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Introduction: Lower uterine segment scarring after cesarean section can decrease intraoperative bleeding during subsequent surgery. We examined whether first elective cesarean section is associated with greater average blood loss compared to repeated surgery., Methods: Decrease in maternal hemoglobin and hematocrit after surgery was retrospectively compared between three study groups, women in their first, second and third or more cesarean section. Surgery length and need for blood transfusion were also compared., Results: Out of 9401 cases reviewed between January 2010 November 2020, 3917 had a first cesarean section, 3159 s cesarean section and 2325 had a third or more cesarean section. Hemoglobin and hematocrit drops were highest after first cesarean section (1.1 vs 1.0 vs 1.0 mg/dL, P < 0.001 and 3.3 vs 3.0, vs 2.9%, P < 0.001, respectively). Surgery length was significantly longer and more patients after third cesarean section required blood transfusions (2.5% vs 1.4% vs. 0.8%, P < 0.001). First cesarean section, younger age and BMI >35 were associated with increased hemoglobin drop in univariate and multivariate analysis., Conclusions: Although repeated cesarean section is associated with longer surgery and higher need for blood transfusion, average hemoglobin drop after first cesarean section is higher. Scarring of the lower uterine segment can explain this paradoxical finding., (© 2022 International Federation of Gynecology and Obstetrics.)

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

Background: Lag phase is a period of time with no growth that occurs when stationary phase bacteria are transferred to a fresh medium. Bacteria in lag phase seem inert: their biomass does not increase. The low number of cells and low metabolic activity make it difficult to study this phase. As a consequence, it has not been studied as thoroughly as other bacterial growth phases. However, lag phase has important implications for bacterial infections and food safety. We asked which, if any, genes are expressed in the lag phase of Escherichia coli, and what is their dynamic expression pattern., Results: We developed an assay based on imaging flow cytometry of fluorescent reporter cells that overcomes the challenges inherent in studying lag phase. We distinguish between lag1 phase- in which there is no biomass growth, and lag2 phase--in which there is biomass growth but no cell division. We find that in lag1 phase, most promoters are not active, except for the enzymes that utilize the specific carbon source in the medium. These genes show promoter activities that increase exponentially with time, despite the fact that the cells do not measurably increase in size. An oxidative stress promoter, katG, is also active. When cells enter lag2 and begin to grow in size, they switch to a full growth program of promoter activity including ribosomal and metabolic genes., Conclusions: The observed exponential increase in enzymes for the specific carbon source followed by an abrupt switch to production of general growth genes is a solution of an optimal control model, known as bang-bang control. The present approach contributes to the understanding of lag phase, the least studied of bacterial growth phases.

Background: Gene regulation networks are made of recurring regulatory patterns, called network motifs. One of the most common network motifs is negative auto-regulation, in which a transcription factor represses its own production. Negative auto-regulation has several potential functions: it can shorten the response time (time to reach halfway to steady-state), stabilize expression against noise, and linearize the gene's input-output response curve. This latter function of negative auto-regulation, which increases the range of input signals over which downstream genes respond, has been studied by theory and synthetic gene circuits. Here we ask whether negative auto-regulation preserves this function also in the context of a natural system, where it is embedded within many additional interactions. To address this, we studied the negative auto-regulation motif in the arabinose utilization system of Escherichia coli, in which negative auto-regulation is part of a complex regulatory network., Results: We find that when negative auto-regulation is disrupted by placing the regulator araC under constitutive expression, the input dynamic range of the arabinose system is reduced by 10-fold. The apparent Hill coefficient of the induction curve changes from about n = 1 with negative auto-regulation, to about n = 2 when it is disrupted. We present a mathematical model that describes how negative auto-regulation can increase input dynamic-range, by coupling the transcription factor protein level to the input signal., Conclusions: Here we demonstrate that the negative auto-regulation motif in the native arabinose system of Escherichia coli increases the range of arabinose signals over which the system can respond. In this way, negative auto-regulation may help to increase the input dynamic-range while maintaining the specificity of cooperative regulatory systems. This function may contribute to explaining the common occurrence of negative auto-regulation in biological systems.

Bacteria regulate the assimilation of multiple nutrients to enable growth. How is balanced utilization achieved, despite fluctuations in the concentrations of the enzymes that make up the regulatory circuitry? Here we address this question by studying the nitrogen system of E. coli. A mechanism based on the avidity of a bifunctional enzyme, adenylyltransferase (AT/AR), to its multimeric substrate, glutamine synthetase, is proposed to maintain a robust ratio between two key metabolites, glutamine and α-ketoglutarate. This ratio is predicted to be insensitive to variations in protein levels of the core circuit and to the rate of nitrogen utilization. We find using mass spectrometry that the metabolite ratio is robust to variations in protein levels and that this robustness depends on the bifunctional enzyme. Moreover, robustness carries through to the bacteria growth rate. Interrupting avidity by adding a monofunctional AT/AR mutant to the native system abolishes robustness, as predicted by the proposed mechanism., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.

Lck encodes a 56-kDa protein-tyrosine kinase, predominantly expressed in T lymphocytes, crucial for initiating T cell antigen receptor (TCR) signal transduction pathways, culminating in T cell cytokine gene expression and effector functions. As a consequence of a high-throughput screen for selective, novel inhibitors of p56(lck), an isothiazolone compound was identified, methyl-3-(N-isothiazolone)-2-thiophenecarboxylate(A-125800), which inhibits p56(lck) kinase activity with IC50 = 1-7 microM. Under similar assay conditions, the isothiazolone compound was equipotent in blocking the ZAP-70 tyrosine kinase activity but was 50 to 100 times less potent against the catalytic activities of p38 MAP kinase and c-Jun N-terminal kinase 2alpha. A-125800 blocked activation-dependent TCR tyrosine phosphorylation and intracellular calcium mobilization in Jurkat T cells (IC50 = 35 microM) and blocked T cell proliferation in response to alloantigen (IC50 = 14 microM) and CD3/CD28-induced IL-2 secretion (IC50 = 2.2 microM) in primary T cell cultures. Inhibition of p56(lck )by A-125800 was dose- and time-dependent and was irreversible. A substitution of methylene for the sulfur atom in the isothiazolone ring of the compound completely abrogated the ability to inhibit p56(lck) kinase activity and TCR-dependent signal transduction. Incubation with thiols such as beta-ME or DTT also blocked the ability of the isothiazolone to inhibit p56(lck) kinase activity. LC/MS analysis established the covalent modification of p56(lck) at cysteine residues 378, 465, and 476. Together these data support an inhibitory mechanism, whereby cysteine -SH groups within the p56(lck) catalytic domain react with the isothiazolone ring, leading to ring opening and disulfide bond formation with the p56(lck) enzyme. Loss of p56(lck) activity due to -SH oxidation has been suggested to play a role in the pathology of AIDS. Consequently, a similar mechanism of sulfhydryl oxidation leading to p56(lck) inhibition, described in this report, may occur in the intact T cell and may underlie certain T cell pathologies., (Copyright 1999 Academic Press.)

A purposive syndromic classification diagnostic system, with known means to ends, has been developed that extracts bits of structural information from endogenous laboratory data. An edifice of structural information for organization, regulation, and decision-making was built for determining future pathophysiological events by asking the fewest questions to define the next event uniquely. The structural information is based on laboratory ordering patterns of physicians for patient populations they serve. Patient history and a physical examination may be included as hardware and software evolves for linking more aspects of the medical record.

Syndromic classifications differ from other taxonomies because they build on an ideal theoretical information standard to amplify information. This ideal standard, a truth table with requisite variety, h, equal to or greater than the generated symbols or system it seeks to control, preserves all of the information about the disease state available in the database. Such a system, interestingly enough, theoretically has no beta errors (diagnostic misses) because all possible alternative disease hypotheses are created by the proper-sized truth table that controls the diagnostic system. Subsequent articles will examine the process in more detail.

An outbreak of an acute respiratory disease in the southwestern United States has led to the recognition of a new hantaviral illness. This report describes a unique spectrum of antemortem and postmortem pathological findings seen in a case series of nine surviving patients and 13 who died. Clinical, laboratory, and autopsy findings were derived from a consecutive series of individuals confirmed to have hantavirus pulmonary syndrome. Laboratory studies included chemical, hematological, and bone marrow analyses as well as flow cytometric and immunohistochemical phenotyping. Autopsy tissues were examined by routine histological stains, immunohistochemical methods, and transmission electron microscopy. The lung is the primary target organ in this illness. Pulmonary abnormalities include pleural effusions, alveolar edema and fibrin, and an interstitial mononuclear cell infiltrate. Large immunoblast type cells are seen in the lungs, blood, bone marrow, lymph nodes, liver, and spleen. A tetrad of hematological findings includes left-shifted neutrophilic leukocytosis, thrombocytopenia, hemoconcentration in severe cases, and circulating immunoblasts. In contrast to previously described nephropathic hantaviral syndromes, hantavirus pulmonary syndrome is characterized by a unique constellation of pulmonary, hematological, and reticuloendothelial pathological findings. The pulmonary findings are distinguishable from fatal adult respiratory distress syndrome. The data suggest a capillary leak syndrome restricted to the pulmonary circulation. Likewise, the hematological picture is unique and may be valuable in the rapid identification of cases for further diagnostic studies.

Background: Dynemicin A is an exceedingly potent antitumor antibiotic derived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH or glutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modify the structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product., Results: A multistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed. The absolute configuration of natural dynemicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation. The route that was developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to non-natural dynemicins of wide structural variability by modifications of these fragments. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH., Conclusions: Enantiomerically pure dynemicin A is now available by laboratory synthesis. The natural, (+)-enantiomer of dynemicin A is shown to possess the 2S, 3S, 4S, 7R, 8R configuration. A wide variety of heretofore unavailable, active analogs of dynemicin A have been prepared and are found to produce subtle variations in sequence specificity of DNA cleavage compared to the natural product and, of potentially greater significance, display variations in the efficiency of DNA cleavage as a function of the activating agent.

During late spring and early summer of 1993, national and international media called worldwide attention to a cluster of deaths in the southwestern United States. These patients succumbed to a rapidly progressive severe respiratory distress syndrome. After notification of state and national health agencies in mid-May, a major effort was launched to determine the cause of this often fatal respiratory distress syndrome, to advise the public on safety measures, and to determine the method of spread of this "mystery illness." Within weeks of recognition of the early cases, the Centers for Disease Control and Prevention announced the probable agent, a Hantavirus. This report details the response of pathologists, medical technologists, and other laboratory scientists to this new viral epidemic, with emphasis on activities that occurred within New Mexico.

The N-terminal decapeptide methyl ester, H-Ala-Asn-Lys-Gly-Phe-Leu-Gla-Gla-Val-Arg-OCH3 (16) of bovine prothrombin fragment 1 has been prepared by standard solution techniques, via a fragment coupling strategy. Hexapeptide Boc-Ala-Asn-Lys epsilon (Boc)-Gly-Phe-Leu-OBzl (9) was obtained by coupling Boc-Ala-Asn-Lys epsilon (Boc)Gly-OH (6) to the trifluoroacetate salt of H-Phe-Leu-OBzl (8). Hydrogenolysis of (9) followed by coupling to HCl. H-Gla gamma (OtBu)2-Gla gamma (OtBu)2-Val-Arg(HCl)-OCH3 (14) gave the fully protected decapeptide (15). Treatment of 15 with 90% trifluoroacetic acid followed by ion exchange chromatography of 15 yielded the methyl ester (16). The decapeptide 16 labeled with 125I using the Bolton-Hunter reagent, did not bind to antibodies specific for the calcium ion-induced conformation of bovine fragment 1.

Changes in the Eu3+ luminescence decay constant observed for Eu3+ bound to prothrombin fragment 1 and the peptide containing residues 1-39 of prothrombin result solely from changes in the number of water molecules in the primary hydration sphere of the ion. Highly coordinated sites which bind Eu3+ in a different manner from simple Gla-containing peptides exist on both the fragment 1 and 1-39 molecules. Metal ions bound at some of these sites do not appear to undergo rapid exchange with metal ions in solution. The binding of other lanthanide ions and calcium ions in the presence of europium ions cause a change in the conformation of the macromolecules, resulting in even tighter coordination of fragment 1 or residues 1-39 to Eu3+. Hydrophilic groups other than the actual Eu3+ binding sites on fragment 1 help to maintain its water solubility when complexes to Eu3+ or Ca2+. Because the 1-39 peptide does not contain as many of these hydrophilic groups, the peptide precipitates upon binding to di- and trivalent cations. Self-association of the 1-39 molecules appears to occur at high peptide concentrations which result in a peptide concentration effect on Eu3+ binding not seen in fragment 1. pH titration yields results which suggest a role for Gla carboxyl groups in Eu3+ complexation to both fragments 1 and 1-39. Although the two molecules are not identical with regard to Eu3+ binding behavior, enough similarities exist that residues 1-39 appear to be a reasonable model of the fragment 1 molecule for the purposes of metal ion complexation studies.

This paper outlines the development and use of a software package developed at the University of New Mexico that allows residents to use a simple menu driven program for record keeping. Selective Procedures, Operative Cases, and Consults (SPOCC) was developed for recording data in individually arranged formats and searching on a number of input parameters. As Residency Review Committees become more stringent in their demand for documentation of activities, this program will give residents the ability to quickly recall any number of selective procedures, consults or operative cases, along with case specific data to enable them to review cases, study results in relation to future follow-up, generate statistics, and stimulate research ideas. SPOCC can be run on any dual floppy or hard disk personal computer that uses MS-DOS or PC-DOS 2.0 or greater. It requires 256 kilobytes of free memory, and a color or monochrome monitor. A printer is optional.