Rickettsial Diseases,

Rickettsial Diseases, including Typhus and Rocky Mountain Spotted Fever

·         The Rickettsiae are small (0.3-0.5 x 0.8-2.0 um), Gram-negative, aerobic, coccobacilli that are obligate intracellular parasites of eucaryotic cells.

·         They may reside in the cytoplasm or within the nucleus of the cell that they invade. They divide by binary fission and they metabolize host-derived glutamate via aerobic respiration and the citric acid (TCA) cycle. They have typical Gram-negative cell walls, and they lack flagella. The rickettsiae frequently have a close relationship with arthropod vectors that may transmit the organism to mammalian hosts

·         The rickettsiae, in spite of their small size and obligate intracellular habitat, are a group of alphaproteobacteria,  which include many well-known organisms such as Acetobacter, Rhodobacter, Rhizobium and Agrobacterium. Very few of the alphaproteobacteria are pathogens of humans. Brucella, Bartonella, Rickettsia, and a related intracellular parasite, Ehrlichia, are the main exceptions.

·         The rickettsiae that are pathogens of humans are subdivided into three major groups based on clinical characteristics of disease: 1. spotted fever group; 2. typhus group; and 3. scrub typhus group.

·         Spotted Fever Group (SFG)
Rickettsia rickettsii is the cause of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae.  Rickettsia rickettsii is found in the Americas and is transmitted to humans through the bite of infected ticks. The bacterium infects human vascular endothelial cells, producing an inflammatory response. The pathogenesis of RMSF is discussed in some detail below.

·         Scrub Typhus Group (STG)
Orientia (Rickettsia) tsutsugamushi is the cause of scrub typhus. Originally called Rickettsia tsutsugamushi, this organism was given its own genus designation because it is phylogenetically distinct from the other rickettsiae, though closely related. Orientia tsutsugamushi is transmitted to humans by the bite of trombiculid mites (chiggers), which are the vector and host. Scrub typhus occurs throughout much of Asia and Australia.

·         Typhus Group (TG)
Rickettsia prowazekii is the cause of epidemic or louse-borne typhus and is the prototypical bacterium from the typhus group of rickettsiae. R. prowazekii infects human vascular endothelial cells, producing widespread vasculitis. In contrast to RMSF, louse-borne typhus tends to occur in the winter. Infection usually is transmitted from person to person by the body louse and, therefore, tends to manifest under conditions of crowding and poor hygiene. The southern flying squirrel is apparently the reservoir in the United States, but the vector involved in transmission from the flying squirrel to humans is unknown. The disease has a worldwide distribution.

·          Signs and Symptoms
Rocky Mountain spotted fever can be very difficult to diagnose in its early stages, even among experienced physicians who are familiar with the disease. Patients infected with R. rickettsii generally visit a physician in the first week of their illness, following an incubation period of about 5-10 days after a tick bite. The early clinical presentation of Rocky Mountain spotted fever is nonspecific and may resemble a variety of other infectious and non-infectious diseases.

·          Initial symptoms may include fever, nausea, vomiting, severe headache, muscle pain, and lack of appetite. Later signs and symptoms include rash, abdominal pain, joint pain and diarrhea.

·          The classic triad of findings for this disease are fever, rash, and history of tick bite. However, this combination is often not identified when the patient initially presents for care. The rash first appears 2-5 days after the onset of fever and is often not present or may be very subtle when the patient is initially seen by a physician. Younger patients usually develop the rash earlier than older patients. Most often it begins as small, flat, pink, non-itchy spots (macules) on the wrists, forearms, and ankles (Figure 13). These spots turn pale when pressure is applied and eventually become raised on the skin. The characteristic red, spotted (petechial) rash of Rocky Mountain spotted fever is usually not seen until the sixth day or later after onset of symptoms, and this type of rash occurs in only 35% to 60% of patients with Rocky Mountain spotted fever (Figure 14). The rash involves the palms or soles in as many as 50% to 80% of patients; however, this distribution may not occur until later in the course of the disease. As many as 10% to 15% of patients may never develop a rash.

·          

·         If the patient is treated within the first 4-5 days of the disease, fever generally subsides within 24-72 hours after treatment with an appropriate antibiotic (usually a tetracycline)

·         Doxycycline (100 mg every 12 hours for adults or 4 mg/kg body weight per day in two divided doses for children under 45 kg [100 lb.]) is the drug of choice for patients with Rocky Mountain spotted fever. Therapy is continued for at least 3 days after fever subsides and until there is unequivocal evidence of clinical improvement, generally for a minimum total course of 5 to 10 days. Severe or complicated disease may require longer treatment courses. Doxycycline is also the preferred drug for patients with ehrlichiosis, another tick-transmitted infection with signs and symptoms that may resemble Rocky Mountain spotted fever.

Classification of Seizure or Epilepsy—

Partial seizure—	§    Simplex §    Complex §    Partial seizure secondarily generalized
Generalized seizure—	§    Tonic-clonic (grand mal) §    Absence (petit mal)—children mostly §    Tonic §    Atonic §    Clonic and myoclonic §    Infantile spasms

Classification of Anti-Epileptic drugs—

Hydantoin group—	§    Phenytoin §    Mephenitoin
Iminostilbene group—	§    Carbamazepine §    Oxcarbazepine
Barbiturates and Benzodiazepines—	§    Phenobarbitone §    Mephobarbitone §    Diazepam	§    Clonazepam §    Lorazepam
Desoxybarbiturates—	§    Primidone
Valproic acid group—	§    Sodium Valproate

Anti-seizure drugs act by—

§    Blocking the Na⁺ channel

§    Blocking the Ca⁺⁺ channel

§    Blocking the excitatory neurotransmitters and ↑ the activity of inhibitory neurotransmitter (GABA)

*** cognitive function of the rain means the intelligence function of the brain

Principle of Mechanism of Action of Anti-Epileptic drugs—

In general, voltage dependent Na-channel enter an inactive state following each action potential. Prolongation of this inactive state with prolongation of the refractory period is the principle of mechanism of action of—

o  Phenytoin

o  Carbamazepine

o  Lamotrizine

o  Sodium Valproate

o  Topiramate

§    A low threshold calcium current govern oscillatory response in thalamic neuron. Some drugs like Ethosuccimide or Dimethadione cause low threshold of the calcium current.

§    Some drugs affect synaptic transmission. Drugs like Benzodiazepines, Barbiturates and possibly Topiramate enhances GABA mediated inhibition.

§    Some drugs like GABA Pentine, Vigabatrin acts by decreasing reuptake or decreasing metabolism of GABA.

§    Some drugs act on excitatory Glutamatergic neurotransmission, they block Glutamatergic AMPA receptor. Drugs of this group are Phenobarbitone, Topiramate.

§    Drugs like Rimacemide block the NMDA receptor. NMDA is N-methyl Daspertate, it is one of the subtype of glutamate and aspartate.

Note—strong stimulation of NMDA receptor lead to neuronal death and NMDA agonist can save the neuron from anoxia.

Comparison between Phenytoin and Carbamazepine—

Phenytoin	Carbamazepine
1. It is a Hydantoin group	1. It is an Iminostilbene group
2. Used in both generalized and partial epilepsy	2. Preferred drug in partial seizure but also highly effective in generalized seizure
3. After absorption about 95% is bound to plasma protein	3. About 70-75% is bound with plasma protein
4. It is available in oral and parenteral form	4. It is available only in oral form
5. Does not cause auto-induction of it’s metabolism	5. Causes auto-induction of its metabolism
6. The main mode of action of Phenytoin is to inhibit Na+ influx across neuronal cell membrane in epileptic foci	6. Mechanism of Action appears to be same as that of Phenytoin
7. Sedation occurs at considerably higher therapeutic dose	7. Usually not sedative in its therapeutic use
8. More risk of cognitive impairment	8. Least risk of cognitive impairment

pedodontics in table

Maternal  attitude	Child  behavior
1 overprotective dominant	Shy, submissive, and  anxious
2 overindulgent	Aggressive , demanding , display temper  tantrums
3 underaffectionate	Well  behavior  uncooperative , shy  and  cries easily
4 rejecting	Aggressive , overactive and  disobedient
5 authoritative	Evasive and  dawding

1 nutritive  sucking  habits	Breast feeding Bottle feeding
2  non nutritive  sucking  habits	Thumb or finger sucking Pacifier sucking

Sickle Cell Anemia

Sickle-cell disease (SCD), or sickle-cell anaemia (or anemia, SCA) or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape.  mutation in the Hemoglobin Beta Gene which can be found in the chromosome 11.
This disease causes the body to make abnormally shapes red blood cells. A normal red blood cell is shaped as a round donut  while the abnormal red blood cell has a “ C “ form

 

Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as "HbSS", "SS disease", "haemoglobin S" or permutations thereof.
In heterozygous people, who have only one sickle gene and one normal adult haemoglobin gene, it is referred to as "HbAS" or "sickle cell trait".
  Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β⁺) and sickle beta-zero-thalassaemia (HbS/β⁰). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele.

Sickle-cell anaemia is caused by a point mutation in the β-globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The β-globin gene is found on chromosome 11, (Robbin's Pathology). The association of two wild-type α-globin subunits with two mutant β-globin subunits forms haemoglobin S (HbS). Under low-oxygen conditions (being at high altitude, for example), the absence of a polar amino acid at position six of the β-globin chain promotes the non-covalent polymerisation (aggregation) of haemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity.

The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low-oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their misshape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically live 90–120 days, but sickle cells only survive 10–20 days.

Normally, humans have Haemoglobin A, which consists of two alpha and two beta chains,  
Haemoglobin A2, which consists of two alpha and two delta chains and
Haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these, Haemoglobin A makes up around 96-97% of the normal haemoglobin in humans.

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the β-globin gene, which results in glutamic acid being substituted by valine at position 6. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, from a GAG to GTG codon mutation, becoming a GUG codon by transcription. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic residues of the valine at position 6 of the beta chain in haemoglobin are able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates.

Aplastic crisis