Suspected medullary washout leading to severe polyuria following delayed cerebral ischemia: a case report.

BACKGROUND: Delayed cerebral ischemia is a clinical entity commonly encountered in patients presenting with acute neurological injury and is often complicated by dysnatremias, such as the cerebral salt wasting syndrome. In this case report, we described an exceptional case of polyuria attributed to an initial cerebral salt wasting phenomenon and iatrogenic-induced medullary washout. CASE PRESENTATION: A 53-year-old woman was admitted to our hospital for the management of a Modified Fisher scale grade 4 subarachnoid hemorrhage due to a ruptured posterior communicating aneurysm. She was initially managed with coil embolization and external ventricular drain due to secondary hydrocephalus. Throughout the course of her hospitalization, she developed severe polyuria reaching up to 40L per day. To keep up with the excessive urinary losses and maintain appropriate cerebral perfusion, fluid replacement therapy was adjusted every hour, reaching up to 1.3 L of crystalloid per hour in addition to aminergic support. An initial diagnosis of partial diabetes insipidus, followed by a cerebral salt wasting syndrome was suspected. While the urine output continued to increase, her serum urea concentration progressively decreased to a point of almost being undetectable on day 9. At that time, the presence of an interstitial medulla washout was hypothesized. Various pharmacological and non-pharmacological interventions were progressively introduced to regain normal renal homeostasis, including non-steroidal anti-inflammatory drugs, fludrocortisone, oral urea and high-protein intake. Medications were progressively weaned, and the patient was successfully discharged from the ICU. CONCLUSIONS: Cerebral salt wasting should be considered in the initial differential diagnosis of a patient presenting with polyuria in the context of acute neurological injury. Early recognition of this entity is critical to quickly implement proper management. However, as shown in this case report, the concomitance of delayed cerebral ischemia may complexify that management.

Molecular mechanism of activation of the immunoregulatory amidase NAAA.

Palmitoylethanolamide is a bioactive lipid that strongly alleviates pain and inflammation in animal models and in humans. Its signaling activity is terminated through degradation by N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase expressed at high levels in immune cells. Pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects in rodent models, pointing to this protein as a potential target for therapeutic drug discovery. To facilitate these efforts and to better understand the molecular mechanism of action of NAAA, we determined crystal structures of this enzyme in various activation states and in complex with several ligands, including both a covalent and a reversible inhibitor. Self-proteolysis exposes the otherwise buried active site of NAAA to allow catalysis. Formation of a stable substrate- or inhibitor-binding site appears to be conformationally coupled to the interaction of a pair of hydrophobic helices in the enzyme with lipid membranes, resulting in the creation of a linear hydrophobic cavity near the active site that accommodates the ligand's acyl chain.

Crystal structure of saposin D in an open conformation.

Saposins are accessory proteins that aid in the degradation of sphingolipids by hydrolytic enzymes. Their structure usually comprises four α-helices arranged in various conformations including an open, V-shaped form that is generally associated with the ability to interact with membranes and/or enzymes to accentuate activity. Saposin D is required by the lysosomal hydrolase, acid ceramidase, which breaks down ceramide into sphingosine and free fatty acid, to display optimal activity. The structure of saposin D was previously determined in an inactive conformation, revealing a monomeric, closed and compact form. Here, we present the crystal structure of the open, V-shaped form of saposin D. The overall shape is similar to the open conformation found in other saposins with slight differences in the angles between the α-helices. The structure forms a dimer that serves to stabilize the hydrophobic surface exposed in the open form, which results in an internal, hydrophobic cavity that could be used to carry extracted membrane lipids.

Current and Emerging Role of Monoclonal Antibody-Based First-Line Treatment in Advanced Gastro-Esophageal and Gastric Cancer.

Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.

Structural basis for the activation of acid ceramidase.

Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes. Abnormal function of aCDase leads to Farber disease, spinal muscular atrophy with progressive myoclonic epilepsy, and is associated with Alzheimer's, diabetes, and cancer. Here, we present crystal structures of mammalian aCDases in both proenzyme and autocleaved forms. In the proenzyme, the catalytic center is buried and protected from solvent. Autocleavage triggers a conformational change exposing a hydrophobic channel leading to the active site. Substrate modeling suggests distinct catalytic mechanisms for substrate hydrolysis versus autocleavage. A hydrophobic surface surrounding the substrate binding channel appears to be a site of membrane attachment where the enzyme accepts substrates facilitated by the accessory protein, saposin-D. Structural mapping of disease mutations reveals that most would destabilize the protein fold. These results will inform the rational design of aCDase inhibitors and recombinant aCDase for disease therapeutics.