OSCE 2nd December 2023
The following is the OSCE made to answer questions around my patient who's case report is in the following link:
Question 1
What is microRNA and how is it being used in the treatment of dengue
MicroRNAs (miRNAs) are ~19–24 nt non-coding RNAs that post-transcriptionally regulate gene expression by binding to target messenger RNAs (mRNAs). miRNAs are expressed by all metazoans and plants, as well as by several DNA viruses, and function as regulators of cellular processes such as development, differentiation, growth, homeostasis, stress responses, apoptosis and immune activation
Cellular miRNAs are post-transcriptional regulators that could play a role in direct regulation of viral genes. Host miRNA expressions could either promote or repress viral replications. Induction of some cellular miRNAs could help the virus to evade the host immune response by suppressing the IFN-α/β signaling pathway while others could upregulate IFN-α/β production and inhibit the viral infection.
The pathogenesis of severe
dengue has been attributed to immunopathogenesis which
elicited an abrupt “cytokine storm”, leading to vascular
leakage, hypotension and shock. The complexity of
DENV infection is due to immune responses that can ei-
ther be protective or pathogenic. Exposure to any of the
four DENV serotypes during primary infection might ren-
der life-long protection against the same serotype. In-
creased risk of severe dengue is highly associated with
heterologous secondary infection, which is a subsequent
DENV infection with a different serotype. Aggravated clin-
ical manifestations of dengue disease from heterologous
secondary infection might be attributed to cross-reactive
T cells or the “antibody-dependent enhancement”
(ADE). The dominance of cross-reactivity of anti-
bodies or T-cell responses towards the primary infecting
DENV serotype over the secondary infecting serotype was
addressed in the “original antigenic sin” concept of sec-
ondary DENV infections .The involvement of cross-
reactive T cell responses observed in severe dengue mani-
festations infers the pathogenic role of T cells in DENV
infection. The original antigenic sin proposed that
cross-reactive memory T cells from primary infection
might have a lower avidity against the secondary infecting
serotype, which in turn, could result in suboptimal TCR
triggering and subsequent production of high levels of
TNF-α that contributed to vascular permeability and
plasma leakage. Several studies demonstrated the role
of CD4+ and CD8+ T cells in the resolution of DENV in-
fection, whereby serotype-specific responses of the T cells
were seen in primary infection of DENV in humans and proliferation of CD4+ T cells responding specifically the NS3 produced IFN-γ that lysed infected cells.
Nevertheless, skewed T-cell responses during secondary heterologous infection might contribute to the severity of
the immunopathogenesis of DHF and/or DSS.
On miRNA as a treatment modality:
miRNA-based therapeutic modalities
In general, there are two miRNA-based therapeutic modalities: miRNA antagonists and miRNA mimics. The former approach could be applied to inhibit miRNAs with
undesired functions such as miRNAs which are proviral.
A miRNA antagonist is usually introduced as a chemically modified miRNA which is known as anti-miR or antago-miR that could complementarily bind to the mature miRNA strand. To date, several chemical modifications
have been introduced to antimiRoligonucleotides with
the aim of increasing their binding affinity, stability and
in vivo delivery. The most commonly used chemical mod-
ifications include locked nucleic acid (LNA), a bicyclic
RNA analogue in which the ribose is locked in a C3’-endo
conformation, 2’ribose modifications such as 2-O-methyl
(2-MO), 2-fluoro (2-F), 2-O-methoxyethyl (2-MOE) and
the modification of phosphorothioate (PS) backbone
Among them, LNA was reported to be the one with the highest affinity towards complementary miRNAs.
Pharma A/S and Hoffman-La Roche as the miRNA chemistry for the very first miRNA therapeutic and administered as antimiR oligonucleotide targeting miR-122 for the treatment of HCV infection
miRNA mimics are synthetic RNA duplexes which mimic endogenous miRNAs. They are introduced to replenish or to further enhance the levels of miRNAs which are crucial to control disease progression. These miRNA mimics provided a promising proof-of-concept for miRNA replacement therapy. The tumor suppressor miR-34 mimic (MRX34) is by far the most clinically advanced therapeutic mimic
.
Question 2: what actually causes mortality in dengue? Is there any record of dengue patient dying of a hemorrhage?
Bleeding, shock and raised SGOT and SGPT levels were identified as predictors of adverse outcomes and mortality in dengue fever.
Twenty fatalities with 80 controls were analyzed. Clinical parameters of postural dizziness (OR 3.2; 95% CI 1.1–8.9), bleeding (OR 31.9; 95% CI 6.08–167.34), presence of plasma leakage (OR 64.6; 95% CI 7.45–560.5), abdominal tenderness (OR 2.24; 95% CI 0.79–6.38), and signs of cardiorespiratory instability at admission increased the risk of dying from dengue. Altered consciousness was exclusively seen in 20% of cases. Laboratory parameters of elevated CRP (OR 1.652; 95% CI 1.28–2.14), AST, or ALT > 500 IU/L (OR 52.5; 95% CI 12.52–220.1) and acute kidney injury (AKI) (OR 103.5; 95% CI 13.26–807.78) during hospital stay increased the odds of dying. Need for assisted ventilation and multiorgan dysfunction (MOD) were exclusively seen in the cases. Multivariate logistic regression revealed bleeding at admission, AKI, and elevated hepatic transaminase >500 IU/L to be independent predictors for mortality.
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