Narrative Review: Pyoderma Gangrenosum.

Pyoderma gangrenosum (PG) is a skin lesion, characteristically a neutrophilic dermatosis, that can be complicated by rapid progression, necrosis, and ulceration. This is an important pathology to be discussed given that there are no established criteria for diagnosis or treatment. This review aims to elucidate characteristics and variations of PG that distinguish it from other ulcerative skin lesions. Variability in presentation can lead to missed or incorrect diagnosis, and some of the currently proposed criteria for categorizing and diagnosing PG have been included here. These criteria distinguish PG in terms of the nature of the lesion, the location, etiology, responsiveness to immunosuppressive therapy, and patient history. The etiology and pathogenesis of PG remain unknown, but we summarize prominent theories and explanations. Furthermore, recent research indicates that the incidence of PG has a strong correlation with autoimmune conditions, particularly inflammatory bowel disease. Major treatments for PG coincide with these findings, as the majority involve targeted anti-inflammatories, immunosuppressants, and surgical interventions. These treatments are addressed in this review, with added context for local versus systemic disease.

Elizabethkingia meningosepticum infections with varied presentations and different antimicrobial susceptibility - A case series.

We report three sporadic infections by Elizabethkingia meningosepticum from Government Medical College Kozhikode in Kerala state, South India over a period of three years. Two cases were commenced in the community in immunocompromised children beyond the newborn period, but both recovered promptly. Another was a hospital-acquired meningitis in a newborn baby who developed neurologic sequelae. In contrast to widespread antimicrobial resistance exhibited by this pathogen, there was good susceptibility to commonly used antimicrobials such as ampicillin, cefotaxime, piperacillin, ciprofloxacin, and vancomycin. Whilst ß lactam antibiotics are found effective in the treatment of Elizabethkingia septicaemia of children, piperacillin-tazobactam, vancomycin combination seems effective empiric choice of antibiotics for neonatal meningitis due to Elizabethkingia; there is a need for guidelines for the management of this infection, especially in neonatal meningitis.

Inferior Vena Cava Filters and Complications: A Systematic Review.

Inferior vena cava (IVC) filters have been used since the 1960s to treat patients with acute risk of pulmonary embolism (PE) to prevent migration of thrombus by trapping it within the filter. Traditional usage has been in patients with contraindication to anticoagulation that carry a significant mortality risk. In this systematic review, we sought to evaluate complications associated with placement of inferior vena cava filters based on published data from the past 20 years. A search was performed on October 6th, 2022, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews, using three databases (ProQuest, PubMed and ScienceDirect) for articles published between the dates of February 1, 2002 and October 1, 2022. Results were filtered to include full-text, clinical studies, and randomized trials written in English pertaining to keywords "IVC filter AND complications", "Inferior Vena Cava Filter AND complications", "IVC filter AND thrombosis" and "Inferior Vena Cava Filter AND thrombosis". Articles identified by the three databases were pooled and further screened for relevance based on inclusion and exclusion criteria. Initial search results yielded 33,265 hits from all three databases combined. Screening criteria were applied, with 7721 results remaining. After further manual screening, including removal of duplicate hits, a total of 117 articles were selected for review. While there are no consensus guidelines for best practice, there is compelling evidence that IVC filters can provide significant protection against PE with minimal complications if the treatment window is appropriate. Increase in the variety of filter models has led to broader availability, but skepticism remains about their efficacy and safety, with ongoing controversy surrounding appropriate indications. Further research is needed to establish clear guidelines on appropriate indications for IVC placement and to determine time course of complications versus benefits for indwelling filters.

Presence of Extracellular Alpha-Synuclein Aggregates Trigger Astrocytic Degeneration Through Enhanced Membrane Rigidity and Deregulation of Store-Operated Calcium Entry (SOCE) into the Endoplasmic Reticulum.

α-Synuclein has a critical role in Parkinson's disease, but the mechanism of how extracellular α-synuclein aggregates lead to astrocytic degeneration remains unknown. Our recent study in astrocytes highlighted that α-synuclein aggregates undergo lower endocytosis than the monomeric-form, even while displaying a higher impact on glutathione-machinery and glutamate-metabolism under sublethal conditions. As optimal intracellular calcium levels are essential for these functions, we aimed to study the effect of extracellular α-synuclein aggregates on ER calcium entry. We assessed the association of extracellular aggregated-α-synuclein (WT and A30P/A53T double-mutant) with the astrocytic membrane (lipid rafts) and studied its effects on membrane fluidity, ER stress, and ER calcium refilling in three systems-purified rat primary midbrain astrocyte culture, human iPSC-derived astrocytes, and U87 cells. The corresponding timeline effect on mitochondrial membrane potential was also evaluated. Post-24 h exposure to extracellular WT and mutant α-synuclein aggregates, fluorescence-based studies showed a significant increase in astrocyte membrane rigidity over control, with membrane association being significantly higher for the double mutant aggregates. α-Synuclein aggregates also showed preferentially higher association with lipid rafts of astrocytic membrane. A simultaneous increase in ER stress markers (phosphorylated PERK and CHOP) with significantly higher SOCE was also observed in aggregate-treated astrocytes, with higher levels for double mutant variant. These observations correlate with increased expression of SOCE markers, especially Orai3, on plasma membrane. Alterations in mitochondrial membrane potential were only noted post-48 h of exposure to α-synuclein aggregates. We therefore suggest that in astrocytes, α-synuclein-aggregates preferentially associate with lipid rafts of membrane, altering membrane fluidity and consequently inducing ER stress mediated by interaction with membrane SOCE proteins, resulting in higher Ca2+ entry. A distinct cascade of events of sequential impairment of ER followed by mitochondrial alteration is observed. The study provides novel evidence elucidating relationships between extracellular α-synuclein aggregates and organellar stress in astrocytes and indicates the therapeutic potential in targeting the association of α-synuclein aggregates with astrocytic membrane.

Astrocytes Differentiated from LRRK2-I1371V Parkinson's-Disease-Induced Pluripotent Stem Cells Exhibit Similar Yield but Cell-Intrinsic Dysfunction in Glutamate Uptake and Metabolism, ATP Generation, and Nrf2-Mediated Glutathione Machinery.

Owing to the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signaling pathways. It also has several pathological mutant-variants, and their incidences show ethnicity biases and drug-response differences with expression in dopaminergic-neurons and astrocytes. Here, we aimed to assess the cell-intrinsic effect of the LRRK2-I1371V mutant variant, prevalent in East Asian populations, on astrocyte yield and biology, involving Nrf2-mediated glutathione machinery, glutamate uptake and metabolism, and ATP generation in astrocytes derived from LRRK2-I1371V PD patient iPSCs and independently confirmed in LRRK2-I1371V-overexpressed U87 cells. Astrocyte yield (GFAP-immunopositive) was comparable between LRRK2-I1371V and healthy control (HC) populations; however, the astrocytic capability to mitigate oxidative stress in terms of glutathione content was significantly reduced in the mutant astrocytes, along with a reduction in the gene expression of the enzymes involved in glutathione machinery and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Simultaneously, a significant decrease in glutamate uptake was observed in LRRK2-I1371V astrocytes, with lower gene expression of glutamate transporters SLC1A2 and SLC1A3. The reduction in the protein expression of SLC1A2 was also directly confirmed. Enzymes catalyzing the generation of γ glutamyl cysteine (precursor of glutathione) from glutamate and the metabolism of glutamate to enter the Krebs cycle (α-ketoglutaric acid) were impaired, with significantly lower ATP generation in LRRK2-I1371V astrocytes. De novo glutamine synthesis via the conversion of glutamate to glutamine was also affected, indicating glutamate metabolism disorder. Our data demonstrate for the first time that the mutation in the LRRK2-I1371V allele causes significant astrocytic dysfunction with respect to Nrf2-mediated antioxidant machinery, AT -generation, and glutamate metabolism, even with comparable astrocyte yields.

Safety and Efficacy of Thalidomide and Hydroxyurea Combination in Beta Thalassemia Patients.

Beta thalassemia results from imbalance in alpha and beta globin chains causing severe anemia, transfusion dependency, and iron overload. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Patients without the option of HSCT may benefit from Hemoglobin F (HbF) inducing agents like thalidomide and hydroxyurea (HU). We conducted a retrospective analysis on 87 beta thalassemia patients who received a combination of low dose thalidomide and HU from January 2017 to December 2020. Patients received combination of HU 500 mg everyday (> 30 kg) or every alternate day (< 30 kg) and thalidomide 100 mg (> 30 kg) or 50 mg (< 30 kg) once daily. Parameters such as transfusion requirement, anthropometry, Hb levels, ferritin, drug side effects etc. were monitored and evaluated at the end of one year of therapy. Sixty-three patients (72%) achieved transfusion independence and were eligible for the study. Median time to transfusion independence was 6 months (range 3-11 months). At the end of 1 year, overall response rate was 72%. There was significant improvement in the Hb levels, ferritin values and height at the end of 1 year of follow up. No grade 3 or 4 toxicities were noted. We document improvement of Hb levels, transfusion independence, reduction in iron overload, and improvement in growth parameters with minimal side effects at the end of 1 year of follow up.

A Prospective Randomised Comparative Study Between Weekly Cisplatin Versus Three Weekly Cisplatin with Radiotherapy in Unresectable Locally Advanced Head and Neck Cancer.

To compare the efficacy, compliance and the complications of weekly cisplatin 40 mg/m2 against the three weekly cisplatin 100 mg/m2 with EBRT(external beam radiotherapy) in unresectable locally advanced head and neck squamous cell carcinoma(LAHNSCC) Study design was Prospective randomized and comparative.85 Patients with histologically proven stage III-IVA LAHNSCC presenting from December 2017 to May 2019 were assigned to concurrent three weekly cisplatin 100 mg/m2 (arm 1) and weekly cisplatin 40 mg/m2 (arm 2) with EBRT. There were 41 patients were in arm 1 and 44 patients in arm 2. Statistical analysis was done using SPSS version 2.0. At 4 week of completion of treatment, response was assessed using RECIST(1.1) criteria.In Arm 1,61% patients and in arm 2 55% patients achieved complete response but the difference was statistically non- significant (p = 0.756).Median follow up was 12 months after which 49% patients in arm 1 and 38% in arm 2 had complete response whereas 12% patients in arm 1 and 15.5% patients in arm 2 had locoregional relapse. There was no statistically significant difference between the two arms in terms of mucositis, nausea,vomiting, dysphagia, acute skin reaction and ototoxicity. Leukopenia (p = 0.003),thrombocytopenia (p = 0.04) and acute renal toxicity (p = 0.004) was significantly more in three weekly arm. As compared to three weekly cisplatin, weekly cisplatin with radiotherapy is an acceptable approach in a limited resource setting due to good patient compliance where a large number of patients are treated on outpatient basis.

Reduction of phosphorylated α-synuclein through downregulation of casein kinase 2α alleviates dopaminergic-neuronal function.

Among the post-translational modifications of α-synuclein, phosphorylation has been reported to modulate the protein's nuclear localization, gene-expression and cytotoxicity. However, its effect on the functional performance of dopaminergic-neurons is not known. We aimed to evaluate the effect of siRNA-silencing of casein kinase (CK)2α in SH-SY5Y-cells overexpressing A53T α-synuclein, in alleviating phosphorylated α-synuclein serine129 (pSyn-129)-induced changes in intracellular Ca2+ ([Ca2+]i) response to physiological stimuli and vesicular-dopamine release. A53T transfection showed distinct increase in basal pSyn-129 expression with simultaneous nuclear localization, and CK2α siRNA decreased ROS-generation and pSyn-129 levels. A significant reduction was observed in KCl-induced ([Ca2+]i) response and vesicular-dopamine release in the A53T-transfected cells with a corresponding decrease in immunopositive-population of resting-vesicles (VMAT2). CK2α siRNA treatment showed recovery in [Ca2+]i rise with a corresponding upregulation of expression of voltage-gated Ca2+-channels (VGCC) CaV1.3 and CaV2.2 and RyR1 responsible for Ca2+ induced Ca2+ release from ER, VMAT2 expression and vesicular-dopamine release. Thus, using CK2α siRNA to reduce phosphorylation improved cellular-pathology in terms of ROS generation and pSyn-129 levels, as well as functional performance of DA-neuronal cells.

Impact of monomeric and aggregated wild-type and A30P/A53T double-mutant α-synuclein on antioxidant mechanism and glutamate metabolic profile of cultured astrocytes.

Serving as a source of glutathione and up-taking and metabolizing glutamate are the primary supportive role of astrocytes for the adjacent neurons. Despite the clear physical association between astrocytes and α-synuclein, the effect of extracellular α-synuclein on these astrocytic functions has not yet been elucidated. Hence, we aim to assess the effect of various forms of α-synuclein on antioxidant mechanism and glutamate metabolism. Wild-type and A53T/A30P double-mutant α-synuclein, both in monomeric and aggregated forms, were added extracellularly to media of midbrain rat astrocyte culture, with their survival, oxidative, and nitrative stress, glutathione and glutamate content, expression of enzymes associated with oxidative stress and glutamate metabolism, glutamate and glutathione transporters being assessed along with the association/engulfment of these peptides by astrocytes. A30P/A53T peptide associated more with astrocytes, and low-extracellular K+ concentration showed prominent reduction in the engulfment of the monomeric forms, suggesting that the association of the aggregated forms was greater with the membrane. The peptide-associated astrocytes showed lower survival and increased oxidative stress generation, owing to the decrease in nuclear localization of Nrf2 and increase in iNOS, and further aggravated by the decrease in glutathione content and related enzymes like glutathione synthetase, glutathione peroxidase, and glutathione reductase. Glutamate uptake increased in aggregate-treated cells due to the increase in GLAST1 expression, de novo synthesis of glutamate by pyruvate carboxylase, and/or glutamine synthase, bolstered by the differential glutamate dehydrogenase enzyme activity. We thus show for the first time that extracellular α-synuclein exposure leads to astrocytic dysfunction with respect to the antioxidant mechanism and glutamate metabolic profile. The impact was higher in the case of the aggregated and mutated peptide, with the highest dysfunction for the mutant aggregated α-synuclein treatment.

Validity of a CB-NAAT assay in diagnosing tuberculosis in comparison to culture: A study from an urban area of South India.

•CB-NAAT performance compared in 831 suspected pulmonary and extrapulmonary suspected cases.•The conventional stained smear and CB-NAAT results were compared to the MGIT culture.•Sensitivity and specificity of CB-NAAT was 84.43% and 94.93%.•The rapid results from CB-NAAT confirms its use in the tuberculosis diagnostic algorithm.•The benefits of disease diagnosis and prevention outweighs the price tag of the CB-NAAT tests.•This is more so for the resource poor countries where the burden of the disease is high.

Congenital leukemia.

Congenital leukemia is a rare but a well-documented disease in which leukemic process is detected at birth or very shortly thereafter (Philip McCoy and Roy Overton, Commun Clin Cytom 22:85-88, 1995). These leukemias represent approximately 0.8 % of all childhood leukemias. We present a case of congenital acute myeloid leukemia manifesting from the very first day of birth. Diagnosis of acute myeloid leukemia was suspected by the presence of blasts in the peripheral blood smear and was confirmed on bone marrow by flowcytometry. Karyotyping revealed Trisomy 21.