Trimethylamine-N-oxide and cerebral stroke risk: A review.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono­oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications.

Role of the Gut Bacteria-Derived Metabolite Phenylacetylglutamine in Health and Diseases.

Over the past few decades, it has been well established that gut microbiota-derived metabolites can disrupt gut function, thus resulting in an array of diseases. Notably, phenylacetylglutamine (PAGln), a bacterial derived metabolite, has recently gained attention due to its role in the initiation and progression of cardiovascular and cerebrovascular diseases. This meta-organismal metabolite PAGln is a byproduct of amino acid acetylation of its precursor phenylacetic acid (PAA) from a range of dietary sources like egg, meat, dairy products, etc. The microbiota-dependent metabolism of phenylalanine produces PAA, which is a crucial intermediate that is catalyzed by diverse microbial catalytic pathways. PAA conjugates with glutamine and glycine in the liver and kidney to predominantly form phenylacetylglutamine in humans and phenylacetylglycine in rodents. PAGln is associated with thrombosis as it enhances platelet activation mediated through the GPCRs receptors α2A, α2B, and ß2 ADRs, thereby aggravating the pathological conditions. Clinical evidence suggests that elevated levels of PAGln are associated with pathology of cardiovascular, cerebrovascular, and neurological diseases. This Review further consolidates the microbial/biochemical synthesis of PAGln and discusses its role in the above pathophysiologies.

Evaluation of Antidepressant Activity of Capsaicin Nanoemulsion in Nicotine Withdrawal-Induced Depression in Mice.

Depression is a low-energy condition that has an impact on a person's thoughts, actions, propensities, emotional state, and sense of wellbeing. According to the World Health Organization (WHO), 5% of adults are depressed. Individuals who are depressed are commonly prescribed antidepressants, and sometimes, individuals may have other psychiatric conditions that share overlapping symptoms with depression. These cooccurring conditions can complicate the diagnostic process, leading to a misdiagnosis and the prescription of antidepressants. Capsaicin (CAP) is a known antidepressant. Hence, this study aimed to assess the antidepressant activity of CAP nanoemulsion in nicotine (NC) withdrawal-induced depression in mice. Mice treated with CAP (3 mg/kg) showed reduced immobility in the forced swimming test (FST), tail-suspension test (TST), and open field test (OFT). During the OFT, the animals treated with nanoemulsion (CAP 3 mg/kg) spent less time in the corners than the control animals. Biochemical parameters, such as superoxide dismutase (SOD) and glutathione (GSH), were observed in reduced quantities in the NC withdrawal model (NWM), where they were slightly increased in the high-dose nanoemulsion (CAP 3 mg/kg) compared to the low-dose nanoemulsion (CAP 1 mg/kg). These results suggest that CAP caused antidepressant activity in the NWM via the nanoemulsion.

Validation of CanAssist Breast immunohistochemistry biomarkers on an automated platform and its applicability in tissue microarray.

CanAssist Breast (CAB) is a prognostic test for early-stage hormone receptor-positive invasive breast cancer. The test involves performing immunohistochemical (IHC) analysis for five biomarkers, namely CD44, ABCC4, ABCC11, N-cadherin, and pan-cadherin. In addition to IHC grading information, three clinical features, i.e., tumor size, grade, and lymph node status, serve as input into the machine learning-based algorithm to generate the CAB risk score. CAB was developed and initially validated using manual IHC. This study's objectives included: i) automate CAB IHC on an autostainer and establish its performance equivalence with manual IHC ii) validate CAB test using samples in Tissue MicroArray (TMA) format. IHC for CAB biomarkers was standardized on Ventana BenchMark XT autostainer. Two IHC methods were compared for IHC gradings and corresponding CAB risk scores/risk categories. A concordance analysis was done using MedCalcTM software. The manual and automated IHC staining methods exhibited a high level of concordance on IHC gradings for 40 cases with an Intra-class Correlation Coefficient (ICC) of >0.85 for 4 of 5 biomarkers. 100% concordance was achieved in risk categorization (low- or high-risk), with very good agreement between the risk scores demonstrated by a kappa statistic of 0.83. TMA versus whole tissue section concordance was analyzed using 45 samples on an autostainer, and the data showed 92% concordance in terms of risk category. The results confirm the equivalence between manual and automated staining methods and demonstrate the utility of TMA as an acceptable format for CanAssist Breast testing.

The usefulness of CanAssist breast in the assessment of recurrence risk in patients of ethnic Indian origin.

Accurate recurrence risk assessment in hormone receptor positive, HER2/neu negative breast cancer is critical to plan precise therapy. CanAssist Breast (CAB) assesses recurrence risk based on tumor biology using artificial intelligence-based approach. We report CAB risk assessment correlating with disease outcomes in multiple clinically high- and low-risk subgroups. In this retrospective cohort of 925 patients [median age-54 (22-86)] CAB had hazard ratio (HR) of 3 (1.83-5.21) and 2.5 (1.45-4.29), P = 0.0009) in univariate and multivariate analysis. CAB's HR in sub-groups with the other determinants of outcome, T2 (HR: 2.79 (1.49-5.25), P = 0.0001); age [< 50 (HR: 3.14 (1.39-7), P = 0.0008)]. Besides application in node-negative patients, CAB's HR was 2.45 (1.34-4.47), P = 0.0023) in node-positive patients. In clinically low-risk patients (N0 tumors up to 5 cms) (HR: 2.48 (0.79-7.8), P = 0.03) and with luminal-A characteristics (HR: 4.54 (1-19.75), P = 0.004), CAB identified >16% as high-risk with recurrence rates of up to 12%. In clinically high-risk patients (T2N1 tumors (HR: 2.65 (1.31-5.36), P = 0.003; low-risk DMFS: 92.66 ± 1.88) and in women with luminal-B characteristics (HR: 3.24; (1.69-6.22), P < 0.0001; low-risk DMFS: 93.34 ± 1.34)), CAB identified >64% as low-risk. Thus, CAB prognostication was significant in women with clinically low- and high-risk disease. The data imply the use of CAB for providing helpful information to stratify tumors based on biology incorporated with clinical features for Indian patients, which can be extrapolated to regions with similarly characterized patients, South-East Asia.

Glioblastoma with signet ring cell morphology: A diagnostic challenge.

Glioblastoma (WHO Grade IV), the most frequent malignant brain tumor, can have varied morphologic variations like epithelial/glandular structures, granular cells, and lipidized cells. Glioblastoma with signet ring cell morphology is very unusual and can mimic a metastatic carcinoma. These rare tumors may be just a morphological variant or may signify a different carcinogenic pathway.

Targeted Therapy Management in NSCLC Patients Using Cytology: Experience from a Tertiary Care Cancer Center.

BACKGROUND: Although biopsy is the gold standard for diagnosis, cytological material has often been used to assist in making a pathologic diagnosis as well as for molecular testing in certain cancers such as in the lung, cervix, and head/neck. OBJECTIVE: Our objective is to share experience from our institution in the use of cytological material in screening for epidermal growth factor receptor (EGFR) mutations in a subset of patients with non-small cell lung cancer (NSCLC). METHODS: Fine needle aspirates, pleural effusion, cell blocks of 223 NSCLC patients, where cytology suggested malignancy were screened for EGFR mutation in exons 18-21 using Scorpion(®) ARMS real-time polymerase chain reaction (PCR) technology. RESULTS: Overall, EGFR mutation was seen in 43.5 % of study samples. Deletions were highest in exon 19 (27.2 %), followed by exon 21 (15.5 %), exon 18 (5.3 %), and exon 20 (1.9 %). Chi-squared analysis revealed a significant correlation for mutation status in women compared with men (χ (2) = 5.88, p = 0.02), with exon 19 mutation predominating (χ (2) = 5.66, p = 0.02). CONCLUSION: Our results demonstrate the successful use of cytology material for molecular testing in a subset of NSCLC patients to direct their treatment.

Superficial temporal artery pseudoaneurysm presenting as extradural hematoma: A case report and review of literature.

Superficial temporal artery (STA) pseudoaneurysm after a craniotomy is very rare with only nine cases reported in the literature. However, no cases have been reported in the literature about this entity presenting as an emergency in the form of extradural hematoma (EDH). This case being one of the rare ones and is also unique wherein the indication for craniotomy being intracranial tuberculoma that is not yet reported in the literature. We report the first case of a postcraniotomy STA pseudoaneurysm induced EDH following craniotomy for intracranial tuberculoma.

Management of Hodgkin's lymphoma with midbrain involvement: A case report and review of literature.

Introduction Primary central nervous system (CNS) involvement of Hodgkin's lymphoma is very uncommon. There are only a few previous reports of Hodgkin's lymphoma of nodular lymphocyte predominant histology involving the CNS concurrently with systemic disease. Case presentation A 12-year-old boy with a history of painless left inguinal swelling and acute diplopia. There was an intensely enhancing lesion in the right midbrain on magnetic resonance imaging. The patient was diagnosed with stage IV Hodgkin's lymphoma of nodular lymphocyte predominance type by routine microscopy and immunohistochemistry of left inguinal lymph node biopsy with computed tomography-assisted staging. It was planned to treat him with six cycles of chemotherapy with intrathecal methotrexate, followed by radiotherapy to the CNS lesions. After two cycles of chemotherapy, the patient entered complete remission of all lesions including the CNS lesion documented by the positron emission tomography scan. Conclusion We are describing the course of this rare presentation of Hodgkin's lymphoma of nodular lymphocyte predominant histology involving the CNS and clinical challenge in its diagnosis and management of this case.

Isolated nasopharyngeal metastasis from hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, the incidence of which parallels that of areas with high prevalence of chronic hepatitis. HCC commonly metastasizes to the lungs, lymph nodes, adrenals and bones with the overall prognosis of metastatic HCC being dismal. PRESENTATION OF CASE: We herein with present a case of a 70-year-old male who was referred to our institution with history of nasal obstruction and nasal bleeding which on further evaluation was diagnosed to have an isolated metastasis to nasopharynx from liver primary. DISCUSSION: Extrahepatic metastasis in HCC occurs in about 30-50% of patients, the commonest site being the lung. Rare sites of extrahepatic metastasis from HCC to the ovaries, kidneys, skeletal and cardiac musculature and brain have been reported. Unusual sites of metastasis in the head and neck area like the mandible have also been documented. With the changing trends in the treatment modalities, these patients are often treated using target therapy. CONCLUSION: This article presents an unusual isolated metastasis to nasopharynx from HCC in the absence of disseminated disease. This case report illustrates the distinctive pathological features of metastatic HCC.

Lymphangiosarcoma arising after 33 years within a background of chronic filariasis: a case report with review of literature.

Cutaneous angiosarcoma or lymphangiosarcoma represents an uncommon aggressive tumor known to arise on a background of chronic lymphedema secondary to various etiologies, principally following surgery or irradiation. There have been rarely reported cases of angiosarcoma following infective conditions that eventuate with lymphatic stasis. We report a case of angiosarcoma arising after 33 years within a background of filariasis. Awareness of this association can lead to early diagnosis and appropriate treatment of this potentially fatal malignant tumor.

Glycogen storage disease type V (Mc Ardle's disease): a report on three cases.

McArdle's disease (myophosphorylase deficiency), an uncommon autosomal recessive metabolic disorder, is characterized clinically by exercise intolerance beginning in childhood, myalgia, cramps, exercise-induced rhabdomyolysis, "second wind" phenomenon, elevated Creatine Kinase (CK) levels at rest, and previous episodes of raised CK levels following exercise. Several mutations in the PYGM gene and geographic variations have been described. We report three biopsy confirmed cases of McArdle's disease.