Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

A Stitch in Time Saves Nine: Planning for Artesunate Supply with Malaria on the Rise.

Background: Malaria is extremely rare in the United States. Physicians should not only be familiar with signs and symptoms, but also be aware of the available resources at their respective institutions to be able to effectively treat it. Presentation: 52-year-old female presented with worsening generalized fatigue. Vitals were stable. Labs were significant for anemia and thrombocytopenia. Peripheral smear showed ring formed parasitic trophozoites consistent with Plasmodium falciparum. Due to unavailability of antimalarial agents at our hospital, the patient was transferred to a tertiary care center. Patient was started on IV artesunate therapy. Repeat smear after 3 days showed <1% parasitemia after 3 days and the patient was discharged with artemether/lumefantrine for 3 additional days, resulting in full recovery. Conclusion: This case gives a unique insight into the challenges that hospitals in non-endemic regions may have to face, in terms of diagnosing malaria and having access to antimalarial agents.

Primary Cardiac Sarcoma: Clinical Characteristics and Prognostic Factors over the Past 2 Decades.

BACKGROUND: Primary cardiac sarcomas (PCS) are extremely rare malignant tumors involving the heart. Only isolated case reports have been described in the literature over different periods of time. This pathology has been associated with a dismal prognosis and given its rarity; treatment options are very limited. Furthermore, there are contrasting data about the effectiveness of current treatment modalities in improving the survival of patients with PCS, including surgical resection which is the mainstay of therapy. There is a paucity of data on the epidemiological characteristics of PCS. This study has the objective of investigating the epidemiologic characteristics, survival outcomes, and independent prognostic factors of PCS. METHODS: A total of 362 patients were ultimately registered in our study from the Surveillance, Epidemiology, and End Results (SEER) database. The study period was from 2000 to 2017. Demographics such as clinical characteristics, overall mortality (OM), and PCS-specific mortality (CSM) were taken into account. A p value of <0.1 in the univariate analysis leads to the incorporation of the variable into multivariate analysis adjusting for covariates. Adverse prognostic factors were represented by a Hazard Ratio (HR) greater than one. The five-year survival analysis was carried out using the Kaplan-Meier method and the log-rank test was used to compare survival curves. RESULTS: Crude analysis revealed a high OM in age 80+ (HR = 5.958, 95% CI 3.357-10.575, p < 0.001), followed by age 60-79 (HR = 1.429, 95% CI 1.028-1.986, p = 0.033); and PCS with distant metastases (HR = 1.888, 95% CI 1.389-2.566, p < 0.001). Patients that underwent surgical resection of the primary tumor and patients with malignant fibrous histiocytomas (HR = 0.657, 95% CI 0.455-0.95, p = 0.025) had a better OM (HR = 0.606, 95% CI 0.465-0.791, p < 0.001). The highest cancer-specific mortality was observed in age 80+ (HR = 5.037, 95% CI 2.606-9.736, p < 0.001) and patients with distant metastases (HR = 1.953, 95% CI 1.396-2.733, p < 0.001). Patients with malignant fibrous histiocytomas (HR = 0.572, 95% CI 0.378-0.865, p = 0.008) and those who underwent surgery (HR = 0.581, 95% CI 0.436-0.774, p < 0.001) had a lower CSM. Patients in the age range 80+ (HR = 13.261, 95% CI 5.839-30.119, p < 0.001) and advanced disease with distant metastases (HR = 2.013, 95% CI 1.355-2.99, p = 0.001) were found to have a higher OM in the multivariate analyses adjusting for covariates). Lower OM was found in patients with rhabdomyosarcoma (HR = 0.364, 95% CI 0.154-0.86, p = 0.021) and widowed patients (HR = 0.506, 95% CI 0.263-0.977, p = 0.042). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups, and lower mortality in patients with Rhabdomyosarcoma. CONCLUSION: In this United States population-based retrospective cohort study using the SEER database, we found that cardiac rhabdomyosarcoma was associated with the lowest CSM and OM. Furthermore, as expected, age and advanced disease at diagnosis were independent factors predicting poor prognosis. Surgical resection of the primary tumor showed lower CSM and OM in the crude analysis but when adjusted for covariates in the multivariate analysis, it did not significantly impact the overall mortality or the cancer-specific mortality. These findings allow for treating clinicians to recognize patients that should be referred to palliative/hospice care at the time of diagnosis and avoid any surgical interventions as they did not show any differences in mortality. Surgical resection, adjuvant chemotherapy, and/or radiation in patients with poor prognoses should be reserved as palliative measures rather than an attempt to cure the disease.

Role of POCUS in the Management of New-onset Tachyarrhythmia in the Setting of SARS-CoV-2: A Case Report.

Introduction: SARS-CoV-2 infection is associated with myocardial inflammation, new onset cardiomyopathy, and arrhythmias. Here, we describe the utilization of POCUS and management of concurrent new onset atrial tachycardia and heart failure with reduced ejection fraction (HfrEF) in a patient with SARS-CoV-2 infection. Presentation: An 80-year-old female with multiple medical problems presented with sudden onset of shortness of breath and cough. She tested positive for SARS-CoV-2. Initially, she was hypoxic on room air and her heart rhythm was sinus tachycardia. CT angiogram of the chest showed consolidation, pleural effusion, and absence of pulmonary embolism. Because of persistent tachycardia, repeat EKGs and POCUS were performed. Subsequent EKGs showed intermittent atrial tachycardia and sinus tachycardia. Initially, home beta blockers were continued on admission, and additional dosages were considered for rate control, but Cardiac POCUS revealed HfrEF and was subsequently confirmed by comprehensive cardiac echocardiogram, consistent with SARS-CoV-2 infection-related cardiomyopathy. Beta blockers were discontinued, and treatment with amiodarone and furosemide showed improvement in symptoms. The patient was discharged with oral amiodarone and supplemental oxygen. Additionally, once the patient's hemodynamics improved, oral carvedilol was also started as part of GDMT for HfrEF. Follow-up echocardiogram 4 months later showed recovery of systolic EF to 60%. Conclusion: It is essential to consider new onset HFrEF in the evaluation and management of new onset tachyarrhythmias since IV fluids and AV nodal blocking agents can be harmful in decompensated HFrEF. With the advent of POCUS, HFrEF can be quickly identified, and therapy can be tailored to that diagnosis.