The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism.

Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion. Interestingly, during HCV infection, the activation of SREBPs occurs under normal cholesterol levels, but the underlying mechanisms are still elusive. Our previous study has demonstrated the activation of the inflammasome complex in HCV-infected human hepatoma cells. In this study, we elucidate the potential link between chronic hepatitis C-associated inflammation and alteration of lipid homeostasis in infected cells. Our results reveal that the HCV-activated NLRP3 inflammasome is required for the up-regulation of lipogenic genes such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, fatty acid synthase, and stearoyl-CoA desaturase. Using pharmacological inhibitors and siRNA against the inflammasome components (NLRP3, apoptosis-associated speck-like protein containing a CARD, and caspase-1), we further show that the activation of the NLRP3 inflammasome plays a critical role in lipid droplet formation. NLRP3 inflammasome activation in HCV-infected cells enables caspase-1-mediated degradation of insulin-induced gene proteins. This subsequently leads to the transport of the SREBP cleavage-activating protein·SREBP complex from the endoplasmic reticulum to the Golgi, followed by proteolytic activation of SREBPs by S1P and S2P in the Golgi. Typically, inflammasome activation leads to viral clearance. Paradoxically, here we demonstrate how HCV exploits the NLRP3 inflammasome to activate SREBPs and host lipid metabolism, leading to liver disease pathogenesis associated with chronic HCV.

Atypical Presentation of Descending Aortic Dissection in an Acute Heart Failure Patient.

Aortic dissection is relatively uncommon, but often presents with acute severe chest or back pain and acute hemodynamic compromise and is associated with high mortality. We present a case of aortic dissection with an atypical presentation in a heart failure patient and the challenges encountered to make the diagnosis. The patient was a 54-year-old African American female who presented with progressively worsening exertional dyspnea and orthopnea for three days and sensation of indigestion and bloating. The patient denied any recent history of chest pain and she was initially admitted for heart failure exacerbation. Her admission chest x-ray showed severe cardiomegaly with a prominence of pulmonary vascular but there was a borderline widening of mediastinum measuring 8.2 cm. Physical exam showed unequal dorsalis pedis pulses (fainter on the right side) and systolic blood pressure difference of more than 20 mmHg between bilateral upper extremities. Computed tomography angiography (CTA) of chest, abdomen, and pelvis confirmed the diagnosis of dissection of thoracic and abdominal aorta extending from the left subclavian artery to the femoral artery. The patient was managed with labetalol drip and later transferred to a tertiary center for an elevated level of care where the endovascular intervention was performed. The patient then followed up with a vascular clinic for serial CTA and heart failure clinic for optimization of core measures. In conclusion, this case highlights the importance of clinical suspicion of aortic dissection and discusses the various clinical presentations of aortic dissection and its management. Being a highly fatal condition, prompt diagnosis is extremely important and is often life-saving. Therefore, it is important for physicians to be aware of atypical presentations of aortic dissection to initiate timely interventions to avoid catastrophic complications.

An Unusual Case of Intraabdominal Abscess After a Colonoscopy With Polypectomy.

The use of colonoscopies in the screening of colorectal cancers has helped in the early detection and treatment of these cancers. Less than 0.5% of patients develop colonoscopy complications, mostly bleeding, and less frequently, perforations. There have been very few reported cases of micro-perforations following colonoscopies. We present a case of a 66-year-old female smoker who had undergone a screening colonoscopy for colorectal cancer with two polyps removed 3 weeks prior, who was brought to the hospital because of altered mental status and hypotension. A computed tomography (CT) scan of the abdomen and pelvis with contrast demonstrated intraabdominal abscess which was drained by interventional radiology. A culture of the pus grew Streptococcus constellatus, a pus-forming bacterium. She was treated with ceftriaxone and metronidazole for a total of 6 weeks, and a repeat CT of abdomen and pelvis demonstrated complete resolution. The only contributing factor to the formation of the intraabdominal abscess was a screening colonoscopy with polypectomy, which might have caused micro-perforations in the colon with the seeding of Streptococcus constellatus. The occurrence of intraabdominal abscess following a colonoscopy is very rare, and requires a high index of suspicion in patients who present with sepsis following colonoscopies.

Delayed brain injury post carbon monoxide poisoning.

A 66-year-old male was found unresponsive and diagnosed with acute carbon monoxide poisoning, with pathognomonic findings on radiological imaging. During his first day's the patient underwent acute neurological deterioration; however, this was followed 2 weeks later with a subsequent improvement to near baseline. The improvement back to baseline was short-lived, and the patient quickly worsened and underwent neurological decompensation. These findings were consistent with delayed post hypoxic leukoencephalopathy, serious sequelae of carbon monoxide poisoning. This case report shows the importance of recognition of carbon monoxide toxicity and aims to improve accurate diagnosis of the sequelae that may follow using computed tomography and magnetic resonance imaging sequences, magnetic resonance spectroscopy in order to prevent or ameliorate further neurological decline.

More than Just Pneumonia: Acute Pulmonary Embolism in Two Middle-Aged Patients with COVID-19.

BACKGROUND: Although severe pneumonia and respiratory compromise have remained the predominant complications of coronavirus disease 19, we are now learning this virus is much more varied in its presentation. In particular, there are increasingly reported cases of thromboembolic events occurring in infected patients. Case Report. In this report, we present two patients, both under the age of 40 with known risk factors for venous thromboembolism, who presented with respiratory distress. Both patients were diagnosed with SARS-CoV-2 pneumonia and pulmonary embolism requiring management with anticoagulation. Both patients were discharged after a short course in the hospital. CONCLUSION: The discussion of a hypercoagulable state induced by coronavirus disease 19 has been well documented; however, the exact mechanisms remain unknown. We suspect that a prothrombotic inflammatory response provoked by coronavirus disease could be the culprit, acting as an additive effect on middle-aged patients with known risk factors for venous thromboembolism. We recommend clinicians closely monitor those with known risk factors for pulmonary embolism.

Complex and non-redundant signals from individual odor receptors that underlie chemotaxis behavior in Drosophila melanogaster larvae.

The rules by which odor receptors encode odors and allow behavior are still largely unexplored. Although large data sets of electrophysiological responses of receptors to odors have been generated, few hypotheses have been tested with behavioral assays. We use a data set on odor responses of Drosophila larval odor receptors coupled with chemotaxis behavioral assays to examine rules of odor coding. Using mutants of odor receptors, we have found that odor receptors with similar electrophysiological responses to odors across concentrations play non-redundant roles in odor coding at specific odor concentrations. We have also found that high affinity receptors for odors determine behavioral response thresholds, but the rules for determining peak behavioral responses are more complex. While receptor mutants typically show loss of attraction to odors, some receptor mutants result in increased attraction at specific odor concentrations. The odor receptor mutants were rescued using transgenic expression of odor receptors, validating assignment of phenotypes to the alleles. Vapor pressures alone cannot fully explain behavior in our assay. Finally, some odors that did not elicit strong electrophysiological responses are associated with behavioral phenotypes upon examination of odor receptor mutants. This result is consistent with the role of sensory neurons in lateral inhibition via local interneurons in the antennal lobe. Taken together, our results suggest a complexity of odor coding rules even in a simple olfactory sensory system.