Dopaminergic neuroprotective effects of inosine in MPTP-induced parkinsonian mice via brain-derived neurotrophic factor upregulation.

Parkinson's disease (PD) is the second most common neurodegenerative disease. However, no curative or modifying therapy is known. Inosine is a purine nucleoside that increases brain-derived neurotrophic factor (BDNF) expression in the brain through adenosine receptors. Herein, we investigated the neuroprotective effects of inosine and elucidated the mechanisms underlying its pharmacological action. Inosine rescued SH-SY5Y neuroblastoma cells from MPP+ injury in a dose-dependent manner. Inosine protection correlated with BDNF expression and the activation of its downstream signaling cascade, as the TrkB receptor inhibitor, K252a and siRNA against the BDNF gene remarkably reduced the protective effects of inosine. Blocking the A1 or A2A adenosine receptors diminished BDNF induction and the rescuing effect of inosine, indicating a critical role of adenosine A1 and A2A receptors in inosine-related BDNF elevation. We assessed whether the compound could protect dopaminergic neurons from MPTP-induced neuronal injury. Beam-walking and challenge beam tests revealed that inosine pretreatment for 3 weeks reduced the MPTP-induced motor function impairment. Inosine ameliorated dopaminergic neuronal loss and MPTP-mediated astrocytic and microglial activation in the substantia nigra and striatum. Inosine ameliorated the depletion of striatal dopamine and its metabolite following MPTP injection. BDNF upregulation and the activation of its downstream signaling pathway seemingly correlate with the neuroprotective effects of inosine. To our knowledge, this is the first study to demonstrate the neuroprotective effects of inosine against MPTP neurotoxicity via BDNF upregulation. These findings highlight the therapeutic potential of inosine in dopaminergic neurodegeneration in PD brains.

Intermittent fasting protects the nigral dopaminergic neurons from MPTP-mediated dopaminergic neuronal injury in mice.

Dietary restriction through low-calorie intake or intermittent fasting benefits many organs, including the brain. This study investigated the neuroprotective effects of fasting in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. We found that fasting every other day rather than weekly increased the levels of brain-derived neurotrophic factor and glial-derived neurotrophic factor in the nigrostriatal pathway. Therefore, we maintained the animals on alternate-day fasting for 2 weeks and injected MPTP (30 mg/kg/day, intraperitoneally [i.p.]) for five days. We observed that alternate-day fasting attenuated MPTP-induced dopaminergic neuronal loss and astroglial activation in the substantia nigra and the striatum. Moreover, neurochemical analysis using high-performance liquid chromatography showed that alternate-day fasting reduced MPTP-induced depletion of striatal dopamine. Consistent with these results, behavioral tests showed that fasting suppressed the motor impairment caused by MPTP. Furthermore, fasting increased the phosphorylation of phosphatidylinositol-3-kinase and protein kinase B, which are downstream signaling molecules of neurotrophic factors. Fasting also increased the phosphorylation of extracellular signal-regulated protein kinase and cAMP response element-binding protein, further supporting the involvement of neurotrophic factors in the observed neuroprotective effects. Hence, our results demonstrated the dopaminergic neuroprotection of intermittent fasting in an MPTP mouse model of Parkinson's disease, supporting the idea that fasting could be an instrumental tool for preventing neurodegeneration in the brain.

Stinging Nettle (Urtica dioica L.): Nutritional Composition, Bioactive Compounds, and Food Functional Properties.

Stinging nettle (Urtica dioica L., Urticaceae) is commonly found in Asia, Africa, and Europe and has a long history of being used as food and traditional medicine. Recently, this plant is gaining attention as a highly nutritious food, where fresh leaves are dried and used as powder or in other forms. Leaves are rich in many bioactive compounds. This review aims to cover the traditional uses in food and medicine, as well as its nutritional composition, including its bioactive chemical constituents and reported food functional activities. Various bioactive chemical constituents have been isolated from stinging nettle to date, such as flavonoids, phenolic acids, amino acid, carotenoids, and fatty acids. Stinging nettle extracts and its compounds, such as rutin, kaempferol, and vitamin A, are also used for their nutritional properties and as anti-inflammatory and antioxidant agents. Future studies should focus on the proper formulation and stability testing of the functional foods containing stinging nettle and their detailed activities in clinical studies.

Methanolic Extract of Boswellia serrata Gum Protects the Nigral Dopaminergic Neurons from Rotenone-Induced Neurotoxicity.

Boswellia serrata gum is a natural product that showed beneficial effects on neurodegenerative diseases in recent studies. In this study, we investigated the effects of Boswellia serrata resin on rotenone-induced dopaminergic neurotoxicity. Firstly, we attempted to see if the resin can induce AMP-activated protein kinase (AMPK) signaling pathway which has been known to have broad neuroprotective effects. Boswellia increased AMPK phosphorylation and reduced phosphorylation of mammalian target of rapamycin (p-mTOR) and α-synuclein (p-α-synuclein) in the striatum while increased the expression level of Beclin1, a marker for autophagy and brain-derived neurotrophic factor. Next, we examined the neuroprotective effects of the Boswellia extract in the rotenone-injected mice. The results showed that Boswellia evidently attenuated the loss of the nigrostriatal dopaminergic neurons and microglial activation caused by rotenone. Moreover, Boswellia ameliorated rotenone-induced decrease in the striatal dopamine and impairment in motor function. Accumulation of α-synuclein meditated by rotenone was significantly ameliorated by Boswellia. Also, we showed that ß-boswellic acid, the active constituents of Boswellia serrata gum, induced AMPK phosphorylation and attenuated α-synuclein phosphorylation in SHSY5 cells. These results suggest that Boswellia protected the dopaminergic neurons from rotenone neurotoxicity via activation of the AMPK pathway which might be associated with attenuation of α-synuclein aggregation and neuroinflammation. Further investigations are warranted to identify specific molecules in Boswellia which are responsible for the neuroprotection.

Enhancement of blood-brain barrier penetration and the neuroprotective effect of resveratrol.

Parkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. The specific molecular mechanisms through which PD-associated neuronal loss occurs remain unclear, and there is no available effective treatment against PD-related neurodegeneration. Resveratrol (RSV) has exhibited promising neuroprotective effects via antioxidant and anti-inflammatory activity. However, its poor bioavailability in the brain represents a challenge for its application in PD treatment. In this study, we synthesized RSV-loaded PLGA nanoparticles (RSV-PLGA-NPs) conjugated with lactoferrin (Lf) to enhance RSV diffusion into the brain and assessed whether this formulation improved the neuroprotective effects of RSV in experimental PD models. The Lf-conjugated RSV-PLGA-NPs (Lf-RSV-PLGA-NPs) exhibited enhanced internalization into SH-SY5Y and human brain microvascular endothelial cells as compared to RSV-PLGA-NPs and free RSV. Further, Lf-RSV-PLGA-NPs were more effective than RSV-PLGA-NPs and free RSV in attenuating the MPP+-induced generation of reactive oxygen species, reduction of mitochondrial membrane potential, and cell death. Importantly, Lf conjugation specifically increased the accumulation of RSV-PLGA-NPs in the brain as determined via bioluminescent imaging analyses. Our formulation substantially enhanced the neuroprotective effects of RSV in the MPTP-induced PD model. Hence, Lf-RSV-PLGA-NPs represent a promising tool for improving RSV bioavailability and neuroprotection within the brain.

LMNA Gene Mutation Presenting with Ventricular Tachycardia in the Absence of Dilated Cardiomyopathy.

Genetic mutations can present with cardiomyopathies and ventricular arrhythmias in young population in the absence of other cardiac risk factors. LMNA genetic mutation is one of the causes of dilated cardiomyopathy (DCM) which can present with conduction abnormalities and arrhythmias. We present a case of LMNA genetic mutation in an African American male who presented with ventricular tachycardia in the absence of dilated cardiomyopathy initially mimicking cardiac sarcoidosis. Diagnostic challenges included initial impression of cardiac sarcoidosis as suggested by cardiac MRI, but negative tissue pathology on endomyocardial biopsy and negative activity on FDG PET scan. Treatment involved initiation of beta blocker and an implantable cardiac defibrillator placement for secondary prevention.

Systemic Sclerosis: Current State and Survival After Lung Transplantation.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by the involvement of skin and internal organs. With the introduction of angiotensin-converting enzyme inhibitors (ACEIs), scleroderma renal crisis (SRC) is no longer considered a leading cause of death in affected patients. In fact, pulmonary manifestations [interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH)] are currently the major cause of death in patients with SSc. Historically, many centers have been reluctant to offer lung transplantation to patients with SSc due to multiple extrapulmonary manifestations and the assumption of poor post-transplant survival. The purpose of this review is to highlight the recent advances in the evaluation and management of patients with pulmonary manifestations of SSc. We also engage in a systematic literature review to assess all the available data on the survival of patients with SSc after lung transplantation.

Predictability of CRP and D-Dimer levels for in-hospital outcomes and mortality of COVID-19.

BACKGROUND: Systemic inflammation elicited by a cytokine storm is considered a hallmark of coronavirus disease 2019 (COVID-19). This study aims to assess the clinical utility of the C-reactive protein (CRP) and D-Dimer levels for predicting in-hospital outcomes in COVID-19. METHODS: A retrospective cohort study was performed to determine the association of CRP and D-Dimer with the need for invasive mechanical ventilation (IMV), dialysis, upgrade to an intensive care unit (ICU) and mortality. Independent t-test and multivariate logistic regression analysis were performed to calculate mean differences and adjusted odds ratios (aOR) with its 95% confidence interval (CI), respectively. RESULTS: A total of 176 patients with confirmed COVID-19 diagnosis were included. On presentation, the unadjusted odds for the need of IMV (OR 2.5, 95% CI 1.3-4.8, p = 0.012) and upgrade to ICU (OR 3.2, 95% CI 1.6-6.5, p = 0.002) were significantly higher for patients with CRP (>101 mg/dl). Similarly, the unadjusted odds of in-hospital mortality were significantly higher in patients with high CRP (>101 mg/dl) and high D-Dimer (>501 ng/ml), compared to corresponding low CRP (<100 mg/dl) and low D-Dimer (<500 ng/ml) groups on day-7 (OR 3.5, 95% CI 1.2-10.5, p = 0.03 and OR 10.0, 95% CI 1.2-77.9, p = 0.02), respectively. Both high D-Dimer (>501 ng/ml) and high CRP (>101 mg/dl) were associated with increased need for upgrade to the ICU and higher requirement for IMV on day-7 of hospitalization. A multivariate regression model mirrored the overall unadjusted trends except that adjusted odds for IMV were high in the high CRP group on day 7 (aOR 2.5, 95% CI 1.05-6.0, p = 0.04). CONCLUSION: CRP value greater than 100 mg/dL and D-dimer levels higher than 500 ng/ml during hospitalization might predict higher odds of in-hospital mortality. Higher levels at presentation might indicate impending clinical deterioration and the need for IMV.

Takotsubo cardiomyopathy: a rare complication of acute viral gastroenteritis.

Takotsubo Cardiomyopathy (TCM) is characterized by a transient but reversible ventricular dysfunction in post-menopausal females following, but not always, a recent emotional or physical stress. Typically, chest pain is reported as a presenting symptom in the majority of patients. The severe diarrheal illness secondary to acute viral gastroenteritis is not commonly reported as the stressor event prior to TCM. We report a unique case of a middle-aged male presented with syncope shortly after loose bowel movements. He was diagnosed with TCM and was successfully managed with supportive care. The purpose of this case is to make clinicians aware of this rare association.

Efficacy of Hydroxychloroquine and Tocilizumab in Patients With COVID-19: Single-Center Retrospective Chart Review.

BACKGROUND: During the initial phases of the COVID-19 pandemic, there was an unfounded fervor surrounding the use of hydroxychloroquine (HCQ) and tocilizumab (TCZ); however, evidence on their efficacy and safety have been controversial. OBJECTIVE: The purpose of this study is to evaluate the overall clinical effectiveness of HCQ and TCZ in patients with COVID-19. We hypothesize that HCQ and TCZ use in these patients will be associated with a reduction in in-hospital mortality, upgrade to intensive medical care, invasive mechanical ventilation, or acute renal failure needing dialysis. METHODS: A retrospective cohort study was performed to determine the impact of HCQ and TCZ use on hard clinical outcomes during hospitalization. A total of 176 hospitalized patients with a confirmed COVID-19 diagnosis was included. Patients were divided into two comparison groups: (1) HCQ (n=144) vs no-HCQ (n=32) and (2) TCZ (n=32) vs no-TCZ (n=144). The mean age, baseline comorbidities, and other medications used during hospitalization were uniformly distributed among all the groups. Independent t tests and multivariate logistic regression analysis were performed to calculate mean differences and adjusted odds ratios with 95% CIs, respectively. RESULTS: The unadjusted odds ratio for patients upgraded to a higher level of care (ie, intensive care unit) (OR 2.6, 95% CI 1.19-5.69; P=.003) and reductions in C-reactive protein (CRP) level on day 7 of hospitalization (21% vs 56%, OR 0.21, 95% CI 0.08-0.55; P=.002) were significantly higher in the TCZ group compared to the control group. There was no significant difference in the odds of in-hospital mortality, upgrade to intensive medical care, need for invasive mechanical ventilation, acute kidney failure necessitating dialysis, or discharge from the hospital after recovery in both the HCQ and TCZ groups compared to their respective control groups. Adjusted odds ratios controlled for baseline comorbidities and medications closely followed the unadjusted estimates. CONCLUSIONS: In this cohort of patients with COVID-19, neither HCQ nor TCZ offered a significant reduction in in-hospital mortality, upgrade to intensive medical care, invasive mechanical ventilation, or acute renal failure needing dialysis. These results are similar to the recently published preliminary results of the HCQ arm of the Recovery trial, which showed no clinical benefit from the use of HCQ in hospitalized patients with COVID-19 (the TCZ arm is ongoing). Double-blinded randomized controlled trials are needed to further evaluate the impact of these drugs in larger patient samples so that data-driven guidelines can be deduced to combat this global pandemic.

Efficacy of Allopurinol in Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND: Given current evidence, the use of allopurinol for the prevention of major cardiovascular events (acute cardiovascular syndrome (ACS) or cardiovascular mortality) in patients undergoing coronary artery bypass graft (CABG), after index ACS or heart failure remains unknown. METHODS: Multiple databases were queried to identify studies comparing the efficacy of allopurinol in patients undergoing CABG, after ACS or heart failure. The unadjusted odds ratio (OR) was calculated using a random effect model. RESULTS: A total of nine studies comprising 850 patients (allopurinol 480, control 370) were identified. The pooled OR of periprocedural ACS (OR: 0.25, 95% confidence interval (CI): 0.06 - 0.96, P = 0.05) and cardiovascular mortality (OR: 0.22, 95% CI: 0.07 - 0.71, P = 0.01) was significantly lower in patients receiving allopurinol during CABG compared to patients in the control group. The overall number needed to treat (NNT) to prevent one ACS event was 11 (95% CI: 7 - 28), while the NNT to prevent one death was 24 (95% CI: 13 - 247). By contrast, the odds of cardiovascular mortality in the allopurinol group were not significantly different from the control group in patients on long-term allopurinol after ACS or heart failure (OR: 0.33, 95% CI: 0.01 - 8.21, P = 0.50) and (OR: 1.12, 95% CI: 0.39 - 3.20, P = 0.83), respectively. Similarly, the use of allopurinol did not reduce the odds of recurrent ACS events at 2 years (OR: 0.32, 95% CI: 0.03 - 3.18, P = 0.33). CONCLUSIONS: Periprocedural use of allopurinol might be associated with a significant reduction in the odds of ACS and cardiovascular mortality in patients undergoing CABG. Allopurinol, however, offers no long-term benefits in terms of secondary prevention of ACS or mortality. Larger scale studies are needed to validate our findings.

Novel Coronavirus (2019-nCoV) in Disguise.

Novel coronavirus (2019-nCoV) pandemic is currently one of the most influential topics as it not only impacts the field of medicine but most importantly, it affects the lives of many individuals throughout the world. We report an interesting 2019-nCoV case in a tertiary community hospital with the initial concern of acute pyelonephritis without respiratory symptoms that ultimately led to the quarantine of a number of healthcare providers. This case emphasizes the importance of radiological evidence in diagnosing 2019-nCoV in the setting of an initial atypical presentation. It also serves as an example of how healthcare providers may need to increase their suspicion for COVID-19 to ensure self-protection and prompt diagnosis in the era of an ongoing pandemic.

Spontaneous Coronary Artery Dissection Secondary to Rheumatological Diseases: A Comprehensive Review.

Spontaneous coronary artery dissection (SCAD) is a life-threatening condition and multiple conditions have been associated with this entity. This study aims to further investigate and characterize the association of the underlying rheumatological disease with SCAD. A comprehensive literature search on four databases was performed using different Medical Subject Headings (MeSH) and all articles on SCAD in association with rheumatological diseases were identified. The analysis was performed using the Statistical Package for Social Sciences (SPSS), v22 (IBM SPSS Statistics, Armonk, NY). Ten articles of SCAD secondary to rheumatological reasons were identified. The majority of presentations were associated with systemic lupus erythematosus (SLE). Most patients presented with a non-ST-elevation myocardial infarction (NSTEMI) involving the left main coronary vessel. The majority of them were successfully managed with stenting. Mortality was less than 20% with prompt identification and management of the SCAD. SLE was the most commonly reported rheumatological condition associated with SCAD. Prompt diagnosis and management of SCAD in such patients can be life-saving.

"Singultus" uncloaking potentially fatal vascular dissections.

Aortic dissection (AD) is a serious condition in which the intimal layer of aorta tears and blood surges in between the intimal and medial layers of aorta causing it to separate (dissect). It usually presents with excruciating pain radiating to the back. Here we present a unique presentation of AD where an old-aged Caucasian male presented with a chronic history of intractable hiccups. His computed tomography (CAT scan) revealed the dissection of the descending thoracic aorta. He was managed conservatively and was discharged home in stable condition. The purpose of this report is to highlight this unusual presentation of AD and unmask the possible etiology of hiccups in such cases.

Immune-mediated Colitis from Dual Checkpoint Inhibitors.

Melanoma is a deadly disease with immunotherapy treatment options that emerged in the last few years and have changed the disease outcome. However, it is associated with immune-related toxic effects despite improving survival. We present the case of a 53-year-old woman who had two weeks of diarrhea after she was treated with dual immunotherapy agents for her advanced melanoma. The final workup revealed pancolitis, possibly due to immunotherapy adverse effects. Initial conservative treatment, unfortunately, did not lead to a clinical improvement until a steroid was introduced. We are reporting this case to alert our fellow physicians about the immune-mediated toxicities of the relatively new checkpoint inhibitors.