You have questions, and we have answers. Starting this week, your favorite USMLE tutors are excited to announce that we are beginning a new post series called Common Questions! Each week, one of our tutors will answer up to 5 random USMLE questions sent to us by students in an effort to spread useful information to everyone studying for the USMLE. This week we are covering 5 topics: granulomas, antibiotics and nontyphoidal salmonellosis, phosphoinositides, accumulation of d-ALA and protopophryin, and the role of ACh in the striatum. Happy Studying!
- Are non-caseating granulomas unique to sarcoidosis? Or do all auto-inflammatory causes of granulomas display non-caseating granulomas? Along the same lines, do all infectious causes of granulomas display caseating granulomas or is it only tuberculosis?
The most common cause of all granuloma formation worldwide is tuberculosis. The formation of granulomas in tuberculosis is thought to be a physiological reaction to prevent the systemic spread of the causative pathogen, the mycobacterium. is immune response typically results in a caseating granuloma with signs of necrosis. Many other infectious agents can trigger granuloma formation as well as foreign body material such as beryllium, and inherited defects in neutrophil function (chronic granulomatous disease). In chronic inflammatory diseases and primary immunodeficiencies with chronic inflammation, the granulomas have not been associated with specific external agents. With the exception of granulomatosis with polyangiitis, these granulomas are non-caseating and typically observed in patients with sarcoidosis, Crohn’s disease and common variable immunodeficiency. Sarcoidosis remains a diagnosis of exclusion.
- How do antibiotics prolong the duration that bacteria are excreted in stool for nontyphoidal salmonellosis? What is the mechanism?
Nelson and colleagues’ early study of children with salmonellosis showed that those who were treated with ampicillin or amoxicillin were more likely to have both prolonged excretion and clinical relapse than were those who were given placebo. Animal studies support the hypothesis that antibiotics do this by suppressing the “protective” effects of endogenous intestinal bacterial flora, which results in recrudescence of the hardy Salmonella species. Many clinicians are not aware that the median duration of fecal shedding of nontyphoidal salmonellae after intestinal infection is ∼1 month in adults and 7 weeks in children <5 years of age.
- What is the role of phosphoinositides in the body and why is their turnover an important component of some drugs?
Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell’s life and death. A wide range of biological processes are regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets.
For Step 1, PI’s are primarily relevant in the signaling pathway downstream of Gq receptor, where PIP2 -> IP3 and DAG, leading to smooth muscle contractions.
- Is it the accumulation of d-ALA and protopophryin what causes the symptoms of lead poisoning or does the lead act independently in cells/other biochemical processes?
The primary cause of lead’s toxicity is its interference with a variety of enzymes because it binds to sulfhydryl groups found on many enzymes. Part of lead’s toxicity results from its ability to mimic other metals that take part in biological processes, which act as cofactors in many enzymatic reactions, displacing them at the enzymes on which they act. Inhibition of d-ALA dehydrates and ferrochelatase lead to accumulation of d-ALA and protoporphyrin. This inhibits heme synthesis and results in anemia. These precursors may also be directly toxic to neurons.
However, lead also acts through other processes to result in neurotoxicity: Lead is able to pass through the endothelial cells at the blood brain barrier because it can substitute for calcium ions and be uptaken by calcium-ATPase pumps. Furthermore, lead also inhibits NMDA receptors.
- What specific role does ACh play in the striatum— excitatory or inhibitory? Which pathway(s) does ACh affect— direct or indirect?
The striatum is a nodal structure of the basal ganglia circuits and is one of the brain areas with the highest concentration of markers of cholinergic transmission. Giant aspiny cholinergic interneurons constitute only 1%–3% of the neurons of the striatum but exert a powerful influence on its output, which is mediated by the medium spiny neurons (MSNs).
ACh, acting via different receptor subtypes, affects the activity of the MSNs both directly and via modulation of glutamate release from corticostriate terminals and of dopamine release from nigrostriatal terminals. Acetylcholine, via its reciprocal interactions with dopamine (DA), has an important role in the differential modulation of striatal output via the so-called direct and indirect pathways of the basal ganglia circuits. The excitatory M1 and the inhibitory M4 receptors are the main cholinergic receptors in MSNs; both the inhibitory M2/M4 and the excitatory nACRs are expressed in presynaptic glutamatergic and dopaminergic terminals.