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Madhya Pradesh Medical Science University, Jabalpur

PG Degree Medical Faculty (MD/MS) Examination October-2025

Subject: General Medicine | Paper-IV | Paper Code: 25AM0107100244

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QUESTION 1 — Long Answer Questions (Attempt Any Two) [2×20 = 40]

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Q.1(a) Early Diagnosis of Heart Failure | Biomarkers | Fifth Pillar of HF Treatment [20 Marks]

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PART I: EARLY DIAGNOSIS OF HEART FAILURE

Clinical Approach to Early Diagnosis

SUSPECTED HEART FAILURE
         │
         ▼
STEP 1: Clinical Assessment
  ├── Symptoms: dyspnea, orthopnea, PND, fatigue, ankle swelling
  ├── Signs: elevated JVP, S3 gallop, displaced apex, basal crackles, pitting edema
  └── History: hypertension, IHD, diabetes, prior cardiac disease, chemotherapy
         │
         ▼
STEP 2: Initial Investigations (ALL patients)
  ├── ECG (LVH, AF, LBBB, ischemic changes)
  ├── Chest X-Ray (cardiomegaly, Kerley B lines, pulmonary congestion)
  ├── BNP / NT-proBNP ← KEY BIOMARKER
  ├── Full blood count, U&E, LFTs, TFTs
  └── Echocardiography (LVEF, wall motion, diastolic function)
         │
         ▼
STEP 3: Define HF Phenotype
  ├── HFrEF: LVEF < 40% (Heart Failure with reduced EF)
  ├── HFmrEF: LVEF 40-49% (mildly reduced EF)
  └── HFpEF: LVEF ≥ 50% (preserved EF)
         │
         ▼
STEP 4: Identify Etiology & Precipitating Factors
  └── Coronary angiography, CMR, stress testing as indicated

Signs and Symptoms (Framingham Criteria)

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PART II: EVOLVING ROLE OF BIOMARKERS IN HF DIAGNOSIS AND PROGNOSIS

Classification of Biomarkers

HEART FAILURE BIOMARKERS
         │
    ─────────────────────────────────────────────
    │                   │                   │
Neurohormonal      Myocardial         Inflammatory
Markers            Injury             Markers
    │                   │                   │
BNP/NT-proBNP      Troponin I/T       IL-6, IL-18
MR-proANP          hs-Troponin        CRP, TNF-α
Aldosterone        H-FABP             ST2 (sST2)
Renin, ADH         Myosin-binding     Galectin-3
                   protein C          
    │
Fibrosis/          Renal              Metabolic
Remodeling         Markers            Markers
    │                   │                   │
Galectin-3         Cystatin C         Uric acid
sST2               NGAL               BUN/creatinine
TIMP-1             Uromodulin         HbA1c
Osteopontin

Key Biomarkers in Detail

• Synthesized and released by ventricular cardiomyocytes in response to increased wall stress
• Cut-off: BNP < 100 pg/mL excludes HF (NPV 90%); > 400 pg/mL confirms HF
• NT-proBNP cut-offs: < 300 pg/mL excludes HF; > 900 pg/mL (age < 75 yrs), > 1800 pg/mL (age ≥ 75 yrs) confirms HF

Acute Dyspnea (ED presentation)
          │
    BNP measurement
    ┌─────┴────────┐
< 100 pg/mL    > 400 pg/mL    100-400 pg/mL
    │               │                │
HF Unlikely     HF Likely      Gray Zone
(NPV ~90%)     (PPV ~90%)    Consider:
                              - RV failure
                              - Atrial fib
                              - PE
                              - CKD

• Elevated BNP at discharge = higher 30-day readmission and mortality
• Serial BNP measurement guides therapeutic optimization
• BNP-guided therapy reduces hospitalizations (SIGNAL-HF, PRIMA trials)

• Indicates ongoing cardiomyocyte injury
• Elevated in acute decompensation, myocarditis, ischemia
• Prognostic marker: elevation predicts worse outcomes

• Soluble decoy receptor for IL-33
• Elevated in ventricular remodeling, fibrosis, and worsening HF
• Not affected by age, BMI, or renal function (unlike BNP)
• Cut-off: > 35 ng/mL = worse prognosis
• Role: monitoring treatment response, predicting mortality

• Marker of cardiac fibrosis and inflammation
• Elevated in HFpEF and HFrEF
• Predicts hospitalization and mortality
• Cut-off: > 17.8 ng/mL = higher risk

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PART III: THE FIFTH PILLAR OF HEART FAILURE TREATMENT

FIVE PILLARS OF HFrEF TREATMENT
              │
    ─────────────────────────────────────
    │       │         │        │        │
 PILLAR 1  PILLAR 2  PILLAR 3  PILLAR 4  PILLAR 5
   ACEi/    Beta-    MRA/     SGLT2     DEVICES/
   ARB/    Blocker  Spirono- Inhibitor  CRT/ICD
   ARNI              lactone  (Fifth
(Sacubitril/         Eplerene  Pillar)
Valsartan)

Why SGLT2 Inhibitors Became the Fifth Pillar:

1. Dapagliflozin (DAPA-HF trial, 2019): Reduced CV death + worsening HF by 26% in HFrEF regardless of diabetes status
2. Empagliflozin (EMPEROR-Reduced, 2020): Reduced CV death + hospitalizations by 25% in HFrEF
3. EMPEROR-Preserved (2021): Empagliflozin also effective in HFpEF - first drug to show benefit
4. DELIVER trial (2022): Dapagliflozin effective in HFmrEF and HFpEF

Mechanisms of SGLT2 Inhibitors in HF:

SGLT2 INHIBITOR MECHANISMS IN HF
              │
    ─────────────────────────────────────────
    │           │           │           │
Hemodynamic  Metabolic   Cardiac     Renal
Effects      Effects     Effects     Effects
    │           │           │           │
Osmotic     ↑Ketone     ↓Cardiac    ↓Intra-
diuresis    bodies      fibrosis    glomerular
Natriuresis  ↓Oxidative  ↓LV        pressure
↓Preload    stress      remodeling  ↓Tubular
↓Afterload  ↑Mitochon-  ↓Interstitial sodium
            drial       inflammation reabsorption
            function    

Standard Four-Pillar Regimen Summary:

Additional Therapies:

• Vericiguat (sGC stimulator): For worsening HF after recent hospitalization
• Diuretics (symptom relief): Loop diuretics - furosemide, torasemide
• Ivabradine: HR reduction when HR > 70 bpm on max beta-blocker
• Iron supplementation (IV ferric carboxymaltose): For iron deficiency (AFFIRM-AHF, HEART-FID trials)
• CRT (Cardiac Resynchronization Therapy): LBBB + LVEF < 35% + QRS > 150 ms
• ICD: Primary prevention, LVEF < 35%

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Q.1(b) Types of Gene Therapy | Indications | CRISPR | CAR-T Cell Therapy [20 Marks]

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PART I: GENE THERAPY — DEFINITION AND TYPES

Classification of Gene Therapy

GENE THERAPY
      │
  ────────────────────────────────────
  │                                  │
SOMATIC GENE THERAPY            GERMLINE GENE THERAPY
(approved for clinical use)     (heritable, currently
      │                          not permitted ethically)
  ────────────────────────
  │                      │
IN VIVO              EX VIVO
(gene delivered       (cells removed,
directly into          modified, then
patient's body)        reinfused)
  │                      │
  ├── AAV vectors      ├── HSC modification
  ├── Lentiviral       ├── CAR-T therapy
  ├── Adenoviral       └── iPSC modification
  ├── Lipid NPs
  └── mRNA therapy

Types of Gene Therapy Strategies

Vectors Used in Gene Therapy

GENE THERAPY VECTORS
        │
   ─────────────────────────────────
   │                               │
VIRAL VECTORS               NON-VIRAL VECTORS
   │                               │
   ├── AAV (Adeno-associated   ├── Liposomes/Lipid NPs
   │   virus) - most common    ├── Polyplexes
   ├── Lentivirus               ├── Electroporation
   ├── Adenovirus               ├── Gene gun
   ├── Retrovirus               ├── Naked DNA injection
   └── Herpes simplex virus     └── mRNA (non-integrating)

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PART II: INDICATIONS OF GENE THERAPY

Approved Gene Therapies (FDA/EMA as of 2025)

Indications by Category:

INDICATIONS FOR GENE THERAPY
           │
   ────────────────────────────────────────
   │          │          │          │      │
Monogenic  Cancer    Infectious  Cardio-  Neurologic
Disorders  Therapy   Diseases   vascular  Disorders
   │          │          │          │         │
Hemo-      CAR-T     HIV (CCR5  VEGF for  SMA
philia    Therapy    knockout)  ischemia  ALS
Beta-Thal  Oncolytic  HPV        LVAD     Parkinson's
SMA        viruses    vaccines   gene     Huntington's
SCID       Checkpoint  HBV       therapy  (trials)
CF (trials) priming

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PART III: CRISPR-Cas9 — Mechanism and Applications

Mechanism:

CRISPR-Cas9 MECHANISM
        │
   ─────────────────────────────────────────
        │
Step 1: Design guide RNA (gRNA) complementary
        to target DNA sequence
        │
        ▼
Step 2: gRNA-Cas9 complex scans DNA for
        target sequence + PAM site (NGG)
        │
        ▼
Step 3: Cas9 endonuclease cleaves BOTH strands
        of DNA → Double Strand Break (DSB)
        │
        ▼
Step 4: Cell's own repair mechanisms activate
  ┌─────────────────────────────────────┐
  │                                     │
NHEJ (Error-prone)                HDR (Precise)
Non-Homologous                    Homology-Directed
End-Joining                       Repair
  │                                     │
Gene disruption                   Gene correction
(Knockout)                        (Knock-in with
                                   donor template)

Types of CRISPR Systems:

• CRISPR-Cas9: Most common, creates DSBs
• Base Editing (CBE/ABE): Converts single nucleotide without DSB
• Prime Editing: "Search and replace" for precise edits without DSB
• CRISPRa/CRISPRi: Gene activation or inhibition without cutting
• CRISPR diagnostics (SHERLOCK, DETECTR): COVID-19, genetic disease detection

CRISPR Applications in Medicine:

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PART IV: CAR-T CELL THERAPY

Structure of CAR:

CAR-T CELL STRUCTURE
        │
EXTRACELLULAR    TRANSMEMBRANE    INTRACELLULAR
DOMAIN               DOMAIN          DOMAIN
    │                   │               │
ScFv antibody      Hinge region    CD3-zeta (signaling)
fragment           CD28/CD8        Co-stimulatory
(targets tumor     transmembrane   domains:
antigen: e.g.      domain          CD28 or 4-1BB
CD19, BCMA,
HER2, GD2)

CAR-T Manufacturing Process:

PATIENT/DONOR
      │
      ▼
T cells harvested via leukapheresis
      │
      ▼
T cells activated ex vivo (anti-CD3/CD28 beads)
      │
      ▼
Viral transduction (lentivirus/retrovirus) 
introducing CAR gene
      │
      ▼
CAR-T cell expansion and quality testing
      │
      ▼
Lymphodepletion chemotherapy 
(Fludarabine + Cyclophosphamide)
      │
      ▼
Infusion of CAR-T cells back into patient
      │
      ▼
CAR-T cells recognize and kill tumor cells

FDA-Approved CAR-T Therapies (2025):

Adverse Effects of CAR-T:

1. Cytokine Release Syndrome (CRS): Fever, hypotension, hypoxia - treated with tocilizumab
2. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Encephalopathy, seizures
3. Cytopenias, infections: Prolonged immunosuppression
4. B-cell aplasia: Anti-CD19 CAR-T (manageable with IVIG)

Generations of CAR-T:

1st Generation: scFv + CD3ζ only (limited persistence)
2nd Generation: scFv + CD3ζ + ONE co-stimulatory domain (CD28 or 4-1BB) ← CURRENT CLINICAL USE
3rd Generation: scFv + CD3ζ + TWO co-stimulatory domains
4th Generation (TRUCK): Secretes cytokines in tumor microenvironment
5th Generation: Universal "off-the-shelf" allogeneic CAR-T

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Q.1(c) Human Microbiota and Its Role in Neurological Disorders [20 Marks]

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PART I: HUMAN MICROBIOTA — DEFINITION AND OVERVIEW

Composition:

HUMAN MICROBIOTA DISTRIBUTION
              │
   ─────────────────────────────────────────
   │         │          │          │        │
 GUT        ORAL       SKIN      LUNG    VAGINAL
(Most      (Second    (1.8 m²  (Sparse) Lactobacil-
abundant)  largest)   surface)         lus dominated
   │
Total: ~38 trillion bacteria
Mass: ~0.2 kg
Genes: ~3.3 million (vs ~23,000 human genes)

Gut Microbiota Composition (Healthy Adult):

• Firmicutes: ~50-75% (Lactobacillus, Clostridium, Ruminococcus)
• Bacteroidetes: ~25-40% (Bacteroides, Prevotella)
• Actinobacteria: ~10% (Bifidobacterium)
• Proteobacteria: ~1-5% (E. coli, Helicobacter)
• Verrucomicrobia: Akkermansia muciniphila (gut barrier)

Factors Modifying Microbiota:

• Mode of delivery (vaginal vs. cesarean)
• Breastfeeding vs. formula feeding
• Antibiotics use
• Diet (fiber, fermented foods)
• Geographic location, stress, age

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PART II: GUT-BRAIN AXIS

GUT-BRAIN AXIS (Bidirectional Communication)
                    │
      ──────────────────────────────────────
      │                                    │
   GUT → BRAIN                       BRAIN → GUT
      │                                    │
   ├── Vagus nerve (80% afferent)      ├── ANS modulation
   ├── Short-chain fatty acids         ├── HPA axis (cortisol)
   │   (SCFA: butyrate, propionate)    ├── Enteric nervous system
   ├── Tryptophan → Serotonin          └── Neuropeptides
   │   (90% serotonin made in gut)
   ├── GABA, dopamine precursors
   ├── Cytokines (TNF-α, IL-6, IL-1β)
   └── LPS (lipopolysaccharide) → 
       neuroinflammation via leaky gut

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PART III: ROLE IN NEUROLOGICAL DISORDERS

1. Parkinson's Disease (PD)

MICROBIOTA-PARKINSON'S DISEASE LINK
         │
         ▼
DYSBIOSIS (↓Prevotellaceae, ↑Enterobacteriaceae)
         │
         ▼
Increased intestinal permeability ("Leaky gut")
         │
         ▼
Alpha-synuclein misfolding begins in ENS (Braak hypothesis)
         │
         ▼
Retrograde propagation via Vagus nerve to CNS
         │
         ▼
Substantia nigra alpha-synuclein accumulation (Lewy bodies)
         │
         ▼
Dopaminergic neuron death → PARKINSONISM

2. Alzheimer's Disease (AD)

• Dysbiosis in AD: ↑Firmicutes/Bacteroidetes ratio; ↑Proteobacteria
• Gut bacteria produce amyloid-like proteins that cross-react with brain amyloid
• LPS from gram-negative bacteria → TLR4 activation → neuroinflammation → amyloid plaque deposition
• SCFA deficiency reduces microglial function and amyloid clearance
• Studies show FMT (Fecal Microbiota Transplant) from AD mice worsens cognition in germ-free mice

3. Multiple Sclerosis (MS)

4. Epilepsy

• Ketogenic diet (anti-seizure mechanism partly microbiota-mediated):
  • ↑Akkermansia muciniphila, Lactobacillus
  • ↑GABA/Glutamate ratio in brain
  • ↓Gamma-proteobacteria
• Fecal microbiota differences in drug-resistant epilepsy patients vs. controls

5. Autism Spectrum Disorder (ASD)

GI SYMPTOMS (70% of ASD patients)
         │
         ▼
DYSBIOSIS: ↑Clostridium, ↓Bifidobacterium, ↓Prevotella
         │
         ▼
↑Propionic acid (bacterially produced)
         │
         ▼
Propionic acid crosses BBB → mitochondrial dysfunction,
neuro-inflammation, altered dopamine metabolism
         │
         ▼
Social behavior deficits, repetitive behaviors

6. Depression and Anxiety (Gut-Brain Mood Axis)

• 90% of body's serotonin is produced in the gut (from tryptophan, by Lactobacillus, Bifidobacterium)
• Dysbiosis → reduced serotonin → low mood
• Psychobiotics: Probiotic strains with psychological benefits (L. rhamnosus JB-1, L. helveticus R0052 + B. longum R0175)
• Clinical trial evidence: Specific probiotics reduce anxiety scores in IBS patients and healthy volunteers

7. Stroke

• Dysbiosis promotes atherosclerosis via TMAO (trimethylamine N-oxide) from gut bacteria metabolizing dietary lecithin/choline
• TMAO promotes platelet hyperreactivity and thrombosis
• Post-stroke gut dysbiosis worsens outcomes via systemic inflammation

Therapeutic Implications:

MICROBIOTA-BASED NEUROLOGICAL THERAPIES
                │
   ─────────────────────────────────────────────
   │           │           │           │         │
Probiotics   Prebiotics   FMT       Dietary     Antibiotics
   │           │           │        Modulation  (targeted)
Lactobacillus  Inulin    C. diff       │
Bifidobac-     FOS       treatment  Mediterranean
terium         Resistant  (proven)   Diet
               starch     MS, ASD,   Fiber intake
                          PD trials  Fermented
                                     foods

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QUESTION 2 — Short Answer Questions (Attempt Any Six) [6×10 = 60]

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Q.2(a) Protein Folding Disorders [10 Marks]

Definition

Normal Protein Folding:

NORMAL PROTEIN FOLDING
Ribosome → Nascent polypeptide → Primary structure
     │
     ▼
Heat Shock Proteins (HSP70, HSP90, HSP60/chaperonins)
     │
     ▼
Correct tertiary/quaternary structure
     │
     ▼
Functional protein
     
IF MISFOLDING OCCURS:
Ubiquitin-Proteasome System → Degradation (quality control)
OR
Autophagy (ERAD - ER-Associated Degradation)

Classification and Examples:

Mechanism of Toxicity:

MISFOLDED PROTEIN ACCUMULATION
           │
    ─────────────────────────
    │                       │
INTRACELLULAR           EXTRACELLULAR
AGGREGATION             AGGREGATION
    │                       │
ER stress               Amyloid plaques
Mitochondrial           (cross-β sheet structure)
dysfunction             Congo red positive
Proteasomal             Apple-green birefringence
overload                under polarized light
Autophagy failure       
    │
    ▼
CELL DEATH / NEURODEGENERATION

Key Diagnostic Tests:

• Congo red staining + polarized light (apple-green birefringence): amyloid
• SAP scan (serum amyloid P scintigraphy): systemic amyloid burden
• Mass spectrometry on biopsy: amyloid typing
• Genetic testing: transthyretin mutations (Val122Ile, Val30Met)

Treatment Approaches:

• Tafamidis: TTR stabilizer (cardiac ATTR - ATTR-ACT trial)
• Patisiran/Inclisiran: siRNA silencing of TTR gene
• Inotersen: Antisense oligonucleotide for TTR amyloidosis
• Bortezomib/Daratumumab: AL amyloidosis (suppress plasma cell clone)
• Lecanemab, Donanemab: Anti-amyloid monoclonal antibodies (Alzheimer's - FDA 2023-24)

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Q.2(b) Role of EUS (Endoscopic Ultrasound) in Gastroenterology [10 Marks]

Definition

EUS Equipment:

• Radial array EUS: 360° circumferential view (staging)
• Linear array EUS: Allows FNA/FNB (biopsy), therapeutic interventions

GI Wall Layers on EUS (5 layers):

LUMEN
  │  Layer 1: Superficial mucosa (hyperechoic)
  │  Layer 2: Deep mucosa (hypoechoic)
  │  Layer 3: Submucosa (hyperechoic)
  │  Layer 4: Muscularis propria (hypoechoic)
  │  Layer 5: Serosa/adventitia (hyperechoic)

Diagnostic Roles:

DIAGNOSTIC EUS APPLICATIONS
          │
   ─────────────────────────────────────────
   │           │           │           │
ONCOLOGY   PANCREATIC  BILIARY    SUBMUCOSAL
           DISEASE     DISEASE    LESIONS
   │           │           │           │
-Esophageal -Pancreatitis -Choledocho- -GIST
 cancer T&N  (severity)   lithiasis   -Carcinoid
 staging    -Pancreatic  -Cholangiocar- -Lipoma
-Gastric     masses       cinoma      -Varices
 cancer     -Cystic      -Biliary    -Glomus
 T staging   lesions (IPMN sludge     tumor
-Rectal      MDT/BDT)   -Ampullary
 cancer      -Autoimmune  cancer
 T&N staging  pancreatitis-Mirizzi
-Lung cancer            syndrome
 (mediastinal
 staging)

EUS-FNA/FNB (Fine Needle Aspiration/Biopsy):

• 19-25 gauge needles
• Diagnostic yield: 85-95% for solid pancreatic lesions
• Safe (bleeding risk < 1%, pancreatitis < 1%)
• Can sample lymph nodes, liver lesions, adrenal masses, peritoneal nodules

Therapeutic EUS (Interventional EUS):

Advantages over CT/MRI:

• Superior for T-staging of GI cancers (accuracy ~85-90%)
• Can sample lesions real-time
• No radiation
• Better detection of small pancreatic lesions (< 1 cm)
• Detects common bile duct stones better than MRCP for stones < 5 mm

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Q.2(c) Epigenetics [10 Marks]

Definition

Core Mechanisms:

EPIGENETIC MECHANISMS
         │
   ──────────────────────────────────────────
   │              │              │           │
DNA           HISTONE        NON-CODING   CHROMATIN
METHYLATION   MODIFICATION   RNA          REMODELING
   │              │              │           │
CpG islands   Acetylation    miRNA       SWI/SNF
5-methylcyto  Methylation    lncRNA      NuRD complex
sine (5mC)    Phosphorylation siRNA      ATP-dependent
DNMT1,3a,3b   Ubiquitination piRNA       remodeling
TET enzymes   Sumoylation    circRNA
(demethyl-    HDACs/HATs
ation)

DNA Methylation:

• Methylation of CpG islands in promoters → Gene silencing
• Writers: DNMT1 (maintenance), DNMT3a/3b (de novo)
• Erasers: TET1/2/3 enzymes (5mC → 5hmC → unmodified)
• Aberrant hypermethylation of tumor suppressor genes = cancer hallmark (e.g., MLH1 in colorectal, BRCA1 in breast)

Histone Modifications:

• Histone acetylation (by HATs): Relaxes chromatin → gene activation
• Histone deacetylation (by HDACs): Compacts chromatin → gene silencing
• Histone methylation: Context-dependent (H3K4me3 = active; H3K27me3 = repressed)

Non-coding RNAs:

• miRNA: Short (20-25 nt), silences target mRNAs post-transcriptionally (RISC complex)
• lncRNA: > 200 nt; scaffolding, chromatin organization (XIST - X chromosome inactivation)
• siRNA: Sequence-specific gene silencing (therapeutic use: patisiran, inclisiran)

Clinical Relevance:

Epigenetic Drugs:

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Q.2(d) Checkpoint Inhibitors [10 Marks]

Definition

The Problem - How Tumors Evade Immunity:

NORMAL T-CELL ACTIVATION
T-cell → TCR + MHC-antigen → Activated T-cell → Kills tumor
         + CD28 + B7 (costimulation)

TUMOR IMMUNE EVASION:
Tumor expresses PD-L1 → binds PD-1 on T-cell → T-cell EXHAUSTION
CTLA-4 competes with CD28 for B7 → Blocks co-stimulation
LAG-3, TIM-3, TIGIT → Additional inhibitory checkpoints

Major Checkpoint Inhibitors (Approved, 2025):

Mechanism of PD-1/PD-L1 Blockade:

CHECKPOINT INHIBITOR MECHANISM
          │
Tumor cell expresses PD-L1
          │
PD-L1 binds PD-1 on T-cell
          │
T-cell EXHAUSTION/ANERGY → tumor grows
          │
PD-1 or PD-L1 antibody blocks this interaction
          │
T-cell REACTIVATED → Cytotoxic killing of tumor

Biomarkers Predicting Response:

• PD-L1 expression (IHC TPS, CPS): Pembrolizumab NSCLC (TPS ≥ 50%)
• Tumor Mutational Burden (TMB): TMB-high (≥ 10 mut/Mb) = better response
• MSI-H/dMMR: Pan-cancer approval for pembrolizumab (KEYNOTE-158)
• EBV status, POLE mutations, HER2 expression

Immune-Related Adverse Events (irAEs):

IMMUNE-RELATED ADVERSE EVENTS (irAEs)
              │
   ─────────────────────────────────────────────
   │          │         │           │          │
 SKIN      ENDOCRINE   GI         LUNG      OTHERS
   │          │         │           │          │
Rash       Thyroiditis Colitis    Pneumonitis Hepatitis
Vitiligo   Hypophysitis Diarrhea  (grade 3-4: Nephritis
Pruritus   T1DM        Enteritis   hold ICI)  Neuro-
Bullous    Adrenal                            toxicity
pemphigoid insufficiency                      Myocarditis
                                              (rare/fatal)

• Grade 1: Monitor, continue ICI
• Grade 2: Hold ICI, start oral steroids (prednisone 0.5-1 mg/kg)
• Grade 3-4: Permanently discontinue, high-dose IV methylprednisolone ± infliximab (colitis), mycophenolate (hepatitis)

---

Q.2(e) Newer Treatment Modalities in Management of Obesity [10 Marks]

Definition

Treatment Algorithm:

OBESITY MANAGEMENT
        │
STEP 1: Lifestyle modification (Diet + Exercise + Behavioral therapy)
        │ (if inadequate response)
        ▼
STEP 2: Pharmacotherapy (BMI ≥ 30 or ≥ 27.5 with comorbidities)
        │ (if inadequate response)
        ▼
STEP 3: Endoscopic procedures
        │ (if inadequate response or contraindication to surgery)
        ▼
STEP 4: Bariatric Surgery (BMI ≥ 40 or ≥ 35 with comorbidities)

NEW Pharmacological Therapies:

Newer Endoscopic Procedures:

ENDOSCOPIC APPROACHES FOR OBESITY
           │
   ────────────────────────────────────────
   │              │               │
INTRAGASTRIC    ENDOSCOPIC     ENDOSCOPIC
BALLOONS        SLEEVE          PLICATION
   │            GASTROPLASTY    (POSE/ROSE)
Orbera (6 mo)   (ESG)              │
Obalon           │             Full-thickness
Elipse           Endoscopic     sutures at
(swallowable)    suturing       fundus/body
                 reduces gastric Weight loss
                 volume 70%     ~15-18%
                 Weight loss
                 ~17-20%

Bariatric Surgery (Newer):

Novel Mechanisms Under Investigation:

• Hypothalamic targeting: MC4R agonists, POMC gene therapy
• Gut microbiome modulation: FMT from lean donors
• Brown adipose tissue activation: Mirabegron (beta-3 agonist), cold exposure
• Leptin sensitizers: For leptin-resistant obesity
• GLP-1/Glucagon/GIP triple agonist implants: Long-acting

---

Q.2(f) Glycemic Variability [10 Marks]

Definition

Why GV Matters:

GLYCEMIC VARIABILITY
         │
    ─────────────────────────────────
    │                               │
HbA1c captures                GV captures
AVERAGE glucose               PEAKS and TROUGHS
(2-3 month mean)              missed by HbA1c
         │                          │
Limitations:                  Important for:
Does not reflect              - Postprandial
hypoglycemia                   spikes → ROS
Does not reflect              - Nocturnal hypo
postprandial spikes           - Cardiovascular
                               risk

Measures of Glycemic Variability:

Continuous Glucose Monitoring (CGM) - Key Technology:

CGM TECHNOLOGY
     │
  ───────────────────────────────────────
  │                     │               │
REAL-TIME CGM      FLASH GLUCOSE    iCGM
(Dexcom G7,        MONITORING       (interoperable
 Medtronic         (FreeStyle       CGM: Dexcom G6/G7,
 Guardian 4)       Libre 3)         Libre 3+ for
     │                              AID systems)
Alarms for
hypo/hyperglycemia
Integration with
insulin pumps (AID)

Consequences of High GV:

HIGH GLYCEMIC VARIABILITY
         │
    ─────────────────────────────────
    │                               │
CELLULAR MECHANISMS          CLINICAL OUTCOMES
    │                               │
Oxidative stress            Cardiovascular events
(ROS from glucose spikes)   Microvascular disease
Protein glycation           (nephropathy, retinopathy)
Endothelial dysfunction     Neuropathy
NF-κB activation            Cognitive decline
Advanced Glycation          Impaired QoL
End Products (AGEs)         Higher mortality (ICU)
Inflammation (IL-6,
TNF-α elevation)

Strategies to Reduce GV:

ADA 2024 GV Recommendations:

• CGM recommended for all patients on intensive insulin therapy
• TIR > 70% as glycemic target (equivalent to HbA1c ~7%)
• TBR < 4% with NO Level 2 hypoglycemia (< 54 mg/dL)

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Q.2(g) Neurotherapeutic Technology in Parkinson's Disease [10 Marks]

Overview of PD Treatment Evolution:

PARKINSON'S DISEASE THERAPEUTIC TIMELINE
         │
1960s: L-Dopa introduced (Cotzias)
         │
1980s: Dopamine agonists (Bromocriptine)
         │
1990s: Deep Brain Stimulation (DBS) - STN
         │
2000s: COMT inhibitors, MAO-B inhibitors
         │
2010s: Levodopa-Carbidopa Intestinal Gel (LCIG)
         │
2020s: Focused Ultrasound, Gene Therapy,
       Adaptive DBS, Closed-loop systems,
       Alpha-synuclein targeted therapies

1. Deep Brain Stimulation (DBS)

DBS TARGETS IN PD
       │
  ─────────────────────────────
  │              │             │
STN (Subthalamic  GPi (Globus   VIM (Ventral
Nucleus) ← MOST  Pallidus      Intermediate
COMMON           Internus)     Nucleus of
  │              │             Thalamus)
Best motor       Best for      Best for
control,         dyskinesias   tremor
reduces          Less cognitive (less effect
medications      effects       on other sx)

• Senses local field potentials (beta oscillations) from STN in real-time
• Adjusts stimulation automatically based on neural feedback
• Reduces stimulation by ~40% while maintaining efficacy
• Reduces side effects compared to conventional DBS
• Medtronic BrainSense DBS (first closed-loop system, 2021)

2. Focused Ultrasound (FUS)

• MRI-guided High-Intensity Focused Ultrasound (MRgFUS)
• Creates precise, incisionless ablative lesion in VIM or STN
• Approved by FDA for essential tremor and PD tremor
• Unilateral procedure (bilateral FDA approved 2023 for EssentialTremor; PD bilateral under trials)
• Advantage: Reversible targeting, no implant required
• Limitation: Skull penetration variability, only tremor benefit

3. Transcranial Magnetic Stimulation (TMS) / Transcranial Direct Current Stimulation (tDCS)

• Non-invasive neuromodulation
• rTMS over primary motor cortex: Improves motor symptoms, gait
• tDCS over prefrontal cortex: Emerging role in cognitive symptoms, depression in PD
• Not yet standard of care

4. Gene Therapy in PD:

GENE THERAPY APPROACHES IN PD
           │
   ─────────────────────────────────────────
   │           │           │           │
GAD Gene    AADC Gene   GDNF/NRTN  Alpha-syn
Therapy     Therapy     Delivery    Silencing
   │           │           │           │
Converts    Restores    Neurotrophic Antisense
glutamate   dopamine    support for  oligonucleo-
to GABA     synthesis   surviving    tides /
in STN      capacity    dopaminergic siRNA
(reduces    (improves   neurons      (reduce
STN over-   "off" time)             aggregation)
activity)   ProSavin
AAV-GAD     trial       Pallidus
Phase II               infusion

5. Cell-Based Therapies:

6. Alpha-Synuclein Targeted Therapies (2024-2025):

ALPHA-SYNUCLEIN THERAPEUTIC TARGETS
              │
   ─────────────────────────────────────────────
   │              │              │              │
REDUCE          PREVENT         ENHANCE        IMMUNOTHERAPY
SYNTHESIS       AGGREGATION     CLEARANCE
   │              │              │              │
ASO/siRNA       LRRK2           Autophagy      Prasinezumab
(Ionis          inhibitors      enhancers      (anti-alpha-syn
Therapeutics)   (Biogen MLi-2)  Beclin-1       antibody) Phase 2
Ambroxol        Nilotinib       activation     Cinpanemab
(chaperone)     (kinase inh.)                  UCB0599

7. Wearable Sensors and Digital Therapeutics:

• PKG (Personal KinetiGraph): Wrist-worn accelerometer measuring tremor, dyskinesia, bradykinesia continuously
• Enables objective dose titration
• AI-based gait analysis apps (mPower, STAT-ON)
• Closed-loop feedback exercise systems: Real-time cueing for freezing of gait

---

Q.2(h) Mitochondrial Diseases [10 Marks]

Introduction

Genetics:

MITOCHONDRIAL DISEASE GENETICS
           │
   ─────────────────────────────────────────
   │                                       │
mtDNA MUTATIONS                      nDNA MUTATIONS
(Maternally inherited)               (Mendelian, AR/AD/XL)
   │                                       │
- Heteroplasmy                       - POLG mutations (ALPERS)
  (variable proportion of            - SURF1 (Leigh syndrome)
  mutant:wildtype mtDNA)             - SCO1/SCO2 (COX assembly)
- Threshold effect                   - Complex I subunits
- Point mutations:                     (NDUFV1, NDUFS1)
  MELAS: tRNALeu A3243G              - Twinkle helicase
  MERRF: tRNALys A8344G              - TK2, DGUOK (mtDNA
  NARP: ATPase A8993G                  depletion syndromes)
- Deletions:
  Single large deletion
  (Kearns-Sayre, CPEO, PS)

Classification of Major Syndromes:

Clinical Spectrum:

MITOCHONDRIAL DISEASE - ORGAN INVOLVEMENT
              │
  HIGH ENERGY-DEMANDING ORGANS MOST AFFECTED
              │
   ─────────────────────────────────────────────
   │       │       │       │       │       │    │
 CNS    MUSCLE   EYE    HEART   EAR    ENDO  KIDNEY
   │       │       │       │       │    CRINE    │
Stroke- Proximal Ptosis  Pre-   SNHL   DM   Fanconi
like    myopathy PEO    excita-  (deaf-  (MIDD, syndrome
epi-    Weakness Optic  tion     ness)   MELAS) proximal
sodes   Fatigue  atro-  conduc-          tubular
Seizures Exercise  phy  tion             acidosis
Dementia intoler- Pigm.  defect
Ataxia  ance     reti-  (KSS:
        Ragged   nopathy  HB,
        red      (KSS)    WPW)
        fibers
        (RRF)

Key Histopathology:

• Ragged Red Fibers (RRF): Gomori trichrome stain - mitochondria accumulate in subsarcolemmal zone (red appearance). Seen in MERRF, MELAS, KSS
• COX-negative fibers: Succinate dehydrogenase (SDH) positive but cytochrome oxidase (COX) negative fibers in complex IV deficiency
• Electron microscopy: Abnormal mitochondrial morphology, paracrystalline inclusions

Diagnosis:

DIAGNOSTIC APPROACH TO MITOCHONDRIAL DISEASE
              │
Clinical suspicion (multi-system + maternal inheritance)
              │
              ▼
BLOOD: Lactate, Pyruvate, L:P ratio (>20 = OXPHOS defect)
CK, amino acids, acylcarnitine profile
              │
              ▼
URINE: Organic acids (Krebs cycle intermediates)
              │
              ▼
NEUROIMAGING: MRI brain
- MELAS: Cortical lesions NOT following vascular territory
- Leigh: Bilateral basal ganglia + brainstem T2 hyperintensity
              │
              ▼
MUSCLE BIOPSY: RRF, COX staining, EM
Respiratory chain enzyme analysis
              │
              ▼
GENETIC TESTING: mtDNA first (blood/urine/muscle)
If negative → Next Generation Sequencing (nDNA panel)

Treatment:

Emerging Therapies:

• Mitochondrial replacement therapy (MRT) / Spindle transfer: Prevents maternal transmission of mtDNA disease (approved in UK)
• Mitochondrially targeted antioxidants: MitoQ, SkQ1
• NAD+ precursors (nicotinamide riboside): Improve complex I activity via NAD+/NADH ratio
• AAV-based gene therapy for specific mutations (e.g., LHON gene therapy - Lumevoq for ND4 mutation)

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SUMMARY TABLE — All Topics at a Glance

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