A retrospective study of 50 cases of lower limb soft tissue infection and its different modalities of presentation and its management

Background: Soft tissue infections are common in everyday practice. They show great variations in their severity. Skin and soft tissue infections are usually preceded by minor traumatic events. Among them soft tissue bacterial infections of lower limbs are more common. Patients having diabetes makes the scenario even worst. Diagnosis, intervention and treatment of these infections are very important. This study aims at understanding the pathology involved for lower limb soft tissue infections, spectrum of organisms and different treatment modalities in various age group and gender.Methods: 50 cases of lower limb soft tissue infections were included in this study. Detailed history, clinical examination, investigations, pre-operative preparation, intraoperative details and post-operative management were included.Results: 94% patients were having history of trauma.88% patients were having history of diabetes. Staphylococcus aureus was the most common (43%) organism cultured from swabs followed by pseudomonas (36%) out of total cases. Minimum stay in hospital was of 4 days to a maximum of 34 days. Most of the patients were managed with regular dressing and debridement.Conclusions: The patients sought treatment only when they had extensive lesions which affect their daily living. Health education regarding foot care forms an integral part of surgical management of lower limb soft tissue infections. Readmissions are mainly due to inadequate local control or fluctuating blood sugar levels and improper foot care due to illiteracy, poverty, ignorance and lack of adequate primary care facilities

A brief review of low-dose rate (LDR) and high-dose rate (HDR) brachytherapy boost for high-risk prostate

For patients with unfavorable or high-risk prostate cancer, dose escalated radiation therapy leads to improved progression free survival but attempts to deliver increased dose by external beam radiation therapy (EBRT) alone can be limited by late toxicities to nearby genitourinary and gastrointestinal organs at risk. Brachytherapy is a method to deliver dose escalation in conjunction with EBRT with a potentially improved late toxicity profile and improved prostate cancer related outcomes. At least three randomized controlled trials have demonstrated improved biochemical control with the addition of either low-dose rate (LDR) or high-dose rate (HDR) brachytherapy to EBRT, although only ASCENDE-RT compared brachytherapy to dose-escalated EBRT but did report an over 50% improvement in biochemical failure with a LDR boost. Multiple single institution and comparative research series also support the use of a brachytherapy boost in the DE-EBRT era and demonstrate excellent prostate cancer specific outcomes. Despite improved oncologic outcomes with a brachytherapy boost in the high-risk setting, the utilization of both LDR, and HDR brachytherapy use is declining. The acute genitourinary toxicities when brachytherapy boost is combined with EBRT, particularly a LDR boost, are of concern in comparison to EBRT alone. HDR brachytherapy boost has many physical properties inherent to its rapid delivery of a large dose which may reduce acute toxicities and also appeal to the radiobiology of prostate cancer. We herein review the evidence for use of either LDR or HDR brachytherapy boost for high-risk prostate cancer and summarize comparisons between the two treatment modalities

Measurement of cervical length using transvaginal sonography for prediction of preterm labour

Background: Preterm labour and delivery cause major health burden to the society due to high perinatal morbidities and mortality and long-term health implications and also affects maternal. An effective and objective way for predicting preterm delivery is measurement of cervical length by transvaginal sonography as it allows better quality and accurate visualization of uterine cervix. Cervical length (<25 mm) is good and accurate cervical biometry for prediction of preterm birth. The objective of this study was to measure cervical length by transvaginal sonography for predicting preterm labour and fetal outcome.Methods: This prospective observational study was conducted in department of obstetrics and gynaecology, at SVPIMSR hospital, Ahmedabad from July 2018 to December 2019 in 150 antenatal women to assess cervical changes (cervical length, dilatation of internal OS, funnelling etc.) between 16 to 24 weeks of gestation and these cases followed till delivery and results were analysed.Results:150 antenatal women who fulfilled the selection criteria were studied using transvaginal ultrasound between 16-24 weeks of gestation, out of them 36 (24%) women delivered preterm babies. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) recorded in this study were 80.5%, 94.73%, 82.85% and 93.91% respectively.Conclusion: Transvaginal sonography is the most useful and better, safe, accurate, most effective, less expensive, objective and acceptable technique for assessing cervical length in all antenatal women and predicting the preterm labour when assessed between 16 -24 weeks of gestational age

Resolving the cofactor-binding site in the proline biosynthetic enzyme human pyrroline-5-carboxylate reductase 1

Pyrroline-5-carboxylate reductase (PYCR) is the final enzyme in proline biosynthesis, catalyzing the NAD(P)H-dependent reduction of [?]1-pyrroline-5-carboxylate (P5C) to proline. Mutations in the PYCR1 gene alter mitochondrial function and cause the connective tissue disorder cutis laxa. Furthermore, PYCR1 is overexpressed in multiple cancers, and the PYCR1 knock-out suppresses tumorigenic growth, suggesting that PYCR1 is a potential cancer target. However, inhibitor development has been stymied by limited mechanistic details for the enzyme, particularly in light of a previous crystallographic study that placed the cofactor-binding site in the C-terminal domain rather than the anticipated Rossmann fold of the N-terminal domain. To fill this gap, we report crystallographic, sedimentation- velocity, and kinetics data for human PYCR1. Structures of binary complexes of PYCR1 with NADPH or proline determined at 1.9 Å resolution provide insight into cofactor and substrate recognition.WeseeNADPHbound to the Rossmann fold, over 25 Å from the previously proposed site. The 1.85 Å resolution structure of a ternary complex containing NADPH and a P5C/proline analog provides a model of the Michaelis complex formed during hydride transfer. Sedimentation velocity shows that PYCR1 forms a concentration-dependent decamer in solution, consistent with the pentamer-of-dimers assembly seen crystallographically. Kinetic and mutational analysis confirmed several features seen in the crystal structure, including the importance of a hydrogen bond between Thr-238 and the substrate as well as limited cofactor discrimination

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments

A hospital based retrospective study of thyroid disorders on obstetric and perinatal outcomes

Background: The study was undertaken in pregnant women to understand and analyze the obstetric and foetal outcomes of thyroid disorders.Methods: TSH estimation was used as universal screening in their first visit to our hospital. Those patients with abnormal TSH values, i.e. above 2.5 mIU/ml in first trimester and above 3 mIU/ml in second and third trimesters were evaluated for free T3, free T4 and TPO Abs. They were treated accordingly and dosage adjustments made and the tests repeated once in 4-6 weeks. They were followed throughout pregnancy and delivery.Results: Total no of pregnant women screened were 904 over a period of 1 year from 15 March 2019 to 14 March 2020, of which 115 had abnormal thyroid functions, thereby the prevalence of thyroid disorders being 12.72%. Of the 115 patients with thyroid disorders, 112 were hypothyroid and 3 were hyperthyroid. Among the 112 hypothyroid cases, 48 were known cases and 64 were new cases. The total cases of subclinical hypothyroidism were 88, prevalence being 9.73% and overt cases were 24, prevalence being 2.65%; 3 cases were overt hyperthyroid, prevalence being 0.33%. 66% of subclinical hypothyroidism were TPO positive and 34% of overt hypothyroidism were TPO positive (p<0.05). Out of 115 abnormal thyroid function patients, 92 patients delivered in our hospital. There were 15 abortions, 13 spontaneous and 2 terminations of pregnancies; 7 patients have delivered outside and 1 patient lost follow up.Conclusions: The prevalence of thyroid disorders during pregnancy was significantly more in our study, hypothyroidism being the commonest. Significant numbers of cases were newly diagnosed on universal screening. The commonest disorder was subclinical hypothyroidism. Adverse maternal and foetal outcomes were almost similar in both subclinical and overt hypothyroidism. The common adverse outcomes noted were abortions, pre-eclampsia, gestational diabetes mellitus, preterm births and increased rates of caesarean sections. The adverse outcomes were significantly more in autoimmune antibody positive patients

Cautionary Tale of Using Tris(alkyl)phosphine Reducing Agents with NAD+-Dependent Enzymes

Protein biochemistry protocols typically include disulfide bond reducing agents to guard against unwanted thiol oxidation and protein aggregation. Commonly used disulfide bond reducing agents include dithiothreitol, β-mercaptoethanol, glutathione, and the tris(alkyl)phosphine compounds tris(2-carboxyethyl)phosphine (TCEP) and tris(3-hydroxypropyl)phosphine (THPP). While studying the catalytic activity of the NAD(P)H-dependent enzyme Δ1-pyrroline-5-carboxylate reductase, we unexpectedly observed a rapid non-enzymatic chemical reaction between NAD+ and the reducing agents TCEP and THPP. The product of the reaction exhibits a maximum ultraviolet absorbance peak at 334 nm and forms with an apparent association rate constant of 231–491 M−1 s−1. The reaction is reversible, and nuclear magnetic resonance characterization (1H, 13C, and 31P) of the product revealed a covalent adduct between the phosphorus of the tris(alkyl)phosphine reducing agent and the C4 atom of the nicotinamide ring of NAD+. We also report a 1.45 Å resolution crystal structure of short-chain dehydrogenase/reductase with the NADP+–TCEP reaction product bound in the cofactor binding site, which shows that the adduct can potentially inhibit enzymes. These findings serve to caution researchers when using TCEP or THPP in experimental protocols with NAD(P)+. Because NAD(P)+-dependent oxidoreductases are widespread in nature, our results may be broadly relevant

Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling

Background: Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. Methods: A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. Results: PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. Conclusions: PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer

Arteriojejunal Fistula Presenting with Recurrent Obscure GI Hemorrhage in a Patient with a Failed Pancreas Allograft

We present a case of a patient with a failed pancreaticoduodenal allograft with exocrine enteric-drainage who developed catastrophic gastrointestinal (GI) hemorrhage. Over the course of a week, she presented with recurrent GI bleeds of obscure etiology. Multiple esophago-gastro-duodenoscopic (EGD) and colonoscopic evaluations failed to reveal the source of the hemorrhage. A capsule endoscopy and a technetium-labeled red blood cells (RBC) imaging study were similarly unrevealing for source of bleeding. She subsequently developed hemorrhagic shock requiring emergent superior mesenteric arteriography. Run off images revealed an external iliac artery aneurysm with fistulization into the jejunum. Coiled embolization was attempted but abandoned because of hemodynamic instability. Deployment of a covered endovascular stent into the right external iliac artery over the fistula site resulted in immediate hemodynamic stabilization. A high index of suspicion for arterioenteric fistulae is needed for diagnosis of this uncommon but eminently treatable form of GI hemorrhage in this patient population

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts