and various neurological signs.

• Charcot joints. In neuropathic joints there is a loss of pain perception and of proprioception. One has to exclude diabetes, leprosy and syphilis. Other causes are amyloidosis and syringomyelitis.

• Kashin-Bek disease. Aetiology is unknown. The disease occurs in certain areas of Asia and appears as a chronic osteoarthritis.

• Haemoglobinopathy, such as in sickle cell patients. Hip joint necrosis, shoulder destruction and hand-foot syndrome (dactylitis) are frequent in homozygotic children. Osteomyelitis is a frequent complication.

• Chronic hip lesions in children may be due to congenital abnormalities such as congenital hip dislocation, subluxation or congenital syphilis, in addition to tuberculosis and sickle cell disease. In Calvé-Legg-Perthes disease there is a usually unilateral necrosis of the femoral epiphysis, as a result of ischaemia (aseptic necrosis).

• Trauma, both acute and chronic. A fracture can sometimes not be noticed at first. Avascular necrosis can follow (head of femur, wrist).

• Psoriasis can be accompanied by articular inflammation. Check skin and nails.

• Congenital diseases such as Gaucher’s disease. There is a form of this disease that occurs in young people, but also one that becomes apparent only in adults. Chronic splenomegaly is usually a feature of this metabolic disease. The hip joint is frequently affected.

• we will have to determine whether it is physiologic or pathologic

• mechanism: normal or altered normal automaticity

• normal sinus tachycardia (NST) is a physiologic response to stimuli, primarily catecholamines, and should not be treated

• instead, underlying causes should be sought and treated. for example, septic patients often have tachycardia, and treat sepsis, not the tachycardia

• “they are an exciting group of arrhythmias; they happen very quickly.” har har

• rate > 100 bpm

• may be physiologic (you’re on the treadmill) or non-physiologic (you’re just sitting there)

• supraventricular tachycardias

  • narrow QRS complex

  • wide QRS complex

• mechanism: abnormal automaticity

• P wave in lead II should be upwards; however, these P waves are upside down

• so that means the direction of impulse conduction is reversed—right atrium to left atrium instead of left to right

• sx

  • palpitations

  • lightheadedness

• rx

  • Ca-channel blockers

  • β-blockers

  • class IC agent to suppress automaticity

  • ablation is often required for cure

• uncomfortable. heart rate is 150 bpm when the patient sits down to watch TV

• inappropriate sinus tachycardia out of proportion to physiologic, pharmacologic, pathologic stimuli

• due to defective norepinephrine uptake in synaptic cleft. this leads to abnormal automaticity

• rx

  • β-blockers

  • modification of SA node with ablation

• in contrast to atrial flutter, the source is typically the left atrium

• very disorganized atrial arrhythmia

• very common—up to 10% of population over age 80

• rx: two strategies

  • 1 rate control: β-blockers, Ca-channel blockers, anticoagulation. leave the patient in atrial fibrillation and block the two bad things that happen (tachycardia, thrombosis)

  • 2 rhythm control: using electrical cardioversion, antiarrhythmic drugs, ablation in an attempt to maintain normal sinus rhythm. pts still need to be anticoagulated

• types

  • paroxysmal

    • starts and stops on its own

    • mechanism: abnormal automaticity and reentry, involving the entire atrium

    • treated medically using rate control and anticoagulation

    • ablation is challenging, but more likely succeed than for persistent AF

  • persistent

    • does not stop spontaneously. needs to be stopped with cardioversion, antiarrhytmics, or ablation

    • mechanisms are reentry and abnormal automaticity

    • treated with rate control medications and anticoagulation

    • ablation is very challenging and less likely to succeed

• ECG: “irregularly irregular RR intervals” or “irregularly irregular QRS complexes” without clear P wave and no flutter waves 40

• on physical exam, you can feel this

• “here is an arrhythmia that is near and dear to my heart…sorry”

• extremely treatable

• mechanism: reentry around tricuspid valve and annulus. has all three requirements for reentry

• ECG
  

  • sawtooth waves with QRS complexes

  • QRS complexes occur at multiples of the sawtooth wave—say, every two or every four

• rx

  • anticoagulation required to prevent thrombosis

  • ablation is recommended for long-term management

• reentry in AV node—this is the example of reentry that we used above

• 40% of individuals have two pathways in their AV node, a slow and a fast pathway

• in most patients, physiologically, the slow pathway doesn’t do anything. we know that because after ablation, people do fine the rest of their lives

• mechanism: one impulse goes down both pathways, but F pathway transmits this to ventricles first. this blocks the transmission in S pathway

• a second, early impulse occurs, and it can’t go down the fast pathway because it is blocked (it’s repolarizing). so instead the impulse goes down the slow pathway

• by the time it finishes the slow pathway, the fast pathway is again ready to accept depolarization, which it gets from the early signal wrapping around the slow pathway. this starts a wave of reentrant activity

• ECG
  

  • narrow-complex arrhythmia

  • conduction is going down and QRS looks normal

  • quite fast, characteristically about 150 bpm

  • relationship between atria and ventricles firing is VA VA instead of AV AV

  • the ventricle is being activated in reverse, so this is pseudo R’ wave

  • you see these little R’ waves and this is indicative

• rx

  • class II β-blockers or class IV Ca-channel blockers

  • however, catheter ablation of slow pathway is > 95% successful and the procedure is assoc with very few complications

• occurs in Wolff-Parkinson-White syndrome

• in this, there is a second conduction pathway along the atrio-ventricular brim

• the reentry involves using both the AV node and an accessory pathway as the retrograde limb

• ECG
  

  • patients with AVRT might not always be in arrhythmia

  • you see a widened QRS caused by preexcitation

  • normally, SA conducts to AV node. AV conducts quite slowly (120 ms)

  • accessory pathway, however, is much faster. by the time the AV node is done conducting, the accessory pathway has long since depolarized the ventricles

  • that gives you a delta wave on the ECG, a big, triangular wave, followed by atrial depolarization p wave. the upslope is the early excitation of the ventricle from accessory pathway

  • narrow complex QRS looking quite normal

  • often difficult to see atrial activity. in AVNRT, P wave is right after R’ wave; in AVRT, P wave is delayed a little bit after R’ wave

• rx

  • increase vagal tone with Valsalva, carotid sinus massage, IV adenosine to terminate AVRT

  • antiarrhythmic drugs to block conduction down accessory pathway (Class I, Class III) or may be used to slow AV node conduction (Class II, Class IV)

  • catheter ablation is treatment of choice for symptomatic patients

• by far the most common

• each VT wave looks about the same and goes on at a normal rate

• occurs in patients who have had heart attacks before—reentry around the scarred myocardium

• VT and VF are responsible for most cases of sudden cardiac death, which accounts for more than 400,000 deaths per year in the US

• if defibrillated early, up to 70% may survive to hospital admission

• however, overall rate of survival to hospital discharge is under 15%

• drug therapy can be considered for patients who survive VT; however, ICD should be considered in almost every patient

• spontaneous ventricular depolarizations not preceded by a P wave

• typically do not need to be treated unless they are very symptomatic or extremely frequent (> 5000 per 24 hours, or, in other terms, every fourth or fifth beat)

• rx: class II medications (β-blockers, e.g. metoprolol) and class III (K+ blockers, e.g. sotalol)

• immediate recognition and treatment with defibrillation are the only immediate therapeutic options for VF

• VF has no pattern—it shows very small fibrillation waves. after about 6 sec of VF, almost all patients will lose consciousness

• just as with VT, survivors of VF should be considered for ICD therapy unless a definite, reversible cause of VF is identified and removed

  • for example, if someone has VF during a heart attack, the ischemia should be fixed at some point. ICD should not be used because atherosclerosis or whatever caused the MI should be treated first

• occurs in patients with early afterdepolarizations or prolonged QT interval

• nomenclature

  • if this occurs in a patient with a prolonged corrected QT interval (QTc), it’s just called polymorphic VT

  • however, if patient has a long QT interval at baseline, it is called torsades de pointes

Drug therapy

• most common and least invasive way is to treat with drugs

• typically, antiarrhythmics are best suited to treat tachyarrhythmias. side effects of medications for bradyarrhythmias preclude long-term use

• antiarrhythmic medications can be used for

  • arrhythmia suppression

  • rate control

  • anticoagulation to prevent thrombotic complications

• drugs are classified according to their major antiarrhythmic effect

• however, several drugs have more than one class of action

  • amiodarone acts in all 4 classes

  • propafenone acts in classes IA and III

• digoxin falls outside this classification scheme but it is commonly used as an antiarrhythmic

• Malaria is very common; a very important cause of mortality and morbidity

• Four different parasites: Plasmodium falciparum, P. vivax, P. ovale, P. malariae

• Transmission via female Anopheles mosquitoes which bite at night

• Symptoms: atypical, fever, coma, anaemia, kidney failure, splenomegaly

• Infections often asymptomatic in semi-immune people (generally low parasitaemia)

• Clinical diagnosis not reliable

• Result is over-diagnosis of malaria and under-diagnosis of other disorders

• Thick smear and thin smear positive => problem of chronic carriers with another disorder

• Treatment of P. malariae: chloroquine

• Treatment of P. vivax and P. ovale: chloroquine with or without primaquine (hypnozoites)

• Treatment of P. falciparum: often insufficient response to chloroquine or Fansidar

• Better: quinine + vibramycin; atovaquone with proguanil (Malarone), artemether/artesunate with or without mefloquine or lumefantrine

• Progressive increasing multidrug resistance of P. falciparum

• Isolated cases of chloroquine resistance of P. vivax

• Resistance of mosquitoes to various insecticides

Malaria is the common name for diseases caused by infection with single-celled parasites of the genus Plasmodium. They belong to the Apicomplexa. Organisms of this group are characterised by what is called an apical complex, a structural feature visible only under an electron microscope. The apical complex consists of a polar ring or rings, rhoptries (saccular organelles), micronemes (thread-shaped organelles), a conoid (cone-like structure) and subpellicular microtubules. Among the parasites of the genus Plasmodium four species have been identified which can cause disease in humans :

• Plasmodium falciparum

• Plasmodium vivax

• Plasmodium ovale

• Plasmodium malariae

Certain plasmodia (P. cynomolgi bastianelli, P. cynomolgi cynomolgi, P. brasilianum, P. schwetzi, P. inui, P. simium, P. knowlesi) which infect monkeys in the wild, may also infect humans, but because of the mild symptomatology and their rare occurrence they pose no problem in clinical practice. It is also possible that due to their rarity these zoonotic infections are missed in the normal clinical setting. Plasmodium ovale was discovered in 1922.

Malaria was a well-studied disease in the West until the middle of the 20^th century. Until that time the disorder was still endemic in North America and large parts of Europe. It was a significant impediment for the European nations during the colonial period. Malaria also played a large part in the wars of the 19^th and 20^th centuries. For many years it had been known that people who died of malaria had large amounts of black pigment in their liver, kidneys, spleen and bone marrow. Yet the cause of this disorder long remained a riddle. In 1880 the French army doctor Charles Louis Alphonse Laveran discovered malaria parasites in fresh blood from a chronic malaria patient in the coastal town of Bone (Annaba), Algeria. He also observed exflagellation (see below), which normally only takes place in the stomach of the mosquito.

The names which were given to the microscopic organisms were “Laverania falcipara” and “Oscillaria malariae”. At that time there were as yet no staining techniques, and microscopes were quite primitive with a limited magnification. In 1884 the German Ernst Karl Abbe, together with Carl Zeiss, developed the oil immersion lens and a few years later the optical condenser, which allowed a greater magnification and clearer, sharper views.

The Russian Dimitri Romanowsky developed a staining method based on methylene blue. The findings of Laveran could now be verified by others. Laveran received the Nobel prize in 1907.

The study of dyes led to the development of various techniques for staining bacterial preparations and histological sections. Romanovsky stains are based on a mixture of basic dyes (positively charged) such as methylene blue, and anionic dyes (negatively charged), such as eosin. The positively charged dye will bind to negative structures (nucleic acids, ribosomes), and the negative dye will attach to positively charged structures (many cytoplasmic proteins). The specific mixtures, techniques and variants were named after those who developed them, e.g. Giemsa, Wright, May-Grünwald.

The transmission of malaria had for long been a mystery. One of the researchers was the Briton Sir Ronald Ross. He left for India with a personal mission to prove transmission via insects. In 1897, after three years of hard work, he demonstrated the parasites in mosquitoes which had bitten patients. Later he also demonstrated the transmission of avian malaria via mosquitoes (Plasmodium relictum transmitted from one sparrow to another via Culex fatigans). He was able to describe the complete development of the parasite in the mosquito and also demonstrated that transmission took place via the bite of the mosquito (and not via the presence of dead mosquitoes in drinking water, as his mentor Patrick Manson had initially thought). For this he received the Nobel prize in 1902. Subsequently the Italian Giovanni Battista Grassi and Patrick Manson confirmed that human malaria could be transmitted by Anopheles mosquitoes by carrying out extensive experiments in Italy and by allowing Manson’s own son to be bitten by Anopheles mosquitoes which had fed on a patient with P. vivax malaria.

• all antiarrhythmics can be proarrhythmic, which means they can cause arrhythmias when they’re trying to suppress it. this is bad

• most commonly assoc with class I Na-channel blockers and class III K-channel blockers, except for amiodarone, which is rarely pro-arrhythmic

• induced arrhythmias can be fatal (e.g. torsades de pointes due to ventricular reentry from QT prolongation, seen in class III drugs)

• block phase 0, i.e. blocks the sodium channels that cause fast depolarization

• this decreases the slope of phase 0

• suppress automaticity when automaticity depends upon sodium channels, so slows sinus rate

• repolarization

  • lengthened by group IA

  • shortened by group IB

  • no effect by group IC

• examples class IA

  • quinidine: class I effects at high doses, class III effects at all doses. side fx: QT prolongation and VT/VF, making this drug fall out of favor

  • procainamide: most useful in a setting of atrial fibrillation with rapid ventricular response due to an AV bypass tract (as in WPW). slows frequency of conduction through the accessory pathway. chronic use is limited by side effects including hypotension and drug-induced lupus

• examples class IB

  • lidocaine is used in the rx of VT and VF and is particularly effective in the setting of ischemia

  • effect is voltage-dependent, meaning that it is more active at reduced membrane potentials, which occur during ischemia

  • therapy limited by systemic toxicity, including CNS toxicity

• example class IC

  • flecainide is used in suppression of atrial fibrillation in patients with otherwise structurally normal hearts

  • test-question-type material: flecainide exhibits use dependence. this means that it has greater efficacy at faster heart rates. there is use-dependence-related widening of QRS complex

  • propafenone is similar, with additional class II (i.e., β-blocker) activity

• increased mortality in ventricular arrhythmias

  • in the past, class I drugs were commonly used to suppress ventricular arrhythmias in patients after MI

  • however, they increased mortality in this setting

• widely used

• several beneficial properties

• side effects

  • bronchospasm

  • bradycardia

  • hypotension

  • worsening of heart failure

• selective (metoprolol) or non-selective (propranolol) for β₁ receptors

• EP properties include

  • rate control: slow AV nodal conduction, so it’s useful in atrial fibrillation to decrease ventricular response rate

  • arrhythmia prevention: reduce mortality in patient post MI, partially because it suppresses arrhythmias

• primarily block phase III repolarizing outward K+ currents, hence prolonging effective refractory period

• importantly, phase 4 K+ current is not affected (I_K1)

• reverse use dependence: greater effect at lower heart rates

• effective for treating several atrial and ventricular arrhythmias

• Amidarone

  • most effective antiarrhythmic; functions in all classes

  • has severe side effects, some of which are irreversible

    • pulmonary fibrosis—completely irreversible, potentially fatal. 4-9%

    • visual side effects: irreversible retinal degeneration or reversible corneal deposits

    • hypothyroidism

    • liver enzyme elevations

    • peripheral neuropathy

    • photosensitivity—skin turns blue

  • physicians should consider annual lung function, eye, thyroid, and liver function tests if a patient is on this drug

• Sotalol

  • very, very useful medicine to prevent atrial fibrillation and suppress ventricular arrhythmias

  • however, require serial ECGs to monitor QT interval (must be <>

  • clearance is via kidneys, so in reduced kidney function, reduce dose or choose another medication

  • β-blocker effects, so take this into account in patients with heart failure or on other β-blockers

• Dofetilide

  • primarily used to treat atrial fibrillation

  • must have serial ECGs to make sure that QTc <>

  • cleared by kidneys

  • UNLIKE sotalol, there is no β-blocking effect

• most frequently used to slow conduction through AV node in…

  • atrial fibrillation

  • WPW

  • AVNRT

• when patients present with atrial fibrillation and rapid ventricular response, they are commonly started on IV diltiazem to control heart rate until oral therapy can begin

• unlike β-blockers, do not decrease mortality post MI, so don’t use in this setting

• side effects—hypotension, bradycardia

• effects on AP 70

  • here you see the action potential of the AV node, and this is where Ca-channel blockers have their greatest effect

  • they slow the phase 0 depolarization and decrease the prolongation phase 2

  • finally, change phase 4 diastolic current

digoxin

• binds and inhibits Na-K-ATPase and enhances vagally-mediated slowing of AV node

• useful adjunct to Ca-channel blockers or β-blockers, but can’t be used by itself for rate control in atrial fibrillation

• rate control effects are overridden by sympathetic stimulation during exercise

adenosine

• very short-acting agent. blocks AV node for 5-10 seconds, but this can break AVNRT or AVRT

• for diagnostic purposes, it’s important to know that adenosine will not terminate reentrant tachycardias that don’t involve the AV node. these include…

  • atrial flutter

  • atrial fibrillation

  • ventricular tachycardia

• used frequently in electrophysiology because there is a high risk of stroke in atrial fibrillation or flutter

Heparin

• this anticoagulates patients right away, unlike coumadin

• unfractionated heparin: given intravenously

• LWMH: patients can give it themselves with injection at home

Warfarin

• used in a majority of patients with atrial fibrillation

• even if you go back to sinus rhythm, atrium can still be stunned, so still anticoagulate these patients

• one exception is younger patients with no other medical problems (lone atrial fibrillation)

• 3-5 days to achieve full therapeutic effect; target INR is between 2 and 3

• this is like a pacemaker, and now every ICD has a pacemaker, too

• but in addition to pacemaking, ICDs also are able to shock the heart in tachycardia or fibrillation

• indications

  • primary

    • congenital predisposition to VT or VF (e.g. long QT syndrome)

    • patients with severe LV dysfunction, as in from heart attack—EF less than 30 or 35%

  • secondary: patients that survive a VT or VF event and do not have reversible predisposing condition

Implanting an ICD

• make incision right under clavicle and put in the pulse generator

• then, poke a lead into the vein and steer it into the heart wall

• with almost every pacemaker, there are leads in the atria and the ventricles so both atria and ventricles can be controlled

• ICD leads have coils that can deliver 35 J inside the heart to defibrillate the heart

• sense when the heart is beating too slowly

• treat bradycardic conditions, including

  • sinus node dysfunction

  • syncope when bradycardia is the dominant component, any advanced AV block

  • symptomatic less severe heart block

• very reliable—8 to 10 years

• complications

  • infection

  • pacemaker-mediated tachycardia

  • pacemaker syndrome

• each ablation must be planned based on arrhythmia mechanism using a strategy to interrupt it

• ablation is first-line therapy for certain arrhythmias, and a physician need not attempt medical management prior to referral for electrophysiology study

• ablation is second-line therapy if it is recommended that medications be tried first

Many lay people regard malaria as a purely tropical disease. However, the distribution of malaria used to be world-wide. Today, it still occurs in some 100 countries. The situation varies from region to region. Until 1938 there was still P. vivax malaria ("polderkoorts") in Belgium, and in the Netherlands as late as 1958, although there was an unexplained (possibly autochtonous) case of P. malariae infection in a child in Zealand in 1969. The WHO declared the Netherlands officially malaria-free only in 1970. It is chiefly the pollution of surface waters which makes reproduction of Anopheles mosquitoes difficult. Yet Anopheles plumbeus, a vector which preferably breeds in water in hollow trees (and car tyres), Anopheles atroparvus, a brackish water mosquito, and its close relative A. messeae, still occur in the Low Countries. Anopheles atroparvus is able to transmit Plasmodium vivax malaria, but cannot transmit Plasmodium falciparum. Anopheles plumbeus was previously an exclusively zoophilic vector, which in recent years has fed more and more on humans. This mosquito can transmit tropical falciparum malaria. In the last century there were important changes in the lifestyle of humans, resulting in less human/mosquito contact. Effective therapy is also available. All these factors mean that malaria has disappeared in Northwest Europe. Cases in Western countries are generally dealt with swiftly and satisfactorily, and one person with malaria very rarely leads to the infection of others. Chronic reintroduction of the disease in Europe is thus very improbable. To maintain an infectious disease it is necessary for one infectious case to lead to one other infectious case, otherwise the disease will die out in the area. In Europe there are at present insufficient gametocyte carriers and vectors to ensure the continuation of the disease.

Malaria is a very important public health problem. The number of clinical cases is estimated at 150 to 300 million per year. Of these, approximately 1 million, mainly young children die every year in Africa alone. Most lethal infections are due to Plasmodium falciparum. The disease causes symptoms such as fever, shivers, headache and muscular pain, anaemia and splenomegaly. Involvement of the brain often leads to death. For some years P. falciparum has been developing increasing resistance to chloroquine and other anti-malaria products. This, of course, makes treatment difficult. Many mosquitoes which are responsible for transmission of the disease are becoming resistant to a number of insecticides and this makes vector control difficult.

• P. falciparum is the most common form in sub-Saharan Africa. It occurs chiefly in Africa, tropical South America and Southeast Asia. The parasite occurred previously in the Mediterranean basin. It does not occur outside the tropics and subtropics.

• P. vivax has the widest distribution area (previously as far as London, Norway, Denmark, New York, southern Canada and even Siberia). In 1922 the number of cases in Texas was estimated at 500,000. It is the most common form in certain regions (e.g. Maghreb countries). P. vivax preferentially penetrates young red blood cells (reticulocytes). To this end the merozoites have two proteins at their apical pole (PvRBP-1 and PvRBP-2). In 1976 Miller discovered that Plasmodium vivax uses the Duffy blood group antigens (Fy^a and Fy^b) as receptors to penetrate red blood cells. These antigens do not occur in the majority of humans in West Africa [phenotype Fy (a-b-)]. As a result P. vivax does not occur in West Africa. Duffy blood group negative erythrocytes are, in vitro, also resistant to infection with P. knowlesi (monkey malaria).

• P. ovale: chiefly West Africa, less elsewhere in Africa and sporadically in the Far East.
  

• P. malariae is not very common anywhere.

There is no completely satisfactory epidemiological classification of malaria. Stable malaria means that the clinical disease is characterised by preferentially affecting children and achieving a protective "immunity" in adults. Stability does not mean that there can be no variation in transmission. In some regions seasonal malaria occurs. In other areas there is unstable malaria: transmission differs greatly from year to year and sometimes epidemics occur. The disease then also occurs in older persons. This is important in many respects, including the fact that irregular control of malaria may lead to changes in the immune status of the population. Sometimes malaria may appear again in a region. For example: in 1972 the disease was eradicated in South Korea following an intensive eradication campaign with case detection and vector control. In 1993 one case of P. vivax was observed. There then followed 22 cases in 1994, in 1995 there were 107 cases, 356 in 1996 and more than 1600 in 1997. In 1995 all cases were still limited to the border area with North Korea, but in 1996 there was also transmission outside the demilitarised zone. After entomological surveys had shown that Anopheles sinensis was the chief vector, measures were taken to control the disease.

Malaria is transmitted by Anopheles mosquitoes. This applies to the malaria of all mammals. Avian malaria on the other hand is chiefly transmitted by Culicinae. There are some 400 Anopheles species, 40 of which are good vectors while 28 are poor vectors. Anopheles mosquitoes are relatively small (8 mm), two-winged insects (Diptera; Gr. di = two and pteryx = wing) sometimes with a typical posture while feeding: head down and the lower body upwards. [There are exceptions to this such as Anopheles culicifacies, which, as its name suggests, is similar in posture to Culex.] As with many mosquitoes there are countless scales on the body and wings. In Anopheles there are darker and lighter coloured scales arranged in groups, which produces a distinctive marking on the wing (a speckled pattern). Culex mosquitoes on the other hand are of an even colour. Anopheles mosquitoes undergo induced color change based on perception of the background against which they are cultured. When larvae are reared on either a black or white background, they become pigmented dark or pale. The degree of darkening depends in part on the length of time the larvae have been cultured on a black background and the degree of fat body development. This color change phenomenon is called homochromy. Anopheles mosquitoes are active at night. They do not buzz much and are not easily noticed. Every species of mosquito has its own characteristics as to behaviour, reproduction, biting habits, etc. This is of course important for mosquito control.

The development of plasmodia (from gametocytes to sporozoites) in a mosquito takes at least 9 days (sometimes as much as 30 days, depending on the temperature). After an infected blood meal a female mosquito will pass through at least 4 or 5 egg-laying periods (and blood meals) before it becomes infectious. There is thus ample time over several days to destroy the vector before she can transmit. Mosquitoes which are infectious are already “middle-aged". They may sometimes survive a month or more, but often the life span is much shorter. This long period before a mosquito becomes infectious is a weak point in the cycle of plasmodia. For example: at a temperature of 30°C at least 70% of mosquitoes need to survive every day if more than 1% of mosquitoes are to survive the 10-day development period.

A practical example can be seen in "airport malaria". Sometimes (due to lack of decontamination or resistance to insecticide) infected mosquitoes are brought to northern airports in aeroplanes. If such a mosquito can remain active due to high environmental temperatures (in a hot summer), bites someone and injects sporozoites, it will already be at least 10 days old. Adding the incubation period for P. falciparum and the time between the first fever and making the diagnosis (in northern regions one does not think quickly of the possibility of malaria), it can then be assumed that the mosquito which caused the disease will probably already be dead when the diagnosis is finally made. Patient's delay and doctor's delay are important factors in lethal malaria. One mosquito can infect several persons (for example if the blood meal is interrupted the mosquito will bite several times), also possibly outside the airport (carried by the wind, or flying). Also, several mosquitoes may be introduced. Due to these factors, clusters of airport malaria may occur in hot summers. The risk that descendants of an infected (or non-infected) mosquito would survive in Europe and find a gametocyte carrier and cause infections again after the incubation period, is very small.

While circulating in human blood Plasmodium falciparum exhibits antigenic variation. On the surface of the infected red blood cell a certain protein is expressed: the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP-1). The parasite is able to make many variants of this protein. By interchanging which variant of PfEMP-1 is present, the parasite can evade the immune response to these immunodominant antigens. PfEMP-1 also inhibits antigen presentation by dendritic cells. The proteins can bind to endothelial receptors [such as ICAM-1 (intercellular adhesion molecule type 1), VCAM-1 (vascular cell adhesion molecule-1), ELAM-1 (E-selectin), CD36 and thrombospondin]. The PfEMP1 proteins are the gene products of what are called var-genes, of which there are 50 to 150 present in the genome of the parasite. There are also some other variant multigenic families, the products of which can be expressed on the surface of infected red blood cells. Antigenic variation has important implications for the development of vaccines. The repertoire of proteins which are expressed in the Anopheles mosquito is far less pronounced, probably because the vector has no adaptive immune system.

Carriers of the sickle cell anaemia gene (heterozygotes for haemoglobin S) have relative protection against severe infection with P. falciparum and thus have a survival advantage (in homozygous patients, malaria may be fatal). The same advantage probably applies to persons deficient in G6PD (a red blood cell enzyme). This may explain why these two conditions are so common in Africa. In Papua New Guinea ovalocytosis is common. These red blood cells have an oval shape and cannot be penetrated by P. falciparum parasites. Heterozygotes are thus protected against P. falciparum (homozygosity is not compatible with life). Haemoglobin C (chiefly West Africa) and haemoglobin E (chiefly Southeast Asia) do not protect against P. falciparum infections. The data on the influence of thalassemia on the clinical severity of malaria are contradictory (many mutations lead to thalassemia, an important confounding factor).

There seems to be several genetic factors that influence the final clinical outcome of an infection. Persons with a gain-of-function mutation in the promoter-region of “inducible nitric oxide synthase” (NOS2), the enzyme which synthetizes NO, have a 75-85% lower risk of severe malaria. NO is a strong vasodilator. High NO levels may be protective against P. falciparum infection by inhibiting cytoadherence. This suggests that the therapeutic potential of NO in the treatment of severe falciparum malaria should be evaluated. Preliminary data suggest that certain TNF-alpha alleles and certain promoters (DNA regios) confer protection against severe malaria. The mean number of complement receptor 1 (CR1, syn. CD35) molecules on erythrocytes in normal individuals is 100-1000 molecules per cell. There seems to be a direct interaction between PfEMP1 on infected cells and a functional site of CR1 on uninfected erythrocytes. This 'stickiness' between PfEMP1 and CR1 contributes to rosetting, and rosetting probably relates to obstruction of blood vessels. Complement-receptor polymorphism probably influences this interaction and therefore the severity of a malaria attack. Certain blood group antigens (e.g. Knops) are located on CR1. The relationship between malaria severity and Knops blood groups (cfr McCoy, Swain-Langley) is being studied at present. A large case-control study of malaria in West African children showed that a human leukocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as sickle-cell trait. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes as well as other genes has evolved primarily through natural selection by infectious pathogens.

• phylum Basidiomycota

• nonfermentative yeast

• produces urease

• one pathogenic and 38 nonpathogenic species

Picture of Crypto

• round yeast with a capsule is Cryptococcus neoformans

• capsule is visualized with a mucicarmine stain, which stains the organism pink. clear areas are the capsule

• SEM of budding

Ecology of Cryptococcus

• var neoformans is found in soil contaminated by pigeon droppings

• var gattii is found in eucalyptus trees

Virulence factors

• ability to grow at body temperature

• capsule

• phenol oxidase, which produces melanin, a black pigment that absorbs free radicals

• mannitol synthesis

Birdseed agar

• the black pigment tells you that you are dealing with C. neoformans rather than any other species of Cryptococcus

Epidemiology of C. neoformans infection

• can cause disease in immunologically normal hosts

• however, vast majority of infections are still in AIDS patients

• in AIDS, C. neoformans var neoformans causes almost all the disease

Pathogenesis of C. neoformans

• organism is inhaled

• can cause pneumonia or disseminate directly

• infects meninges, occasionally skin

• in AIDS patients, can cause widespread disease

• serologic and skin testing reagents are cross-reactive, so incidence of asymptomatic or self-limited infection is unknown

Host defenses against Cryptococcus

• T-cell-mediated immunity

• NK cells

• macrophages

• ? whether anti-capsular antibody can be protective

Diagnosis of Crypto

• cryptococcal antigen, not antibody, in CSF or serum

• culture of the organism

• albicans

• glabrata

• parapsilosis

• tropicalis

• krusei

• causes 75% of disease

• forms germ tubes, which arelong projections that form when the organism is incubated at 37^oC in the presence of serum

• unlike the other Candida, it is sensitive to fluconazole, which is old and cheap

Evolving targets: changing clinical challenges in high-risk patients

• big chunk is albicans

• C. glabrata, parapsilosis, tropicalis share the remainder almost equally, with a very small slice for krusei

Why do we care what species of Candida?

• albicans usually sensitive to low concentrations of fluconazole and eichinocandins

• glabrata, krusei are resistant to these agents

• ability to form pseudohyphae

• ability to adhere to epithelial surfaces

• ? proteases

• normal flora in the GI tract; this is unique because pretty much every other pathogenic fungus is in the dirt

• antibiotics can cause overgrowth

• immunocompromised

  • thrush

  • vulvovaginitis

  • esophagitis

Babies also get thrush

• as they make a transition from a state with no normal flora to abundant normal flora, sometimes the yeast get ahead of the bacteria. however, these are usually self-limited infections

• can also cause diaper rashes

Very rare disease: mucocutaneous candidiasis

• a specific immunodeficiency that is not entirely understood leads to horrible, horrible candida infections of hands and feet as well as thrush

GI disease

• occurs in immunocompromised—AIDS patients or newborns. get disease in esophagus as well as mouth

• babies and people on antibiotics get disease limited to mouth only

Vulvovaaginitis

• female AIDS patients

• less severe—antibiotics patients

Host defenses against Candida

• normal intestinal flora

• normal T-cell function

Invasive candidiasis

• most common invasive fungal infection

• particularly common in those with central venous catheters or those on antibiotics

• particularly severe in neutropenics

• no good antibody or antigen test

• diagnosis rests with culture of blood or sterile body fluids

Utility of β-glucan detection in invasive fungal detection (not used in US, but used in other countries)

• measure amount of circulating β-glucan, which is present in all fungi, but specificity is actually not that bad, 90%

• other fungi will of course be detected

• widely distributed in nature

• about 400,000 species

• facultative anaerobes or strict aerobes. none are obligate anaerobes

• get nutrients by absorption

Typical mold growing up into the air. conidiophore, which holds the conidia, is the reproductive form of molds in nature

Fungi are ubiquitous

• most common organisms in the air that we breathe

• we are all exposed to fungi on a daily basis

• those who live in a moldy environment are more exposed than others

• fungi are not spread person-to-person because they don’t form spores in tissue

Fungi are eukaryotes

• 80s ribosomes

• sterols

• bound organelles

• multiple linear chromosomes

Fungal nutrition

• they grow into their food

• they live on dead organic matter and secrete enzymes that break down complex carbohydrates/proteins

• do not photosynthesize

Fungal cell wall

• glucan: β- (or α-) linked glucose

• mannan: α-linked mannose

• chitin: β-linked N-acetylglucosamine

Layers of the candidal cell wall

• most prominent layer of the candidal wall is mannoprotein

• underneath, glucan, then glucan-chitin, another mannoprotein layer, and finally the plasma membrane

Membrane

• primary sterol is ergosterol rather than cholesterol

• this difference is the basis for two classes of antifungal drugs

  • amphotericin B

  • imidazoles

• yeasts

  • reproduce by budding

  • daughter cell is significantly smaller than mother

• molds

  • in culture, form spores or conidia

  • spores are spread by wind

  • spores are the infectious form

  • in tissue, the mold reproduces by fragmentation of hyphae. they do not form spores inside tissue

• yeasts

  • unicellular

  • divide by budding

  • assume a colony appearance like bacteria

• molds

  • multicellular

  • divide by elongation

  • colony is fuzzy because they’re growing up into the air

molds: fuzzy on petri dish. yeasts are a solid disc

hyphae and pseudohyphae are intermediates in fungal division

Growth patterns of molds

• they grow lengthwise

Types of mycelia

• vegetative: undifferentiated; form early; grow into media

• aerial: bear spores; form later; grow up into the air

• requires spore formation (sporulation)

• therefore, we cannot conclusively identify a mold from hyphae in tissue—all we can say is whether the mycelia are segmented or non-segmented

A word about sex

• most, but not all, fungi have a sexual form

• fungi typically look different in the sexual vs asexual state

• so, mycologists give the sexual state a different name than the asexual state

• we will use the asexual names
  

• causes 90% of human disease due to molds

• not the most common fungus in the world, but the most common spores in the air

• causes invasive disease only in the immunocompromised, except in very rare exceptions

• allergic disease

• fungus ball

• 150 species

• septate hyphae

• very common in environment

• all species produce enzymes, like most fungi

Aspergillus fumigatis

• gray-green color is distinctive

Aspergillus flavis

• colony is yellow-green

• spores come off all the way around the head, so it looks like a daisy

Aspergillus niger

• looks like flavis, but has black spores

• a small number of environmental molds can cause invasive disease in people

• most common: Aspergillus

• another: Mucor/Rhizopus

• many other molds can cause disease in rare situations

• invades lung

• mortality rate is pretty high

Aspergillus host defenses

• PMNs kill the organism

• animal models require PMN↓ and corticosteroids in order to develop aspergillosis

Patients at risk

• neutropenic patients

• those on steroid therapy

• chronic granulomatous disease patients

• those with AIDS or other severe T-cell deficit

• small spores are easily airborne and reach alveoli

• ability to grow at 37^oC

• other factors as well, probably

• disease that occurs almost entirely in asthmatics

• IgE level high

• responds to cortcicodsteroids

• no need for antifungals

• does testing for galactomannan work?

• a study found that sensitivity = 94%, specific = 99%; PPV 94%, NPV 99%

• another concluded that prospective screening for GM and CT play important role in early detection of aspergillosis

• infiltrate with cavity on CXR or chest CT suggestive

• difficult to grow mold from sputum or bronchoscopy wash

• direct exam for hyphae has low sensitivity

• serum antigen assay: galactomannan is useful to identify aspergillus

• PCR-based assays have had variable results; further, none are commercially available

Radiology

• 10% on CXR

• consolidation is common

• nodular shadows with cavitation

• thin or thick wall cavities

• pleural effusion

• CT scan plays a major role in early dx

• most distinctive early lesions are one or more small nodules surrounded by a halo

• fungal ball in previous cavity

• see the ball in different positions when the patient is moved

• use of antifungals is controversial, but bleeding probably indicates microinvasion

• found on decaying organic matter

• bread mold

Mucormycosis

• caused by fungi of the zygomyces class/mucofales order

• Mucor, Rhizopus, Absidia most common

• all these organisms form non-septate hyphae

Mucor host defense

• PMNs kill the organism

• low pH enhances growth, interferes with PMN function

• low pH shifts Fe-Hgb dissociation curve, making iron available to the organism

Patients at risk for Mucor infection

• those with diabetic ketoacidosis

• those on desferoxamine: makes people urinate iron

• neutropenic patients

Changing clinical challenges in high-risk patients

• organ transplant patients get a variety of molds and yeasts

• everyone has Aspergillus and Mucor, but aside from that, infectious agents differ throughout the country

• able to cause disease in immunologically-normal people

• only a very small fraction of the fungi in the world are able to do this

Common features of primary pathogenic fungi

• dimorphism

• found in soil

• able to grow at 37^o and survive in tissue

• cell-mediated immune responses (rather than humoral) are critical

Primary pathogenic fungi

• Blastomyces dermatitidis

• Coccidioides immitis

• Histoplasma capsulatum

• Sporothrix schenckii

• first identified in the San Joaquin Valley, particularly in Bakersfield

• also, Phoenix and Tuscon, West Texas, and Mexico

• the Sonoran desert is pretty much endemic for coccidioidomycosis

• it’s found in the soil in PB

C. immitis and C. posadasii

• the former is found primarily in California

• the latter is found primarily elsewhere—US but not CA, Mexico, South America

• the two are distinguished by their DNA structure

• they separated 12 million years ago

• however, they are clinically identical

• 25-yo African-American man presents with fever, nonproductive cough, skin lesion. sick for a month

• temperature 102^o F, diffuse rales, patchy infiltrates on CXR

• wart-like lesions on his back that shows round structures with internal structures inside them, termed spherules. this is the tissue form of Coccidioides

• histology: caseation surrounding spherules and large endospores coming out of a spherule. indeed, endospores are the internal structures of the spherules

• in soil, forms conidia within the mycelium, not externally like most other fungi

• when these are broken up and inhaled, they begin to round up (forming a spherule) and divide internally until they are full off endospores and release them (~96 hours after inhalation)

SEM and TEM of arthroconidia of Coccidioides

• these mycelia contain arthroconidia, which are fungal spores produced by segmentation of pre-existing hyphae (Wikipedia)

• every other cell in the hyphae is an empty cell that can be broken by wind to form one infectious particle

• then, these round up and form spherules after inhalation

Micrograph

• internal division inside the spherule occurs; the endospores get smaller and smaller until the spherule ruptures and pours them all out

• each endospore has the capacity to grow into a completely mature spherule or, if coughed up, to form more mycelia in the soil

• so it can go either way, and what makes the decision is the environment

• found in desert regions in the southwestern US and in Mexico; you can indeed get cocci in SD or LA

• risk factors involve disturbing soil

• most common in the fall

• variable year-to-year

Pathogenesis

• organism is inhaled

• sx in 35-60%

• 95% of infections resolve spontaneously in the immunocompetent

• about 5% either linger for months or disseminate beyond the lungs

• there is a much higher rate of dissemination in the immunocompromised

• skin

• bones and joints

• meninges: coccimeningitis without treatment has a 1-year mortality rate of 100%

T cells are important for immunity

• when it was available, positive skin test was a good prognostic sign. the test is no longer performed

• transplant, chemo rx, and AIDS predispose to disseminated disease

• in mice, T cells transfer immunity

Is a Th1 immune response required?

• high titers of antibody (higher than 1:16) are associated with poor prognosis in people

• exogenous IL-12 improves outcomes in mice

• IL-10 knockout mice are more resistant to infection

Coccidioidomycosis at Lemoore US Naval Air Station, 1961 to 1977

• African-Americans and Filipinos are at a high risk for disseminated cocci

• similarly, some mice strains are more susceptible

• antibody titer is sensitive and specific

• complement fixation titer > 1:16 is associated with disseminated disease

• culture is the gold standard