Inflammatory Response and Defects on Myelin Integrity in the Olfactory System of K18hACE2 Mice Infected with SARS-CoV-2.

Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity, the olfactory epithelium (OE) is particularly sensitive to infections which may lead to olfactory dysfunction. In patients suffering from coronavirus disease 2019, deficits in olfaction have been characterized as a distinctive symptom. Here, we used the K18hACE2 mice to study the spread of SARS-CoV-2 infection and inflammation in the olfactory system (OS) after 7 d of infection. In the OE, we found that SARS-CoV-2 selectively targeted the supporting/sustentacular cells (SCs) and macrophages from the lamina propria. In the brain, SARS-CoV-2 infected some microglial cells in the olfactory bulb (OB), and there was a widespread infection of projection neurons in the OB, piriform cortex (PC), and tubular striatum (TuS). Inflammation, indicated by both elevated numbers and morphologically activated IBA1+ cells (monocyte/macrophage lineages), was preferentially increased in the OE septum, while it was homogeneously distributed throughout the layers of the OB, PC, and TuS. Myelinated OS axonal tracts, the lateral olfactory tract, and the anterior commissure, exhibited decreased levels of 2',3'-cyclic-nucleotide 3'-phosphodiesterase, indicative of myelin defects. Collectively, our work supports the hypothesis that SARS-CoV-2 infected SC and macrophages in the OE and, centrally, microglia and subpopulations of OS neurons. The observed inflammation throughout the OS areas and central myelin defects may account for the long-lasting olfactory deficit.

Flow Diversion as a Definitive Treatment for Recurrently Ruptured A1-A2 Anterior Cerebral Artery Aneurysm Following Clipping and Coiling.

Even after clipping of intracranial aneurysms, patients may experience incomplete occlusion or the future recurrence of their treated aneurysm. This paper presents a distinctive case of a recurrent A1-A2 anterior cerebral artery aneurysm that underwent four interventions over 16 years. The aneurysm was treated with two clippings, subsequent coiling, and flow diversion for definitive treatment. The challenges encountered in managing bifurcation aneurysms are discussed, emphasizing the importance of considering hemodynamic factors, vessel geometry, and recurrence risk factors in treatment decisions. The case highlights the need for closer follow-up of ruptured bifurcation aneurysms due to the higher likelihood of recurrence. The role of flow diverters in reinforcing vessel anatomy and preventing recurrence is also highlighted.

α-Synuclein Pathology and Reduced Neurogenesis in the Olfactory System Affect Olfaction in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6-7 and 12-14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12-14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12-14 months. Our data suggest that (1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; (2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; (3) α-syn pathology is restricted to projection neurons in the olfactory pathway; (4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and (5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.SIGNIFICANCE STATEMENT Olfactory dysfunction is a characteristic symptom of Parkinson's disease (PD). Using the human A30P mutant α-synuclein (α-syn)-expressing mouse model, we demonstrated the appearance of olfactory deficits at late stages of the disease, which was accompanied by the accumulation of α-syn pathology in projection neurons (PNs) of the olfactory system. This dysfunction included a reduction in olfactory bulb (OB) neurogenesis as well as changes in synaptic vesicular transport affecting synaptic function, both of which are likely contributing to olfactory behavioral deficits.

Surface tension examination of various liquid oral, nasal, and ophthalmic dosage forms.

Surface tension at the surface-to-air interface is a physico-chemical property of liquid pharmaceutical formulations that are often overlooked. To determine if a trend between surface tension and route of administration exists, a suite of oral, nasal, and ophthalmic drug formulations were analyzed. The surface tension at the surface-to-air interface of the oral formulations studied were in or above the range of the surface tension of gastric, duodenum, and jejunum fluids. The range of surface tensions for oral formulations were 36.6-64.7 dynes/cm. Nasal formulations had surface tensions below that of the normal mucosal lining fluid with a range of 30.3-44.9 dynes/cm. Ophthalmic OTC formulations had the largest range of surface tensions at the surface-to-air interface of 34.3-70.9 dynes/cm; however, all formulations indicated for treatment of dry eye had surface tensions higher than that of normal tears, while those for treatment of red eye had surface tensions below. Therefore, surface tension at the surface-to-air interface of liquid formulations is dependent on the route of administration, environment at site of introduction, and for ophthalmics, what the formulation is indicated for.