Laparoscopic Partial Splenectomy for a Splenic Hamartoma

Objective We discuss current knowledge and management of splenic hamartoma, an uncommon form of benign tumor. Summary background data A splenic hamartoma is a rare form of benign splenic mass, often found incidentally while working up other complaints, and is typically treated by surgical resection of the mass. In this case, we discuss the management of an incidentally found splenic hamartoma that was treated with laparoscopic partial splenectomy. Methods The patient presented in the Emergency Department complaining of periumbilical pain after having been struck in the abdomen with a soccer ball the previous day. Following a physical exam and blood work, an ultrasound was performed that revealed a hypoechoic area within the spleen. The patient received a diagnosis of gastroenteritis and an appointment for follow-up at 2 months. At 2-month follow-up, an ultrasound indicated that the mass had grown. The mass appeared consistent with a splenic hemangioma, so the patient was scheduled for laparoscopic partial splenectomy. Results The mass was completely resected without any complications. The patient had an uncomplicated postoperative course. Conclusions When there are no other indications for a total splenectomy and malignancy is unlikely, laparoscopic partial splenectomy appears to be a reasonable treatment modality for a splenic hamartoma

Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.

SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently of activation of outer membrane stress pathways. Thus SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins

Hypersensitivity reaction with metformin: a case report

Metformin is a biguanide derivative widely used for treatment of diabetic patients. The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort and diarrhoea). As with other drugs, allergic reactions can occur with metformin also, but these are very rare. A case of hypersensitivity reaction with metformin was reported in adverse drug monitoring centre. A 59-year-old female, newly diagnosed case of diabetes mellitus II, started on metformin tablet 500 mg twice daily, developed purpuric skin lesions on her arms, legs and back few days after starting the drug. metformin was stopped and patient was put on glimepiride tablet. The lesions slowly started subsiding after stopping metformin

In Vivo Biotinylation of the Toxoplasma Parasitophorous Vacuole Reveals Novel Dense Granule Proteins Important for Parasite Growth and Pathogenesis.

UnlabelledToxoplasma gondii is an obligate intracellular parasite that invades host cells and replicates within a unique parasitophorous vacuole. To maintain this intracellular niche, the parasite secretes an array of dense granule proteins (GRAs) into the nascent parasitophorous vacuole. These GRAs are believed to play key roles in vacuolar remodeling, nutrient uptake, and immune evasion while the parasite is replicating within the host cell. Despite the central role of GRAs in the Toxoplasma life cycle, only a subset of these proteins have been identified, and many of their roles have not been fully elucidated. In this report, we utilize the promiscuous biotin ligase BirA* to biotinylate GRA proteins secreted into the vacuole and then identify those proteins by affinity purification and mass spectrometry. Using GRA-BirA* fusion proteins as bait, we have identified a large number of known and candidate GRAs and verified localization of 13 novel GRA proteins by endogenous gene tagging. We proceeded to functionally characterize three related GRAs from this group (GRA38, GRA39, and GRA40) by gene knockout. While Δgra38 and Δgra40 parasites showed no altered phenotype, disruption of GRA39 results in slow-growing parasites that contain striking lipid deposits in the parasitophorous vacuole, suggesting a role in lipid regulation that is important for parasite growth. In addition, parasites lacking GRA39 showed dramatically reduced virulence and a lower tissue cyst burden in vivo Together, the findings from this work reveal a partial vacuolar proteome of T. gondii and identify a novel GRA that plays a key role in parasite replication and pathogenesis.ImportanceMost intracellular pathogens reside inside a membrane-bound vacuole within their host cell that is extensively modified by the pathogen to optimize intracellular growth and avoid host defenses. In Toxoplasma, this vacuole is modified by a host of secretory GRA proteins, many of which remain unidentified. Here we demonstrate that in vivo biotinylation of proximal and interacting proteins using the promiscuous biotin ligase BirA* is a powerful approach to rapidly identify vacuolar GRA proteins. We further demonstrate that one factor identified by this approach, GRA39, plays an important role in the ability of the parasite to replicate within its host cell and cause disease

Rola zarejestrowanej objętości wyrzutu płynu mózgowo-rdzeniowego w przewidywaniu wyniku w zmodyfikowanej skali Rankina przy wypisie ze szpitala u pacjentów z krwawieniami podpajęczynówkowymi (DROPSS)

Introduction. External ventricular drain (EVD) placement is common among aneurysmal subarachnoid hemorrhage (aSAH). Draining cerebrospinal fluid (CSF) from the EVD is also common, yet little is known about how much to drain, the length of time to drain, or how drainage impacts patient outcomes. Aim. The purpose of this study is to correlate amount of CSF drainage to patient outcomes, via modified Rankin Score (mRS). Material and Methods. This retrospective review of data located in a local hospital-based registry and electronic medical record. A linear mixed effects model was constructed to examine CSF drainage volume as a predictor of mRS at discharge. Results. Data from 82 patients was included in this analysis. There was no statistically significant relationship between CSF totals and mRS at hospital discharge (p = 0.3614, r² = 0.01). After controlling for age, Hunt and Hess score, and subject as random effect, there was still no significant relationship between CSF drained and mRS score at hospital discharge (p = .9042). Conclusions. There is no correlation between the total volume of CSF drained and mRS at discharge. Future research should explore CSF drainage documentation practices. (JNNN 2022;11(2):43–48) Key Words: acute care, aneurysmal subarachnoid hemorrhage, cerebrospinal fluid, external ventricular drain, patient outcomesWstęp. Założenie drenu komorowego zewnętrznego (EVD) jest powszechne w przypadku tętniakowatego krwotoku podpajęczynówkowego (aSAH). Drenaż płynu mózgowo-rdzeniowego (cerebrospinal fluid, CSF) z EVD jest również powszechny, jednak niewiele wiadomo na temat ilości płynu, czasu trwania drenażu i wpływu drenażu na wyniki leczenia. Cel. Celem tego badania jest korelacja ilości drenażu płynu mózgowo-rdzeniowego z wynikami leczenia pacjentów w zmodyfikowanej skali Rankina (modified Rankin Score, mRS). Materiał i metody. Retrospektywny przegląd danych znajdujących się w lokalnym rejestrze szpitalnym i elektronicznej dokumentacji medycznej. W celu zbadania objętości drenażu płynu mózgowo-rdzeniowego jako predyktora mRS przy wypisie ze szpitala skonstruowano liniowy model efektów mieszanych. Wyniki. Do analizy włączono dane od 82 pacjentów. Nie stwierdzono istotnej statystycznie zależności między całkowitą objętością płynu mózgowo-rdzeniowego a mRS przy wypisie ze szpitala (p = 0,3614, r² = 0,01). Po uwzględnieniu wieku, punktacji w skali Hunta i Hessa oraz podmiotu jako efektu losowego, nadal nie było istotnej zależności między odsączonym płynem mózgowo-rdzeniowym a wynikiem mRS przy wypisie ze szpitala (p = .9042). Wnioski. Nie ma korelacji między całkowitą objętością zdrenowanego płynu mózgowo-rdzeniowego a mRS przy wypisie ze szpitala. W przyszłych badaniach należy przeanalizować sposób prowadzenia dokumentacji drenażu płynu mózgowo-rdzeniowego. (PNN 2022;11(2):43–48)

PatientExploreR: an extensible application for dynamic visualization of patient clinical history from electronic health records in the OMOP common data model.

MotivationElectronic health records (EHRs) are quickly becoming omnipresent in healthcare, but interoperability issues and technical demands limit their use for biomedical and clinical research. Interactive and flexible software that interfaces directly with EHR data structured around a common data model (CDM) could accelerate more EHR-based research by making the data more accessible to researchers who lack computational expertise and/or domain knowledge.ResultsWe present PatientExploreR, an extensible application built on the R/Shiny framework that interfaces with a relational database of EHR data in the Observational Medical Outcomes Partnership CDM format. PatientExploreR produces patient-level interactive and dynamic reports and facilitates visualization of clinical data without any programming required. It allows researchers to easily construct and export patient cohorts from the EHR for analysis with other software. This application could enable easier exploration of patient-level data for physicians and researchers. PatientExploreR can incorporate EHR data from any institution that employs the CDM for users with approved access. The software code is free and open source under the MIT license, enabling institutions to install and users to expand and modify the application for their own purposes.Availability and implementationPatientExploreR can be freely obtained from GitHub: https://github.com/BenGlicksberg/PatientExploreR. We provide instructions for how researchers with approved access to their institutional EHR can use this package. We also release an open sandbox server of synthesized patient data for users without EHR access to explore: http://patientexplorer.ucsf.edu.Supplementary informationSupplementary data are available at Bioinformatics online

Engineering nucleotide specificity of succinyl-CoA synthetase in blastocystis: the emerging role of gatekeeper residues

Charged, solvent-exposed residues at the entrance to the substrate binding site (gatekeeper residues) produce electrostatic dipole interactions with approaching substrates, and control their access by a novel mechanism called "electrostatic gatekeeper effect". This proof-of-concept study demonstrates that the nucleotide specificity can be engineered by altering the electrostatic properties of the gatekeeper residues outside the binding site. Using Blastocystis succinyl-CoA synthetase (SCS, EC 6.2.1.5), we demonstrated that the gatekeeper mutant (ED) resulted in ATP-specific SCS to show high GTP specificity. Moreover, nucleotide binding site mutant (LF) had no effect on GTP specificity and remained ATP-specific. However, via combination of the gatekeeper mutant with the nucleotide binding site mutant (ED+LF), a complete reversal of nucleotide specificity was obtained with GTP, but no detectable activity was obtained with ATP. This striking result of the combined mutant (ED+LF) was due to two changes; negatively charged gatekeeper residues (ED) favored GTP access, and nucleotide binding site residues (LF) altered ATP binding, which was consistent with the hypothesis of the "electrostatic gatekeeper effect". These results were further supported by molecular modeling and simulation studies. Hence, it is imperative to extend the strategy of the gatekeeper effect in a different range of crucial enzymes (synthetases, kinases, and transferases) to engineer substrate specificity for various industrial applications and substrate-based drug design

Targeting melanoma growth and viability reveals dualistic functionality of the phosphonothionate analogue of carba cyclic phosphatidic acid

<p>Abstract</p> <p>Background</p> <p>Although the incidence of melanoma in the U.S. is rising faster than any other cancer, the FDA-approved chemotherapies lack efficacy for advanced disease, which results in poor overall survival. Lysophosphatidic acid (LPA), autotaxin (ATX), the enzyme that produces LPA, and the LPA receptors represent an emerging group of therapeutic targets in cancer, although it is not known which of these is most effective.</p> <p>Results</p> <p>Herein we demonstrate that thio-ccPA 18:1, a stabilized phosphonothionate analogue of carba cyclic phosphatidic acid, ATX inhibitor and LPA1/3 receptor antagonist, induced a marked reduction in the viability of B16F10 metastatic melanoma cells compared with PBS-treated control by 80-100%. Exogenous LPA 18:1 or D-sn-1-O-oleoyl-2-O-methylglyceryl-3-phosphothioate did not reverse the effect of thio-ccPA 18:1. The reduction in viability mediated by thio-ccPA 18:1 was also observed in A375 and MeWo melanoma cell lines, suggesting that the effects are generalizable. Interestingly, siRNA to LPA3 (siLPA3) but not other LPA receptors recapitulated the effects of thio-ccPA 18:1 on viability, suggesting that inhibition of the LPA3 receptor is an important dualistic function of the compound. In addition, siLPA3 reduced proliferation, plasma membrane integrity and altered morphology of A375 cells. Another experimental compound designed to antagonize the LPA1/3 receptors significantly reduced viability in MeWo cells, which predominantly express the LPA3 receptor.</p> <p>Conclusions</p> <p>Thus the ability of thio-ccPA 18:1 to inhibit the LPA3 receptor and ATX are key to its molecular mechanism, particularly in melanoma cells that predominantly express the LPA3 receptor. These observations necessitate further exploration and exploitation of these targets in melanoma.</p

Feasibility of using a novel non-invasive ambulatory tibial nerve stimulation device for the home-based treatment of overactive bladder symptoms

BACKGROUND: To evaluate safety, acceptability and pilot efficacy of transcutaneous low-frequency tibial nerve stimulation (TNS) using a novel device as home-based neuromodulation. METHODS: In this single-centre pilot study, 48 patients with overactive bladder (OAB) (24 with neurogenic and 24 with idiopathic OAB) were randomized to use a self-applicating ambulatory skin-adhering device stimulating transcutaneously the tibial nerve at 1 Hz for 30 minutes, either once daily or once weekly, for 12 weeks. Changes in OAB symptoms and QoL were measured at baseline, weeks 4, 8, and 12 using validated scoring instruments (ICIQ-OAB and ICIQ-LUTSqol), 3-day bladder diary and a Global Response Assessment (GRA) at week 12. RESULTS: Thirty-four patients completed the study (idiopathic n=15, neurogenic n=19). No significant adverse effects were noted. Patients found the device acceptable. Eighteen patients (53%) reported a moderate or marked improvement in symptoms from the GRA. Between baseline and week-12, ICIQ-OAB part A sub-scores improved from mean (SD) 9.3 (2.5) to 7.5 (3.1), and from 9.1 (1.9) to 5.9 (1.7) in the daily and the weekly arms, respectively. ICIQ-LUTSqol part A sub-scores improved from mean (SD) 51 (12.8) to 44.2 (13.1) and 44.9 (9.0) to 35.9 (8.8) in the daily and the weekly arms, respectively. Bladder diary mean 24-hour frequency episodes improved from 11.5 to 8.8 at week 12 for both arms. CONCLUSIONS: This novel ambulatory transcutaneous TNS (TTNS) device is safe and acceptable for use in patients reporting OAB symptoms as a form of home-based neuromodulation. A larger study however is required to confirm clinical efficacy

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON