Effect of lysosomotropic molecules on cellular homeostasis.

Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal-lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities.

Alexithymia in people with subjective cognitive decline, mild cognitive impairment, and mild Alzheimer's disease.

BACKGROUND: Behavioral and psychological symptoms are widely accepted as accelerator factors in progression to dementia. Although alexithymia is closely related to normal aging process and poor neurocognitive performance, alexithymia has not been included in these symptoms yet. AIMS: Here, we aimed to investigate alexithymia features in people with prominent clinical memory complaints. METHODS: The participants (n = 82) were classified into three groups as: subjective cognitive decline (n = 30), mild cognitive impairment (n = 27), and mild Alzheimer's disease (n = 25) after Mini-Mental State Examination, Clinical Dementia Rating Scale, neuropsychological test battery, Geriatric Depression Scale, and Hachinski Ischemic Scale. All participants were assessed with 20-item Toronto Alexithymia Scale. RESULTS: The patients with mild Alzheimer's disease and mild cognitive impairment have significantly greater alexithymia features than individuals with subjective cognitive decline in Toronto Alexithymia Scale (p < 0.05 for all). The alexithymia features in patients with mild Alzheimer's disease and mild cognitive impairment did not significantly differ (p > 0.05, for all). DISCUSSION: People who have objective cognitive decline seem to have more alexithymia features than people with subjective cognitive decline. Moreover, alexithymia features seem to be similar in people mild Alzheimer's disease and in mild cognitive impairment. CONCLUSION: Alexithymia might be an important searching domain of behavioral-psychological symptoms in people with cognitive problems beyond aging.

Merkel cell carcinoma presenting as a malignant pleural effusion post-COVID-19 hospitalization: A case report and literature review.

Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine carcinoma of the skin, associated with immunosuppression, UV light exposure, and the Merkel cell polyomavirus (MCPyV). Cases of metastatic MCC diagnosed in body fluid cytology are extremely rare; only five cases have been reported previously in the English literature. We present a case of a 65-year-old male with acute respiratory failure and an enlarged right pleural effusion. He had two hospitalizations for COVID-19 pneumonia 2 months prior, for which he received steroid treatment and tocilizumab. Emergent thoracentesis was done, with pleural fluid sent for cytologic evaluation. Both the Papanicolaou stained ThinPrep slide and cell block demonstrated clusters of predominantly small to medium sized blue round cells with hyperchromatic nuclei, scant cytoplasm and fine chromatin, in a background of rare mesothelial cells, macrophages and numerous lymphocytes. Tumor cells were positive for CD56, chromogranin, synaptophysin, SAT2B, MCPyV, and CK20 in perinuclear dot like pattern, while negative for TTF-1 and CD45 immunostains. Ki67 proliferative index was approximately 40%. The patient had a history of MCC of the right ulnar forearm 4 years before the current presentation, which was unknown to us at the time of cytologic evaluation. To the best of our knowledge, this is the sixth case of metastatic MCC diagnosed by fluid cytology and the first reported in a patient receiving immunosuppressive treatment for COVID-19. Further reporting of such cases may increase awareness, especially when prior history is not readily available, such as in our case.

Solid Pseudopapillary Neoplasm of the Uncinate Process of the Pancreas: A Case Report and Review of the Literature.

Solid pseudopapillary neoplasm (SPN) is a rare pancreatic neoplasm that accounts for 1-3% of all pancreatic tumors. SPNs are most commonly found in females in their third and fourth decades of life. Even though the majority of the tumors are benign, malignant tumors have also been reported. Given its rare occurrence, it remains a clinical dilemma in gastroenterology, oncology, and pathology. It is critical to diagnose it early and differentiate it from other similar pancreatic tumors or cysts to ensure favorable patient outcomes. Advanced imaging techniques, characteristic histologic findings, and immunohistochemical analysis can help in diagnosing solid pseudopapillary tumors. Early diagnosis and surgical resection can result in a cure in most cases, and tumor recurrence is extremely rare. In this report, we present a case of a 40-year-old female patient who presented to the emergency room and was diagnosed with SPN of the pancreas.

Ultrasound-guided fine-needle aspiration biopsy of thyroid neoplasms with lipomatous stroma: Report of two cases.

Thyroid tumors with abundant adipose tissue component are rare, reportedly accounting for 0.98-2.8% of all thyroid nodules, and include entities such as thyroid lipoadenoma and thyroid carcinoma with lipomatous stroma (TCLS). They may be encountered on fine-needle aspiration biopsy (FNAB), which is widely used in evaluation of thyroid nodules. However, due to their relative rarity, adipose elements rarely are recognized preoperatively in these tumors. Herein, we report two cases of thyroid tumors with abundant adipose tissue, along with cytologic, histologic, and ultrasonographic features. Although an intermixture of adipose tissue and thyroid follicular cells is the key cytologic feature of thyroid tumors with adipose stroma, other cytologic findings, such as abundant fat droplets or isolated fragments of adipose tissue, also should raise the possibility of a fat-containing tumor, particularly when a biopsy is performed by a cytopathologist under ultrasonographic guidance and adequate radiologic-pathologic correlation. Cytopathologists should be aware that overlooking lesional adipose tissue within a thyroid neoplasm might give the false impression of a non-diagnostic or sparsely cellular FNAB specimen.

PD-1 Dynamically Regulates Inflammation and Development of Brain-Resident Memory CD8 T Cells During Persistent Viral Encephalitis.

Programmed cell death-1 (PD-1) receptor signaling dampens the functionality of T cells faced with repetitive antigenic stimulation from chronic infections or tumors. Using intracerebral (i.c.) inoculation with mouse polyomavirus (MuPyV), we have shown that CD8 T cells establish a PD-1hi, tissue-resident memory population in the brains (bTRM) of mice with a low-level persistent infection. In MuPyV encephalitis, PD-L1 was expressed on infiltrating myeloid cells, microglia and astrocytes, but not on oligodendrocytes. Engagement of PD-1 on anti-MuPyV CD8 T cells limited their effector activity. NanoString gene expression analysis showed that neuroinflammation was higher in PD-L1-/- than wild type mice at day 8 post-infection, the peak of the MuPyV-specific CD8 response. During the persistent phase of infection, however, the absence of PD-1 signaling was found to be associated with a lower inflammatory response than in wild type mice. Genetic disruption and intracerebroventricular blockade of PD-1 signaling resulted in an increase in number of MuPyV-specific CD8 bTRM and the fraction of these cells expressing CD103, the αE integrin commonly used to define tissue-resident T cells. However, PD-L1-/- mice persistently infected with MuPyV showed impaired virus control upon i.c. re-infection with MuPyV. Collectively, these data reveal a temporal duality in PD-1-mediated regulation of MuPyV-associated neuroinflammation. PD-1 signaling limited the severity of neuroinflammation during acute infection but sustained a level of inflammation during persistent infection for maintaining control of virus re-infection.

Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital.

OBJECTIVE: Ketamine has emerged as a rapid-acting antidepressant, though controversy remains whether sufficient data exist to justify its use outside of research protocols. In October 2014, the authors' institution began providing ketamine as an off-label therapy on a case-by-case basis for patients unable to participate in research protocols. Here, the participant experience during 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders through February 2017 is described. METHODS: Patients were initially treated with a single- or double-infusion protocol (0.5 mg/kg for 40 minutes intravenously) and were later transitioned to a 4-infusion protocol over 2 weeks. RESULTS: Fifty-four patients received ketamine, with 518 total infusions performed. A subset of 44 patients with mood disorders initiated the 4-infusion protocol, of whom 45.5% responded and 27.3% remitted by the fourth infusion. A subsample (n = 14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks. No evidence was found of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subsample. CONCLUSIONS: In general, ketamine infusions were tolerated well. The response and remission rates in this clinical sample were lower than those observed in some research protocols. The small number of patients who were treated on a maintenance schedule limits the conclusions that can be drawn regarding the long-term safety of ketamine; however, no long-term adverse effects were observed in this sample.