In the Loop: Endovascular Pedal Arch Revascularization.

Advanced endovascular techniques are increasingly being utilized to treat patients with peripheral arterial disease and chronic limb-threatening ischemia to improve lower extremity arterial perfusion. In diabetic patients, pedal arch patency has been associated with improved wound healing, limb salvage, and overall survival. Pedal-plantar loop revascularization is a technique that can restore arterial inflow between the dorsal and plantar arteries of the foot. This article will describe the inframallelolar arterial anatomy and focus on imaging, percutaneous endovascular techniques, and clinical study outcomes of pedal artery interventions.

Practical Review of Necrotizing Fasciitis: Principles and Evidence-based Management.

Necrotizing fasciitis is a severe, life-threatening soft tissue infection that presents as a surgical emergency. It is characterized by a rapid progression of inflammation leading to extensive tissue necrosis and destruction. Nonetheless, the diagnosis might be missed or delayed due to variable and nonspecific clinical presentation, contributing to high mortality rates. Therefore, early diagnosis and prompt, aggressive medical and surgical treatment are paramount. In this review, we highlight the defining characteristics, pathophysiology, diagnostic modalities, current principles of treatment, and evolving management strategies of necrotizing fasciitis.

Association of COVID-19 with Comorbidities: An Update.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which was identified in Wuhan, China in December 2019 and jeopardized human lives. It spreads at an unprecedented rate worldwide, with serious and still-unfolding health conditions and economic ramifications. Based on the clinical investigations, the severity of COVID-19 appears to be highly variable, ranging from mild to severe infections including the death of an infected individual. To add to this, patients with comorbid conditions such as age or concomitant illnesses are significant predictors of the disease's severity and progression. SARS-CoV-2 enters inside the host cells through ACE2 (angiotensin converting enzyme2) receptor expression; therefore, comorbidities associated with higher ACE2 expression may enhance the virus entry and the severity of COVID-19 infection. It has already been recognized that age-related comorbidities such as Parkinson's disease, cancer, diabetes, and cardiovascular diseases may lead to life-threatening illnesses in COVID-19-infected patients. COVID-19 infection results in the excessive release of cytokines, called "cytokine storm", which causes the worsening of comorbid disease conditions. Different mechanisms of COVID-19 infections leading to intensive care unit (ICU) admissions or deaths have been hypothesized. This review provides insights into the relationship between various comorbidities and COVID-19 infection. We further discuss the potential pathophysiological correlation between COVID-19 disease and comorbidities with the medical interventions for comorbid patients. Toward the end, different therapeutic options have been discussed for COVID-19-infected comorbid patients.

Neuroprotective Effect of Swertiamarin in a Rotenone Model of Parkinson's Disease: Role of Neuroinflammation and Alpha-Synuclein Accumulation.

Parkinson's disease (PD) is a progressive neurodegenerative disease with no permanent cure affecting around 1% of the population over 65. There is an urgency to search for a disease-modifying agent with fewer untoward effects. PD pathology involves the accumulation of toxic alpha-synuclein (α-syn) and neuronal inflammation leading to the degeneration of dopaminergic (DAergic) neurons. Swertiamarin (SWE), a well-studied natural product, possesses a strong anti-inflammatory effect. It is a secoiridoid glycoside isolated from Enicostemma littorale Blume. SWE showed a reversal effect on the α-syn accumulation in the 6-hydroxydopamine (6-OHDA)-induced Caenorhabditis elegans model of PD. However, there are no reports in the literature citing the effect of SWE as a neuroprotective agent in rodents. The present study aimed to evaluate the anti-inflammatory activity of SWE against lipopolysaccharide (LPS)-induced C6 glial cell activation and its neuroprotective effect in the intrastriatal rotenone mouse PD model. SWE treatment showed a significant reduction in interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) levels in LPS-induced C6 glial cell activation. Further, our studies demonstrated the suppression of microglial and astroglial activation in substantia nigra (SN) after administration of SWE (100 mg/kg, intraperitoneally) in a rotenone mouse model. Moreover, SWE alleviated the rotenone-induced α-syn overexpression in the striatum and SN. SWE ameliorated the motor impairment against rotenone-induced neurotoxicity and mitigated the loss of DAergic neurons in the nigrostriatal pathway. Therefore, SWE has the potential to develop as an adjunct therapy for PD, but it warrants further mechanistic studies.

Chlorogenic Acid: a Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson's Disease by GLP-1 Secretion.

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50 mg/kg, orally for 13 weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3ß through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD.

AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin's neuroprotection in a rotenone-induced mouse model of Parkinson's disease.

Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson's disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5'AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.

Living Donor Liver Transplantation in a Cohort of Recipients With Left Ventricular Systolic Dysfunction.

Background: Data on feasibility, management, and outcomes of liver transplantation (LT) in patients with pre-existing left ventricular systolic dysfunction (LVSD), severe coronary artery disease (CAD) or cirrhotic cardiomyopathy (CCM) is scarce. Methods: We reviewed outcomes of living donor liver transplantation (LDLT) in recipients with LVSD (ejection fraction [EF] < 50%) from our series of 1946 LDLT's performed between July 2010 and July 2018. Results: LVSD was detected in 12 male patients with a mean age, BMI and MELD of 52 ± 9 years, 25 ± 5 kg/m2, and 19 ± 4 respectively. Out of these, 6 patients had CAD (2 with previous coronary artery bypass graft, 1 following recent percutaneous transluminal coronary angioplasty, 2 post myocardial infarction, 1 noncritical CAD), and 6 had CCM. The EF ranged from 25% to 45%. Ethanol was the predominant underlying etiology for cirrhosis (50%). During LDLT, 2 patients developed ventricular ectopic rhythm and were managed successfully with intravenous lidocaine. Stress cardiomyopathy manifested in 3 patients post operatively with decreased EF, of which 2 improved, while 1 needed IABP support and succumbed to multiorgan failure on 8th postoperative day (POD). Another patient died on POD30 due to septic shock. Both these patients had higher MELD scores (actual MELD), extremes of BMI (17.3and 35.8 kg/m2) and were diabetic. There were no long-term cardiac deaths. The 1-year, and 5-year survival were 75%, and 66%, respectively. Conclusion: Among potential LT recipients with LVSD, those with stable CAD and good performance status, and well optimized CCM patients may be considered for LDLT after careful risk stratification in experienced centers.

The Iron Response of Mycobacterium tuberculosis and Its Implications for Tuberculosis Pathogenesis and Novel Therapeutics.

Most pathogenic bacteria require iron for growth. However, this metal is not freely available in the mammalian host. Due to its poor solubility and propensity to catalyze the generation of reactive oxygen species, host iron is kept in solution bound to specialized iron binding proteins. Access to iron is an important factor in the outcome of bacterial infections; iron limitation frequently induces virulence and drives pathogenic interactions with host cells. Here, we review the response of Mycobacterium tuberculosis to changes in iron availability, the relevance of this response to TB pathogenesis, and its potential for the design of new therapeutic interventions.

Effect of Prophylactic Use of Intranasal Oil Formulations in the Hamster Model of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection initiates with viral entry in the upper respiratory tract, leading to coronavirus disease 2019 (COVID-19). Severe COVID-19 is characterized by pulmonary pathologies associated with respiratory failure. Thus, therapeutics aimed at inhibiting the entry of the virus or its internalization in the upper respiratory tract are of interest. Herein, we report the prophylactic application of two intranasal formulations provided by the National Medicinal Plant Board (NMPB), Anu oil and til tailya, in the hamster model of SARS-CoV-2 infection. Prophylactic intra-nasal instillation of these oil formulations exhibited reduced viral load in lungs and resulted in reduced body weight loss and lung-pneumonitis. In line with reduced viral load, histopathological analysis revealed a reduction in lung pathology in the Anu oil group as compared to the control infected group. However, the til tailya group did not show a significant reduction in lung pathology. Furthermore, molecular analysis using mRNA expression profiling indicated reduced expression of pro-inflammatory cytokine genes, including Th1 and Th17 cytokines for both the intranasal formulations as a result of decreased viral load. Together, the prophylactic intranasal application of Anu oil seems to be useful in limiting both viral load and severity in SARS-CoV2 infection in the hamster model.

Diffuse Alveolar Hemorrhage With Avelumab Maintenance Therapy.

Immune checkpoint blockade is a rapidly expanding therapeutic modality in oncology. However, its adverse effects extend beyond the cytotoxicity of conventional chemotherapy. Pneumotoxicity associated with immune checkpoint therapy presents a diagnostic conundrum that has been further complicated by the COVID-19 pandemic. We report a case of a patient with metastatic urothelial carcinoma who developed diffuse alveolar hemorrhage (DAH) following treatment with avelumab.

How informed is the informed consent?

BACKGROUND: Informed consent is a cornerstone of the ethics of modern medical care. In an ideal world, informed consent is a process of education - a conversation between a surgeon and a patient or family that allows the patient or family to make the best possible decision regarding care. OBJECTIVE: The study was conducted with objectives of assessing information given to the patient before taking consent for surgery and determining the compliance to various contents of the consent forms. MATERIAL AND METHODS: This was a prospective study over a period of 12 weeks in wards of various surgical departments of a 1000+ bedded tertiary care hospital. Patient interviews were conducted to assess their level of information and the consent forms were reviewed to assess the compliance. OBSERVATIONS: The overall level of information r4egarding various aspects among the participants was 75.14%. The level of information varied statistically with age, literacy level, annual income and the type of surgery. All the patients (100%) stated that they were informed about the current clinical condition/ problem, while only 34% were informed about risk and 26% about the alternative options. All the forms (100%) had a statement regarding the explanation of procedure to the patient/ guardian and none of the forms (0%) contained names of all practitioners performing the procedure. CONCLUSION: There is need to create awareness among doctors and also to educate patients regarding the importance of informed consent.

Dynamics of a gas-phase SNAr reaction: non-concerted mechanism despite the Meisenheimer complex being a transition state.

The commonly accepted mechanism of the nucleophilic aromatic substitution (SNAr) reaction has been found to be governed by the nature of the Meisenheimer structure on the potential energy surface. A stable Meisenheimer intermediate favors a stepwise mechanism, while a Meisenheimer transition state favors a concerted mechanism. Here, we show by using a detailed potential energy map (using the DFT and DLPNO-CCSD(T)/CBS methods) and ab initio classical trajectory simulations that the F- + C6H5NO2 SNAr reaction involves a Meisenheimer transition state and follows a stepwise mechanism in contrast to the expected concerted pathway. The stepwise mechanism observed in the trajectory simulations takes place by the formation of various ion-dipole and σ-complexes. While the majority of the trajectories follow the multi-step mechanism and avoid the minimum energy path, a considerable fraction exhibit a roaming atom mechanism where the F atom hovers around the phenyl ring before the formation of the products.

Refractory thoracic endometriosis.

Thoracic endometriosis syndrome (TES) is a rare entity caused by thoracic implantation of endometrial tissue, manifesting as catamenial pneumothorax, pleural effusion and haemoptysis in young female individuals. Its management and long-term prevention of recurrences, can be challenging. We present the case of a young woman who presented with recurrent pneumothorax, haemopneumothorax and pleural effusion. The diagnosis of TES was confirmed based on cytological findings of pleural fluid. She underwent treatment with mechanical pleurodesis twice but continued to have recurrences. Hormonal treatment failed to produce a satisfactory resolution. She underwent chemical pleurodesis, which successfully induced remission of her TES. A review of the literature suggests that chemical pleurodesis produces better results compared with mechanical pleurodesis and that hormonal treatment with gonadotropin-releasing hormone agonists is effective at preventing recurrences.

Pulmonary mucinous cystadenocarcinoma: an unusual presentation and literature review.

Cystic lung disease is a group of heterogeneous pulmonary diseases resulting from hereditary/congenital disorders, systemic disorders and infectious causes among others. Pulmonary mucinous cystic neoplasia is a spectrum of neoplastic cystic diseases with abundant mucin, of which pulmonary mucinous cystadenocarcinoma (PMC) is a rare malignant subtype. We present a case of a 66-year-old man who presented with dyspnoea, cough, fatigue and weight loss. Imaging of his chest showed numerous cavitary lesions, and the diagnosis of PMC was made based on lung biopsy. He received palliative chemotherapy and died 1 year later. We present a literature review of PMC based on 26 reported cases, including our own.

Protective effect of alpha mangostin on rotenone induced toxicity in rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive, late-onset, and degenerative disorder that affects the central nervous system with an unknown etiology. Due to its incredible complexity in disease nature, many of the existing treatment approaches show a vain recovery in Parkinson's patients. Therefore, an in search of disease-modifying therapeutics for an effective recovery is essential. Alpha mangostin is an important polyphenolic xanthone reported for its neuroprotective effect against rotenone-induced α-synuclein aggregation and loss of tyrosine hydroxylase positive (TH+)-neurons in SH-SY5Y cells. Hence, the current study aims to test its protective effect in managing the in-vivo rat model of PD. To justify this aim, adult male Sprague Dawley rats (250 ± 20 g) were subjected to chronic treatment of rotenone (2 mg/kg/day, s.c.) for 21 days. In parallel alpha mangostin treatment (10 mg/kg, i.p) was administered along with rotenone for 21 days. Chronic rotenone treatment for 21 days increased lipid peroxidation, nitrite concentration, and decreased glutathione levels. Further, depletion of TH+-dopaminergic neuron expression in substantia nigra pars compacta (SNc), and the development of motor and behavioral deficits in rotenone treated animals like cognitive impairment, muscle incoordination, and neuromuscular weakness were observed. Moreover, western blot studies ascertained the reduced normal alpha-synuclein levels and increased phosphorylated α-synuclein levels in comparison to the vehicle-treated group. Treatment with alpha mangostin significantly restored the locomotor activity, memory deficits, and improved the levels of antioxidant enzymes. It also significantly reduced the levels of phosphorylated α-synuclein which in turn gave protection against TH+-dopaminergic neuronal loss in SNc, suggesting it's anti-oxidant and anti-aggregatory potential against α-synuclein. In conclusion through our current results, we could suggest that alpha mangostin has a potential neuroprotective effect against rotenone-induced PD and might be used as a neuroprotective agent. Further mechanistic studies on preclinical and clinical levels are required to be conducted with alpha mangostin to avail and foresee it as a potential agent in the treatment and management of PD.

Voice hoarseness in a patient with underlying Eisenmenger's syndrome: a case report.

BACKGROUND: The natural history of patients diagnosed with Eisenmenger's Syndrome typically revolve around the pediatric population. Medical advances have allowed these patients to live longer and present with a different subset of symptoms as a result of the progression of their disease process. CASE PRESENTATION: In this case report, we discuss a 77-year-old Caucasian female with Eisenmenger's Syndrome presenting with hoarseness. Clinical and imaging studies reveal a left vocal cord paralysis secondary to a progressively enlarging patent ductus arteriosus (PDA) and dilation of pulmonary arteries causing mass effect on the left recurrent laryngeal nerve. CONCLUSION: From a clinical perspective, this case highlights the need for otolaryngologists to be aware of the pathophysiology of Eisenmenger's Syndrome as it progresses with age.

Comparative analysis of homologous aminopeptidase PepN from pathogenic and non-pathogenic mycobacteria reveals divergent traits.

Mycobacterium tuberculosis (Mtb) secretes proteases and peptidases to subjugate its host. Out of its sixty plus proteases, atleast three are reported to reach host macrophages. In this study, we show that Mtb also delivers a lysyl alanine aminopeptidase, PepN (Rv2467) into host macrophage cytosol. Our comparative in silico analysis shows PepNMtb highly conserved across all pathogenic mycobacteria. Non-pathogenic mycobacteria including M. smegmatis (Msm) also encode pepN. PepN protein levels in both Mtb (pathogenic) and Msm (non-pathogenic) remain uniform across all in vitro growth phases. Despite such tight maintenance of PepNs' steady state levels, upon supplementation, Mtb alone allows accumulation of any excessive PepN. In contrast, Msm does not. It not only proteolyzes, but also secretes out the excessive PepN, be it native or foreign. Interestingly, while PepNMtb is required for modulating virulence in vivo, PepNMsm is essential for Msm growth in vitro. Despite such essentiality difference, both PepNMtb and PepNMsm harbor almost identical N-terminal M1-type peptidase domains that significantly align in their amino acid sequences and overlap in their secondary structures. Their C-terminal ERAP1_C-like domains however align much more moderately. Our in vitro macrophage-based infection experiments with MtbΔpepN-expressing pepNMsm reveals PepNMsm also retaining the ability to reach host cytosol. Lastly, but notably, we determined the PepNMtb and PepNMsm interactomes and found them to barely coincide. While PepNMtb chiefly interacts with Mtb's secreted proteins, PepNMsm primarily coimmunoprecipitates with Msm's housekeeping proteins. Thus, despite high sequence homology and several common properties, our comparative analytical study reveals host-centric traits of pathogenic and bacterial-centric traits of non-pathogenic PepNs.

Microangiopathic Hemolytic Anemia and Fulminant Renal Failure: A Rare Manifestation of Pheochromocytoma.

Pheochromocytoma is a rare adrenal tumor that is classically associated with the triad of paroxysmal tachycardia, diaphoresis, and headaches. However, it can have myriad manifestations. We present a case of a 31-year-old male who presented with abdominal pain, hypertensive emergency, and renal failure. Abdominal imaging demonstrated a left adrenal mass. Plasma metanephrines (153 pg/ml, n < 57) and normetanephrines (1197 pg/ml, n < 148) were noted to be elevated, leading to the diagnosis of pheochromocytoma. Intravenous antihypertensives were utilized to control his blood pressure. Hemodialysis was initiated given the degree of renal dysfunction. The patient subsequently developed hemolytic anemia, requiring the transfusion of multiple units of packed red cells. He developed acute respiratory failure leading to intubation, but was thereafter liberated from the ventilator following clinical stabilization. Uncontrolled hypertension precipitated by pheochromocytoma can cause microangiopathic hemolytic anemia and renal insufficiency. This case is notable not only for the occurrence of this rare presentation, but also for the severity of manifestations in a young male with no known significant comorbidities.