Modulation of Neurotransmitter Pathways and Associated Metabolites by Systemic Silencing of Gut Genes in C. elegans.

The gut is now recognized as the "second brain" of the human body due to its integral role in neuronal health and functioning. Although we know that the gut communicates with the brain via immunological factors, microbial metabolites, and neurotransmitters, the interplay of these systems remains poorly understood. To investigate this interplay, we silenced 48 genes that are exclusively or primarily expressed in the C. elegans intestine. We studied the associated effects on various aspects of neurodegeneration, including proteotoxicity induced by α-Syn expression. We also assayed behaviours, such as mobility and cognition, that are governed by various neurotransmitters. We identified nine gut genes that significantly modulated these events. We further performed HR-MAS NMR-based metabolomics to recognize the metabolic variability induced by the respective RNAi conditions of R07E3.1, C14A6.1, K09D9.2, ZK593.2, F41H10.8, M02D8.4, M88.1, C03G6.15 and T01D3.6. We found that key metabolites such as phenylalanine, tyrosine, inosine, and glutamine showed significant variation among the groups. Gut genes that demonstrated neuroprotective effects (R07E3.1, C14A6.1, K09D9.2, and ZK593.2) showed elevated levels of inosine, phenylalanine, and tyrosine; whereas, genes that aggravated neurotransmitter levels demonstrated decreased levels of the same metabolites. Our results shed light on the intricate roles of gut genes in the context of neurodegeneration and suggest a new perspective on the reciprocal interrelation of gut genes, neurotransmitters, and associated metabolites. Further studies are needed to decipher the intricate roles of these genes in context of neurodegeneration in greater detail.

Breast Carcinoma in Young Females: A Prospective Study in Terms of Clinicopathological Presentation at a Tertiary Care Center in India.

INTRODUCTION: The incidence of breast carcinoma in young women is on the rise, particularly in developing Asian countries like India. Owing to a unique presentation in terms of genetic background, clinical features, and histological characteristics, the prognosis becomes challenging, which therefore entails a detailed study for better understanding and management of the disease. This study aimed to establish the role of clinical and pathological parameters in breast cancer disease in young women. METHODS: This was a prospective comparative study conducted at the Department of Surgery, Hamidia Hospital, Bhopal, India, which spanned a total duration of one year between November 2018 and October 2019, and included a total of 98 consecutive in-house breast carcinoma patients. The patients were categorized into two groups based on age, i.e., the young age group (age < 40 years) and the old age group (age ≥ 40 years). RESULTS: Of the patients, 37 fell in the young age group and 61 in the old age group. There was a significant association between positive family history of breast carcinoma and young age (p = 0.01). Estrogen and progesterone receptor positivity was found to be associated more commonly with old age group patients. The proportion of patients with human epidermal growth factor receptor 2 (HER2)/neu over-expression was higher among the young age group. Triple negativity was more frequently observed amongst young age group patients. CONCLUSION: Hormone receptor analysis should be an absolute part of the initial work-up of breast carcinoma. Raising awareness among women in society should be of paramount importance. Family history is crucial, particularly in young women, and should not be dismissed. With timely presentation and effective diagnosis, a safer state with a relatively better prognosis can be achieved.

Anomalous Anatomical Variations of Coeliac Trunk: A Cadaveric Study.

Background The celiac trunk, celiac axis or celiac artery is the first major abdominal branch of the aorta. Anatomical variations of the coeliac trunk and along with the other branches of the abdominal aorta result from changes in the ventral segmental arteries supplying the digestive tube during foetal development. Panagouli performed a systemaic review and proposed a new classification describing all celiac trunk variations through a systematic review. Knowledge of the celiac trunk anatomy and any variations is clinically relevant in esophageal, gastroduodenal, hepatic, biliary and pancreatic angiographic and surgical procedures. The purpose of this study is to report the pattern of the celiac trunk and its variations in a sample of the Indian population as per the Panagouli classification. Methods This was an observational study done in the period from September 2018 to October 2020 in the department of surgery of Gandhi Medical College & Hamidia Hospital, Bhopal, India. Cadaveric dissection was carried out in the department of forensic medicine and toxicology after obtaining approval from the ethical committee. Results We did our study in 50 cadavers to look for further anatomical variations. The most common form found was true tripus Halleri. The rest of the variations noted included false tripus Halleri. Other variations were hepatosplenic trunk with left gastric artery arising from the aorta (6%), hepatosplenic trunk with no normal left gastric artery (2%), Hepatosplenic trunk with gastromesenteric trunk (2%) and coeliacomesenteric trunk (2%). Conclusions The congenital anomalies of the coeliac trunk have been long recognized and are of significant clinical importance as they may surprise the surgeon during surgery. Also, the wide spectrum of anomalies present in this area can be recognized by modern radiological evaluations like multi-detector helical computed tomography, MRI and magnetic resonance cholangiopancreatography (MRCP). Having the knowledge of these anatomical variations in mind may prevent inadvertent injuries during routine and complex hepato-pancreaticobiliary procedures.

Not a piece of junk anymore: Pseudogene T04B2.1 performs non-conventional regulatory role and modulates aggregation of α- synuclein and ß-amyloid proteins in C. elegans.

The conventional notions of pseudogenes being 'junk DNA' have largely been offset as research studies have established their role in multiple biological processes. Our studies towards identification of genetic modulators employing C. elegans model, that associate reproductive health and age-related neurodegenerative diseases, led us to identification and functional characterization of a pseudogene T04B2.1, which when knocked down, exacerbates the aggregation of α-Synuclein and ß-Amyloid proteins, induces lipid deposition and alters morphometric endpoints in worms. Whole transcriptome analysis of worms under knockdown condition of T04B2.1 revealed an altered expression of 187 sequences, most of these being non-coding RNAs, miRNAs and piRNAs modulating the RNAi regulatory processes. Our gene ontology and pathway enrichment analysis demonstrated the role of T04B2.1 in protein quality control, metabolic pathways and development. We further performed a signature motif search and successfully identified a common motif that is present between all piRNA and miRNA molecules, which are significantly altered upon T04B2.1 silencing. This study unveils the non-conventional regulatory role of pseudogene T04B2.1 with respect to effects associated with neurodegenerative diseases and encourages further studies to decipher the regulatory mechanism governed by pseudogenes.

Perioperative Considerations in the Management of Anticoagulation Therapy for Patients Undergoing Surgery.

PURPOSE OF REVIEW: As ambulatory surgery has become increasingly more common, the appropriate management of anticoagulation therapy in patients undergoing invasive procedures has become progressively more relevant to healthcare professionals. The purpose of this literature review is to provide an overview of current common anaticoagulants and their pharmacological properties and to evaluate recent relevant literature and bridging therapy and provide recommendations on risk-guided therapy. RECENT FINDINGS: With the development of new drugs and the advancing study and practice of anticoagulation use, clinicians must keep up-to-date on the optimal management of patients requiring anticoagulation. NOACs and warfarin continue to be the mainstays of treatment, with varying timelines regarding when to hold administration of the different agents within the perioperative period. There are numerous factors that are considered in patients with multiple comorbidities including the risk for stroke on long-term anticoagulation and risk for thromboembolism, particularly in the perioperative setting when certain medication regimens may be altered and/or briefly held. There is ongoing investigation whether certain NOACs have more efficacy or greater safety profiles, depending on the degree of surgical intervention.

Perioperative Hypertensive Urgency After Methylene Blue in a Patient With Undiagnosed Pheochromocytoma: A Case Report.

We report the perioperative course of a 75-year-old woman undergoing robotic-assisted laparoscopic hysterectomy and tumor debulking. The patient developed severe, persistent hypertension after intraoperative methylene blue administration requiring a Surgical Intensive Care Unit admission with further investigative evaluation revealing a previously undiagnosed pheochromocytoma. Our discussion focuses on the differential diagnoses for her perioperative hypertension. We evaluate whether methylene blue triggered a pheochromocytoma crisis in our patient and emphasize the caution and critical thinking we all should demonstrate while providing anesthetic care.

C.el Phosphatome: A Catalogue of Actual and Pseudo Phosphatases Based on In-Silico Studies in Caenorhabditis elegans.

Phosphatases are well known to carry out important functions via counter activity of kinases and they serve as mechanism for dephosphorylating the monophosphate esters from the phosphorylated serine, threonine, tyrosine and histidine residues. The biological relevance of phosphatases could be explored further employing newer technologies and models. Caenorhabditis elegans is a powerful genetic model system that bears significant homology with humans, hence providing with a precious tool towards studying important signalling pathways. We carried out the present study to catalogue the C. elegans protein phosphatome, referred here as 'C.el phosphatome' and annotated the corresponding dataset. We further classified these phosphatases based on presence of catalytic conserved motif; GDxHG, GDxVDRG, GNHE, RxxD, DGxxG, DG, GxxDN for Ser/Thr phosphatases, HC(x)5 R for tyrosine phosphatases and DxDxT/V for aspartate based phosphatases. Bioinformatics tool DAVID was employed to decipher the biological relevance of phosphatases. Our findings show Ser/Thr phosphatases (114), Tyr phosphatases (121) and Asp phosphatases (0) in C. elegans genome based on the hallmark sequence identification. Amongst them, 34 and 57 Ser/Thr and Tyr phosphatases respectively contain the catalytic motif. This catalogue offers a precious tool for further studies towards understanding important biological processes and disease conditions.

Functional Characterization of Novel Circular RNA Molecule, circzip-2 and Its Synthesizing Gene zip-2 in C. elegans Model of Parkinson's Disease.

Circular RNAs (circRNAs) are peculiar non-coding RNA molecules which are known to be present across taxa. Considering the body of evidence that establishes critical functions of non-coding RNA molecules, we endeavored to study circRNAs in the context of Parkinson's disease (PD). Employing transgenic C. elegans model of PD, we used RNase R-mediated cleavage of linear RNA followed by divergent primer-based amplifications towards identifying circzip-2, a novel circRNA molecule. We went on to sequence circzip-2 which is synthesized from functionally important gene zip-2. Studying RNAi-induced knockdown conditions of zip-2, we observed a reduced aggregation of α-synuclein protein along with an enhanced lifespan of the worms. We further carried out transcriptome analysis of zip-2 silenced worms, which suggested that zip-2 might be functioning via Daf-16 pathway. Further interaction studies revealed that circzip-2 possibly sponges microRNA molecule miR-60 towards asserting an important role in various processes associated with PD.

Use of Hypotonic Maintenance Intravenous Fluids and Hospital-Acquired Hyponatremia Remain Common in Children Admitted to a General Pediatric Ward.

AIM: To evaluate maintenance intravenous fluid-prescribing practices and the incidence of hospital-acquired hyponatremia in children admitted to a general pediatric ward. METHODS: This is a prospective observational study conducted over a 2-month period in children ages 2 months to 5 years who were admitted to a general pediatric ward and who were receiving maintenance intravenous fluids. The composition, rate, and duration of intravenous fluids were chosen at the discretion of the treating physician. Serum biochemistries were obtained at baseline and 24 h following admission. Patients who were at high risk for developing hyponatremia or hypernatremia or had underlying chronic diseases or were receiving medications associated with a disorder in sodium and water homeostasis were excluded. Intravenous fluid composition and the incidence of hyponatremia (sodium <135 mEq/L) were assessed. RESULTS: Fifty-six children were enrolled. All received hypotonic fluids; 87.5% received 0.18% sodium chloride (NaCl) and 14.3% received 0.45% NaCl. Forty percent of patients (17/42) with a serum sodium (SNa) less than 140 mEq/L experienced a fall in SNa with 12.5% of all patients (7/56) developing hospital-acquired or aggravated hyponatremia (126-134 mEq/L) with fall in SNa between 2 and 10 mEq/L. CONCLUSION: Administration of hypotonic fluids was a prevalent practice in children admitted to a general pediatric ward and is associated with acute hospital-acquired hyponatremia.

Bacterial cell killing mediated by topoisomerase I DNA cleavage activity.

DNA topoisomerases are important clinical targets for antibacterial and anticancer therapy. At least one type IA DNA topoisomerase can be found in every bacterium, making it a logical target for antibacterial agents that can convert the enzyme into poison by trapping its covalent complex with DNA. However, it has not been possible previously to observe the consequence of having such a stabilized covalent complex of bacterial topoisomerase I in vivo. We isolated a mutant of recombinant Yersinia pestis topoisomerase I that forms a stabilized covalent complex with DNA by screening for the ability to induce the SOS response in Escherichia coli. Overexpression of this mutant topoisomerase I resulted in bacterial cell death. From sequence analysis and site-directed mutagenesis, it was determined that a single amino acid substitution in the TOPRIM domain changing a strictly conserved glycine residue to serine in either the Y. pestis or E. coli topoisomerase I can result in a mutant enzyme that has the SOS-inducing and cell-killing properties. Analysis of the purified mutant enzymes showed that they have no relaxation activity but retain the ability to cleave DNA and form a covalent complex. These results demonstrate that perturbation of the active site region of bacterial topoisomerase I can result in stabilization of the covalent intermediate, with the in vivo consequence of bacterial cell death. Small molecules that induce similar perturbation in the enzyme-DNA complex should be candidates as leads for novel antibacterial agents.