Female circumcision (female genital mutilation): a problem for brachytherapy in cervical cancer

Female circumcision is a traditional practice common in African countries. It involves partial or total removal of external female genitalia. It has led to many complications, in particular, the scarring of the external genitalia. The consequence is a very narrow introitus making the intracavitary brachytherapy treatment component difficult when these women develop cancer of cervix. We present two such cases from our institution. Our aim is to make the radiation and gynecological oncologists, both in developed and developing countries, aware of this practice and the problems they can encounter in the management of such cases. Intracavitary brachytherapy is an important component in the potentially curative role of radiation therapy for cervical cancer. Every effort should be made to ensure that the sequelae of genital mutilation does not deprive these women of the same standard of care as the general population.     

The effect of divalent cations on neuronal nitric oxide synthase activity.

Neuronal nitric oxide synthase (NOS I) is a Ca(2+)/calmodulin-binding enzyme that generates nitric oxide (NO*) and L-citrulline from the oxidation of L-arginine, and superoxide (O(2)*(-)) from the one-electron reduction of oxygen (O(2)). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca(2+), which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca(2+) binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca(2+), we demonstrate that Ni(2+), Ba(2+), and Mn(2+) can activate NOS I to metabolize L-arginine to L-citrulline and NO*, and afford O(2)*(-) in the absence of L-arginine. In contrast, Cd(2+) did not activate NOS I to produce either NO* or O(2)*(-), and the combination of Ca(2+) and either Cd(2+), Ni(2+), or Mn(2+) inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO*, O(2)*(-) and products derived from these free radicals.     

QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis

The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site—the FCS, loop length, and glycosylation—are required for efficient SARS-CoV-2 replication and pathogenesis.

SARS-CoV-2 emerged in late 2019 and has caused the largest pandemic since the 1918 influenza outbreak (1). An unusual feature of SARS-CoV-2 is the presence of a furin cleavage site (FCS) in its spike protein (2). The CoV spike is a trimer of spike proteins composed of the S1 and S2 subunits, responsible for receptor binding and membrane fusion, respectively (1). After receptor binding, the spike protein is proteolytically cleaved at the S1/S2 and S2′ sites to activate the fusion machinery. For SARS-CoV-2, the spike protein contains a novel cleavage motif recognized by the host cell furin protease (PRRAR) directly upstream of the S1/S2 cleavage site that facilitates cleavage prior to virion release from the producer cell. This FCS, not found in other group 2B CoVs, plays a key role in spike processing, infectivity, and pathogenesis as shown by our group and others (3, 4).Importantly, another novel amino acid motif, QTQTN, is found directly upstream of the FCS. This QTQTN motif, also absent in other group 2B CoVs, is often deleted and has been pervasive in cultured virus stocks of the alpha, beta, and delta variants (5–8). In addition, the QTQTN deletion has been observed in a small subset of patient samples as well (9–11). Because this deletion has been frequently identified, we set out to characterize it and determine whether it has consequences for viral replication and virulence. Using our infectious clone (12, 13), we demonstrated that the loss of this motif attenuates SARS-CoV-2 replication in respiratory cells in vitro and pathogenesis in hamsters. The QTQTN deletion results in reduced spike cleavage and diminished capacity to use serine proteases on the cell surface for entry. Importantly, mutations of glycosylation-enabling residues in the QTQTN motif results in similar replication attenuation despite intact spike processing. Together, our results highlight elements in the SARS-CoV-2 spike in addition to the FCS that contribute to increased replication and pathogenesis.     

Timely follow‐up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium

Timely follow‐up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow‐up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer‐specific recommendations for times to follow‐up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow‐up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow‐up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low‐resource settings. CA Cancer J Clin 2018;68:199–216 . © 2018 American Cancer Society .     

Mental health consequences of intimate partner abuse: a multidimensional assessment of four different forms of abuse

Battered women are exposed to multiple forms of intimate partner abuse. This article explores the independent contributions of physical violence, sexual coercion, psychological abuse, and stalking on symptoms of posttraumatic stress disorder (PTSD) and depression among a sample of 413 severely battered, help-seeking women. The authors test the unique effects of psychological abuse and stalking on mental health outcomes, after controlling for physical violence, injuries, and sexual coercion. Mean scores for the sample fall into the moderate to severe range for PTSD and within the moderate category for depression scores. Hierarchical regressions test the unique effects of stalking and psychological abuse, after controlling for physical violence, injuries, and sexual coercion. Psychological abuse and stalking contribute uniquely to the prediction of PTSD and depression symptoms, even after controlling for the effects of physical violence, injuries, and sexual coercion. Results highlight the importance of examining multiple dimensions of intimate partner abuse.     

An assessment of water quality,physical habitat,and biological integrity of an urban stream in Wichita,Kansas, prior to restoration improvements (phase I)

Urban development alters the natural hydrological conditions of many streams and rivers often resulting in the degradation of water quality, physical habitat, and biotic integrity of lotic systems. Restoration projects attempt to improve and maintain the ecological integrity of urban streams; however, few projects have quantified improvements to stream ecology following implementation of restoration measures. This paper summarizes pre-restoration data collected as part of an urban stream restoration project on Gypsum Creek in Wichita, Kansas. Water quality monitoring revealed eutrophic conditions in the stream and the presence of pesticides. Channelization has led to changes in physical habitat including bank erosion, sedimentation, loss of substrate and channel diversity, elimination of in-stream aquatic habitat, removal of riparian vegetation, and decreased base flows. Benthic macroinvertebrate communities appear degraded with more than 90% of individuals collected described as tolerant to anthropogenic stressors. Fish communities were assessed with an Index of Biotic Integrity and were rated as poor to fair, with trophic structure dominated by generalists, no sensitive species present, and one-third of the species collected considered non-native. Overall, the data collected strongly suggest that site-specific restoration measures need to be implemented in order to improve and maintain the ecological condition of Gypsum Creek. Recommendations for improvements have been made to city managers, with implementation beginning in spring 2003 (dependent upon funding availability). Received: 28 March 2002/Accepted: 24 July 2002     

The relative utilization of eicosapentaenoic and arachidonic acids by the 1-acylgycerophosphorylcholine and the 1-acylglycerophosphorylinositol acyltransferase pathways in human platelet microsomes

The relative entry of eicosapentaenoic acid (EPA) and arachidonic acid (AA) via 1-acylglycerophosphorylcholine and 1-acylglycerophosphorylinositol acyltransferase activity into phosphatidylcholine (PC) and phosphatidylinositol (PI), respectively, was studied in human platelets. A known mixture of [¹⁴C]EPA and [³H]AA along with an acyl-CoA generating system and lyso-acceptor phospholipids were incubated with a platelet mixed membrane preparation. The radioactivities in the products were determined following lipid extraction and thin-layer chromatographic separations. The [³H]AA/[¹⁴C]EPA ratios in the products, PC and PI, indicated some preference of both acyltransferase pathways for EPA over AA at 50 μM exogenously-added lysoPC or lysoPI. Altering the concentration of lysoPC (10–50 μM) did not significantly affect the selectivity for EPA. In contrast, reducing the concentration of lysoPI from 50 μM to 10 μM changed the selectivity of the acyltransferase pathway from favouring EPA to slightly favouring AA. The presence of a mixture of lysoPC and lysoPI resulted in a partitioning of EPA more towards PC and less towards PI which may account, in some part, for the greater AA/EPA mass ratio observed in the PI from human subjects consuming fish oil. The magnitude of the differences between PC and PI in their AA/EPA mass ratios observed in vivo, however, cannot be explained by the selectivity demonstrated herein by the acyltransferase pathways.     

An internal fixator for posterior application to short segments of the thoracic, lumbar, or lumbosacral spine. Design and testing

A new spinal implant has been designed and biomechanical testing completed, intended for application to "short-segment" spinal defects such as disc degeneration, fracture, spondylolisthesis, or tumor. Major improvements over currently available devices include: only 2-3 vertebrae are spanned, not 5-7 as with Harrington rods; true three-dimensional fixation is achieved, preventing such problems as hook or rod dislocation; three-dimensional adjustment is easily accomplished, allowing fracture or spondylolisthesis reduction to be readily performed; attachment to vertebrae is by means of transpedicular screws eliminating deliberate encroachment into the spinal canal, such as Luque wires or Harrington hooks; no special alignment between screws is needed (such as with holes or slots in a plate), allowing screw placement to fully conform to anatomic structures; and laminectomy sites and lumbosacral junction are readily instrumented. Background investigations presented here for design of this device include: CT-defined pedicle morphometry showing that screws may be larger than those currently used; effect of pitch, minor diameter, and tooth profile on screw pull-out strength; mechanical testing of a compact, three-dimensionally adjustable, strong, nonloosening articulating clamp; and establishing of the relationship between depth of penetration and strength of fixation of transpeduncular screws.