Favorites of brain cells: The game of genetics

Hey Awesomites

Many cells in the brain express two copies of a gene - maternal and paternal. But some express only one. If the single copy that is expressed carries a genetic mutation, it may result in cellular dysfunction and thus there are consequences.

Research on newborn mouse suggests that in about 85 percent of genes in the dorsal raphe nucleus, known for secreting serotonin, differentially activate their maternal and paternal gene copies. Ten days later in the juvenile brain, both copies are activated equally for all but 10 percent of genes.

The disparity also occurs in humans and in other systems like liver and muscles.

Like for example, in humans, a gene called DEAF1 that is implicated in autism and intellectual disability, shows a preferential expression of one copy of genes in multiple areas of brain. This is true for genes in other mental and neurologic disorders like Huntington's disease, schizophrenia, ADHD, and bipolar disorder.
( Source )


Thats all
- Jaskunwar Singh

Novel Monoclonal Antibodies: Emicizumab and Caplacizumab

Emicizumab:

Patients with Haemophilia A need regular infusions of Factor VIII, and a majority of patients develop antibodies against this exogenous factor VIII rendering the therapy less effective.

Emicizumab is here to solve this problem. It mimics the physiological function of factor VIII, that is to enhance the interaction between activated factor IX and factor X to facilitate the activation of factor X. Emicizumab binds both factor IXa and factor X and increases the interaction between them.

Caplacizumab:

Patients with Thrombotic Thrombocytopenic Purpura(TTP) has antibodies against ADAMTS13. Reduction of ADAMTS13 levels leads to formation of vWF multimers that enhance platelet aggregation and consequent thrombus formation in all major systemic blood vessels. The current therapy protocol consists of Plasma exchange and Immunosuppressants.

Caplacizumab binds to vWF and prevents its interaction with GP1b receptor on platelets, thereby inhibiting platelet aggregation.




-VM

Fact of the day: Liquid biopsy for cancer detection

Hey Awesomites

We have known since long that surgical biopsies done routinely in cancer patients to diagnose and detect progression of the disease may increase the risk of carcinogenic changes in the cells in future, due to the changes that had prompted the biopsies.

A non - invasive and painless diagnostic tool that replaces the cutting is "liquid biopsy" that finds the hidden cancer cells anywhere in the body. The liquid biopsy is taken from a simple blood test to look for microscopic pieces of DNA circulating in the blood that contains genetic mutations causing tumors to spread, among billions of other DNA that were in the blood.
A year ago, a circulating tumor DNA test was approved by FDA that spots these mutations.


Thats all
- Jaskunwar Singh

Poikilocytosis

Red blood cells

Also known as erythrocytes, is the most common type of blood cell and the principal means of oxygen transport in the body.

The normal biconcave shape is the essential feature of its biological function.
Through various stages of development and maturation, RBC loses its nucleus and most organelles in order to accommodate maximum space for haemoglobin.
This feature of RBC is critically affected by genetic and acquired pathological conditions.

Poikilocytosis is the term used to denote the variation in the shape of red blood cells.
Let's look at the major abnormalities in the shape of RBCs and the conditions in which they are seen:

1. Spherocyte - hereditary spherocytosis, autoimmune haemolytic anaemia, ABO haemolytic disease of the new born

2. Schistocyte - thalassemia, hereditary elliptocytosis, megaloblastic anaemia, iron deficiency anaemia and severe burns

3. Irregular contracted red cells - drug and chemical induced haemolytic anaemia, unstable haemoglobinopathies

4. Target cell (a type of leptocytosis)- iron deficiency anaemia, thalassemia, chronic liver disease and after splenectomy

5. Sickle cell (drepanocyte)- sickle cell anaemia

6. Tear drop cell - myelofibrosis, underlying marrow infiltrate

7. Crenated red cell - in blood films due to alkaline pH, presence of traces of fatty sustances on the slides or film allowed to stand over night

8. Acanthocyte - post splenectomy, chronic liver disease, Abetalipoproteinemia, McLeod blood group phenotype

9. Burr cell - uremia, liver disease, artifact

10. Stomatocyte - hereditary stomatocytosis, chronic alcoholism

11. Ovalocyte - hereditary ovalocytosis, hereditary elliptocytosis, severe iron deficiency anaemia

The diagram given represents the corresponding cells





Credits to: Shivani Mangalgi.

Myopathies series- Part 2

METABOLIC MYOPATHIES

In previous post, I gave an introduction of metabolic myopathies.

Today we cover:-

I.Diagnostic role of creatine kinase in metabolic myopathies.

II.Metabolic myopathies and its types.

Diagnostic role of enzyme in myopathies.

The following diagram shows the enzymes related to myopathies and their associated metabolic reactions.( Note:- The metabolic pathway is not only for skeletal muscle .It is in general . My main aim is to show enzymes of liver and muscle along with the pathways.Remember urea cycle occurs in liver )

http://chemistry.elmhurst.edu/vchembook/images/641serumenzymes.gif

Creatine kinase: - This enzyme will help us to evaluate different METABOLIC myopathies.

1. ELEVATED CK: - In Glycogen storage disease associated myopathies.
    (In some GSD there will be mild elevated CK)
2. MILD ELEVATED CK:- In Fatty acid oxidation disorder.
3. NORMAL CK: - In Mitochondrial myopathies.Also in some fatty acid oxidation disorder.
   
   Metabolic myopathies types:-

I.                    DISORDER OF GLYCOGEN METABOLISM (MUSCLE GYCOGENOSES)

II.                  DISORDER OF FATTY ACID OXIDATION

III.                MITOCHONDRIAL MYOPATHIES

CLINICAL FINDINGS :-

1. Second wind phenomenon: - suggestive of GSD V / McArdle’s

2. Out-of-wind phenomenon: - suggestive of GSD VII/ Tarui

3. Myoglobinuria (Burgundy colored urine):- GSD V, GSD IX
                                                                         LDH, PGM or PGK enzyme deficiency
                                                                         CPTII Deficiency
4. Proximal weakness: - GSD II / Pompe.

5. Exercise intolerance,ataxia,multisystem involvement:- Mitochondrial disorder, Coenzyme Q10 Deficiency.

LAB TESTS:-

1. Serum CK levels.

2. Lactate 

3.Serum electrolytes.

4. ammonia

5.AST,ALT,GGT 

6. Urinalysis

7.Forearm exercise test.

8.EMG

9.Routine muscle biopsy

SPECIFIC TESTS:- 

1. Urine organic acids

2. Plasma acylcarnitine profile

CONFIRMATORY BUT COSTLY :-

1. Enzyme analysis

2. DNA Analysis on leukocytes, fibroblasts and liver.

Click on the below given link to read on how to differentiate between McArdle, CPT II deficieny and mitochondrial myopathy. (this link helped me with the notes) 

*If you are running short of time, then Read only Case 1 and Case 2

 http://www.the-rheumatologist.org/article/diagnosis-myopathy/

I hope it helped. 

-Upasana Y. :)

Fact of the day: Gonorrhea and vulvovaginitis

Gonorrheal infection is generally limited to superficial mucosal surfaces lined with columnar epithelium. The areas most frequently involved are the cervix, urethra, rectum, pharynx, and conjunctiva. 

Evaluation of Pseudophakia

Clinical evaluation of a case of Pseudophakia.

Pseudophakia is a term used to describe the condition wherein an artificial intraocular lens is implanted after surgery for cataract.

On history - History of cataract surgery present.

On examination -

1) Deep Anterior Chamber (the posterior support for the iris is lost as the IOLs are thinner that the natural lens)
2) Conjunctival flap and subconjunctival hemorrhage ( seen only in recent cases)
3) Scleral/ Corneal incision and scar.
4) Iridodonesis (tremulous iris)
5) Jet black pupil
6) Shimmering light reflex from the IOL.

Oculocardiac Reflex

Oculocardiac Reflex/Aschner phenomenon.

This is one of the trigeminovagal reflexes produced on digital massage of eye. Digital massaging of the eyeball is done to lower intraocular pressure after producing a retrobulbar or a peribulbar block. But rarely....this event is followed by cardiac depression, asystole and even death. The afferent is by the ophthalmic division of trigeminal nerve which relays in the visceral motor nucleus of the vagus nerve. The efferent is carried by the parasympathetic vagus nerve to the heart. It is most commonly seen in pediatric cases during squint surgery.
It is not seen very commonly in adults and in other surgeries as the procedure would involve just one eye and massaging of this eye is not sufficient to produce bradycardia normally.

Treatment: atropine or glycopyrrolate . Cardiopulmonary resuscitation might be needed in severe cases.

Bulbar and Psuedobulbar palsy : Overview

Here's a short overview of Bulbar and Pseudobulbar palsy !

If there is a lesion is at the level of Medulla - affecting the motor neurons : The nuclei of the cranial nerves -  you get LMN Palsy features - Flaccid paralysis of 9 10 11 12 Cranial nerves. This is called a 'Bulbar palsy' as the bulb (Medulla) is involved in isolation.

Now , essentially when the fibres supplying the motor neurons of the bulb (your Medulla)  are affected themselves - that is any neurons above the nucleus of the nerve - it's a UMN lesion. So you get 9 10 11 12 UMN palsy - Spastic paralysis.
This would be Pseudo-bulbar as same CN involved but lesion is above the Medulla

So Pseudobulbar you'd have a hyper active gag reflex while it'll be absent in Bulbar.(Mediated by 9th cranial nerve).

You'd have a Hot potato like speech in Pseudobulbar as your vocal muscles of larynx and tongue are spastic. - (10th and Cranial 11th. )

While you'd see a nasal twang in Bulbar (also called Donald duck speech)
As your soft palate doesn't abut against the nasal cavity (due to LMN flaccid paralysis). Also causing nasal Regurgitation of food in Bulbar.

So they both essentially present with 9 10 features and some of the 11 12. Hence one is Pseudo and the other is true Bulbar.

Psuedobulbar would also have emotional problems. Called Pseudobulbar affect (as the higher fibres are involved - lesions are generally multiple infarcts in the cortex).

A few important causes : 

Psuedobulbar palsy :

- Vascular = B/L Frontal lobe lesion , B/L Pontine stroke , Vascular dementia = Multi infarct dementia.

- Central Pontine Myelinolysis

- Degenerative = Multiple sclerosis  , Motor neuron disease

- Cerebral Palsy

_________________________________
Bulbar palsy :

- Guillian Barre Syndrome

- Polio

- Motor neuron Disease

- B/L Medullary infarction

Hoping this helped !
Happy studying guys !
And stay awesome !!

~ A.P.Burkholderia.

Myopathies series - Part 1

Hello :)

Before starting with the series, I will post on the basics you need to know for myopathies.

Q. What do you mean by muscular dystrophy and myopathy?

A. I found that following definition from Harrison is simple.

Skeletal muscle disease myopathies, are disorder with structural changes or functional impairment of muscle.

Muscular dystrophy refers to a group of hereditary progressive diseases with unique phenotypic and genetic features.

Do you know glycogen storage diseases?

Yes! But why do you need to mention it here? Because, skeletal muscles are the store house of glycogen. It gets converted into glucose-6-phosphate (Note:- Never in glucose unlike liver. Why? Otherwise glucose will move out from the myocyte to blood. And myocytes will fail to utilize their own stored glycogen. That is why muscle lack an enzyme called glucose-6-phosphatase.)

There are some glycogen storage disease which will lead to myopathies.

For now remember that myopathies have different way of presentation. 

Muscle weakness is one of the clinical feature.

The muscle weakness can either be 1. Intermittent or 2. Persistent.

If there is energy deficiency in muscle, it will become weak.

Today, we are focusing mainly on skeletal muscle energy metabolism.

Glycogen storage disease are described in the Roman numerals. Not all glycogen storage disease lead to myopathies. Some glycogen storage disease lead to myopathies is mentioned in the diagram.

 More is coming up.:) 

-Upasana Y.  

Pathophysiology of laboratory findings in tumor lysis syndrome

Which of the following electrolysi abnormalities will you see in tumor lysis syndrome?
Answer either high, normal or low for each of these - calcium, phosphate, potassium, uric acid.

Answers:
Labs in tumor lysis syndrome -
Hypocalcemia 
Hyperuricemia
Hyperphosphatemia
Hyperkalemia

Why?

When cancer cells lyse, they release potassium, phosphorus, and nucleic acids, which are metabolized into hypoxanthine, then xanthine, and finally uric acid. 

This leads to:

Hyperkalemia can cause serious — and occasionally fatal — dysrhythmias.

Hyperphosphatemia can cause secondary hypocalcemia, leading to neuromuscular irritability (tetany), dysrhythmia, and seizure, and can also precipitate as calcium phosphate crystals in various organs (e.g., the kidneys, where these crystals can cause acute kidney injury).

Uric acid can induce acute kidney injury not only by intrarenal crystallization but also by crystal-independent mechanisms, such as renal vaso-constriction, impaired autoregulation, decreased renal blood flow, oxidation, and inflammation.

Crystal-induced tissue injury occurs in the tumor lysis syndrome when calcium phosphate, uric acid, and xanthine precipitate in renal tubules and cause inflammation and obstruction.

That's all!

-IkaN

Causes of microcytic erythrocytosis

A high RBC count combined with a low mean volume is seen in:

1. Thalassemia minor, either alpha or beta
2. Polycythemia vera with iron deficiency
3. Secondary polycythemia (hypoxia) with incidental iron deficiency.

Differentiating thalassemia minor from polycythemia vera:

The RBC size distribution curves reliably distinguish between thalassemia minor and polycythemia with iron deficiency.

RDW is elevated in iron deficiency. It is normal in thalassemia minor.

That's all!

-IkaN

Type 2 RTA pathophysiology, notes and mnemonic

Hello! This post is on type 2 renal tubular acidosis.

What causes Type 2 RTA?
Defect in proximal bicarbonate reabsorption - resulting in a hypokalemic hyperchloremic metabolic acidosis.

The defect in proximal reabsorption of filtered HCO3-  in effect leads to decreased proximal NaCl reabsorption and a tendency for salt wasting. This causes hyperaldosteronism -  leading to increased K secretion by the distal nephrons.