Talazoparib: Zenith of novelty

Recently, talazoparib was approved by FDA for BRCA mutated breast cancer. Several other drugs related to it such as niraparib, olaparib are already approved for ovarian and breast cancer.

So how they work:

In eukaryotic cells, there is highly intricated network of sensors, transducers and mediators for DNA damage recognition and subsequent successful repair.

One of the such molecule is PARP (polyADP ribose polymerase) which serves to identify single strand breaks (SSBs) and seal them.

If PARP is inhibited (say, by talazoparib) then SSBs would progress to double strand breaks (DSBs). DSBs can also be effectively repaired by BRCA 1 and BRCA 2 complex by homologous recombination method.

However, in cancer cells with mutated BRCA, DSBs would not be repaired, ultimately causing apoptosis via molecules such as PUMA (p53 upregulated modulator of apoptosis), NOXA and p21.

Furthermore, talazoparib is known to induce formation of cytotoxic PARP-DNA complex, further contributing to it's mechanism.

That is definitely zenith of novel mechanism.

Stones in Crohn's disease

Hello everyone, 

In this post, I'll be talking about the different types of stones seen in Crohn's disease. Let's learn why they form! 

CHOLESTEROL GALLSTONES: Either due to ileal involvement or ileostomy, in Crohn's, enterohepatic circulation of bile acids is perturbed resulting in supersaturation of bile with the cholesterol, altering the delicate composition of bile acids, phospholipids, and cholesterol of 10:3:1 in bile fluid.

CALCIUM BILIRUBINATE GALLSTONES: Due to alteration in colonic flora conjugated bilirubin is converted to unconjugated bilirubin, which along with seepage of excessive unabsorbed bile acids from the ileum, results in enhanced absorption of bilirubin from the colon causing increased concentration in bile.

CALCIUM OXALATE RENAL STONES:

Usually, calcium in the GI tract forms a complex with oxalate ions resulting in its excretion in stool but in Crohn's due to steatorrhea excessive unabsorbed negatively charged fatty acids bind with calcium, leaving unbound oxalate to be absorbed and subsequently excreted by urine causing nephrolithiasis.

URIC ACID RENAL STONES: Diarrhea in Crohn's causes metabolic acidosis due to decreased bicarbonate absorption or increased excretion from the colon which increases the acidity of tubular fluid. The increased acidity, simultaneous dehydration, hypocitraturia, and hypomagnesemia in such patients precipitate uric acid stones.

-Kirtan Patolia

Authors' diary: Residency and life so far (after moving to the US)

Hey!

I am video blogging now :)

True or False #9

1.Atopic dermatitis presents on flexor surfaces in infants. T or F

ANSWER

F

Extensor surfaces

Flexor in older children and adults

How to remember this?

Infants slEEEEEEEp a lot right.

Hence EEEEEEEExtensor surface involved in infants in atopic dermatitis

That will help you remember the opposite ( flexor surfaces) involved in older children and adults

That's all.

Calcium monitoring in ethylene glycol poisoning

Seizures often occurs in ethylene glycol poisoning.  It has multifaceted pathophysiology but one of the major cause is hypocalcemia.

Hypocalcemia occurs in ethylene glycol poisoning because ethylene glycol is metabolized to oxalate, which forms calcium oxalate depleting calcium from ECF.

Also, correcting associated metabolic acidosis by bicarbonate supplementation can further cause hypocalcemia due to increased binding of calcium to albumin.

This is why, calcium levels should always be monitored meticulously in such patients.

- Kirtan Patolia ( BJ medical college)

Cryptic conundrum in ET: Thrombosis or bleeding?

In essential thrombocytosis, contrary to what might be surmised, bleeding is more of threat than thrombosis.

This is because high platelet count especially above 1 million/mm3 cause acquired von willebrand disease, much like type 2b von willebrand disease, where excessive affinity of vWF for platelet Gpib result in excessive removal of platelet-vWF complex by spleen results in  thrombocytopenia and loss of high molecular weight vWF multimers.

However, incidence of erythromelalgia , transient ischemic attack and other microvascular events are also high in patients with essential thrombocytosis.

Pretty complex and contradictory, right?

- Kirtan Patolia ( BJ medical college).

Diabetic amyotrophy

Hello everyone!

Today, I will be talking about diabetic amyotrophy.

Diabetic amyotrophy has a lot of names!

It is also known as Bruns-Garland syndrome, diabetic myelopathy, proximal diabetic neuropathy, diabetic polyradiculopathy, diabetic motor neuropathy, diabetic radiculoplexopathy, diabetic lumbosacral plexopathy, and diabetic LRPN.

Diabetic amyotrophy typically occurs in patients with type 2 diabetes mellitus. The traditional features include the acute, asymmetric, focal onset of pain followed by weakness involving the proximal leg, with associated autonomic failure and weight loss. Progression occurs over months and is followed by partial recovery in most patients.

The diagnosis of diabetic amyotrophy is mainly based upon the presence of suggestive clinical features in a patient with known or newly diagnosed diabetes mellitus. Appropriate laboratory investigations, particularly electrodiagnostic studies, and neuroimaging in select patients, are useful to exclude other peripheral and central nervous system etiologies as a cause of the neurologic symptoms and signs.

No treatments are proven to be effective for diabetic amyotrophy or for idiopathic LRPN.

PS: Distal symmetric sensorimotor polyneuropathy is the most common type of diabetic neuropathy - it is characterized by a progressive loss of distal sensation correlating with loss of sensory axons, followed, in severe cases, by motor weakness and motor axonal loss. Classic "stocking-glove" sensory loss is typical in this disorder.

Source: UpToDate

That's all!

-IkaN

Zebra series: Lemierre's syndrome

Hello everyone!

Let's talk about Lemierre's syndrome today.

Lemierre's syndrome is characterized by disseminated abscesses and thrombophlebitis of the internal jugular vein after infection of the oropharynx. The predominant pathogen is a gram-negative anaerobic bacillus, Fusobacterium necrophorum.

That's the Zebra for the day!

IkaN

True or False #8 Lower GI Bleed

1. Angiodysplasia is a high volume arterial bleed. T or F

2. Diverticulosis is a low volume arterial bleed. T or F

ANSWERS

1. FALSE

Angiodysplasia  more often than not involves low volume venous bleeding.

Angiodysplasias are composed of ectatic, dilated, thin-walled vessels that are lined by endothelium alone or endothelium along with small amounts of smooth muscle. Studies in which casts of angiodysplasias were made by injecting a silicone material demonstrated that the most prominent feature in angiodysplasias is the presence of dilated, tortuous submucosal veins.
Small arteriovenous communications are also present and are due to incompetence of the precapillary sphincter. Enlarged arteries may be seen in larger angiodysplasias and may be associated with arteriovenous fistulas, which explains why bleeding can be brisk in some patients.
Histologic confirmation is often difficult. When obtained, it shows dilated vessels in the mucosa and submucosa, sometimes covered by only a single layer of surface epithelium.

2. FALSE

Diverticular bleeding involves high volume arterial bleed

Diverticular bleeding — As a diverticulum herniates, the penetrating vessel responsible for the wall weakness at that point becomes draped over the dome of the diverticulum, separated from the bowel lumen only by mucosa. Over time, the vasa recta is exposed to injury along its luminal aspect, leading to eccentric intimal thickening and thinning of the media. These changes may result in segmental weakness of the artery, predisposing to rupture into the lumen. Diverticular bleeding typically occurs in the absence of diverticulitis

Authors' diary: Internist's disease

Hello,

We had an interesting morning report today and I learnt this from Dr. L (L for Legend!)

Zebra series: Stauffer syndrome

Hello,

I'll be talking about Stauffer syndrome today!

Authors' diary: Zebra series

Hello!

I am starting a Zebra Series on Medicowesome.

True or False #7

1.Depression increases the risk of morbidity and mortality in Cardiovascular disease. T or F

2. Patients with Cardiovascular disease are more likely to develop Depression. T or F