Three families of CD4-induced antibodies are associated with the capacity of plasma from people living with HIV to mediate ADCC in presence of CD4-mimetics.

CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses normally samples a "closed" conformation which occludes epitopes recognized by CD4-induced (CD4i) non-neutralizing antibodies (nnAbs). CD4mcs induce conformational changes on Env resulting in the exposure of these otherwise inaccessible epitopes. Here we evaluated the capacity of plasma from a cohort of 50 people living with HIV to recognize HIV-1-infected cells and eliminate them by antibody-dependent cellular cytotoxicity (ADCC) in the presence of a potent indoline CD4mc. We observed a marked heterogeneity among plasma samples. By measuring the levels of different families of CD4i Abs, we found that the levels of anti-cluster A, anti-coreceptor binding site and anti-gp41 cluster I antibodies are responsible for plasma-mediated ADCC in presence of CD4mc.

The relationship of couples' time perspective to pregnant women's depression symptoms and stress: Preliminary results.

OBJECTIVE: The aim of the study was to examine the relationship of a couple's time perspective to a woman's depression symptoms and stress. METHOD: The participants were 48 pregnant women and 46 male partners of these women. The measurements have been taken during the first and third trimester. Women were examined by gynecologists during gynecological visits. During these visits measurements of gynecological pregnancy evaluation were administered. Then women completed online questionnaires: the Zimbardo Time Perspective Inventory Past Negative scale, the Dark Future Scale, the Edinburgh Postpartum Depression Scale and the Perceived Stress Scale at home. Men completed online questionnaires: the Zimbardo Time Perspective Inventory Past Negative scale, and the Dark Future Scale at home. RESULTS: The results showed that women's past negative perspective in the first trimester was related to depression symptoms and stress in the first trimester. In the third trimester, women's future negative perspective was related to depression symptoms. Men's future negative perspective in the first trimester was related to women's stress in the first trimester. Moreover, the results suggest that the level of the woman's future negative perspective significantly increases during pregnancy. CONCLUSIONS: Attitudes towards time of both the pregnant woman and her partner are related to the emotional state of the woman during pregnancy.

Case report: treatment of a lower leg defect in the course of sarcoma with microvascular tissue.

INTRODUCTION: During normal wound healing, angiogenesis leads to re-establishment of a functioning microcirculation to deliver oxygen and nutrients required for clinically effective tissue repair. In refractory wounds, however, this process can be severely compromised due to insufficient vascularity and resulting senescent microenvironment. CASE REPORT: This case report follows a patient undergoing aggressive chemotherapy and neoadjuvant radiotherapy who presented with a complicated 25 cm2 left leg wound and exposed tibial bone after failed skin grafting and advanced biologic treatment. PMVT, a structural microvascular tissue allograft, was selected to improve microvascular blood flow around this poorly vascularized and senescent irradiated environment. The initial clinical objective was to stabilize the wound during continued chemotherapy and bridge the time until tissue flap surgery. Despite ongoing treatment for sarcoma, 22 weeks after initial PMVT treatment, the wound had fully closed with thick epidermis covering the residual granulating part of the wound site. CONCLUSION: Achieving wound healing with weekly PMVT treatment in this immunocompromised patient undergoing active chemotherapy, thus increasing quality of life without flap surgery, was unexpected. The use of PMVT to repair and reconstruct deficient microvascular tissue appeared to change the trajectory of healing and enhance the wound healing process.

The incidence of adult type hypolactasia in patients with irritable bowel syndrome.

Introduction: The incidence of lactose intolerance in irritable bowel syndrome (IBS) varies in the literature (27-72%). Primary adult lactase deficiency (adult type hypolactasia) is the most common type of primary enzyme deficiency. Complaints related to lactose intolerance may overlap with the symptoms of IBS. Aim: To assess the prevalence of primary hypolactasia in patients with IBS. Material and methods: The study included 56 patients with IBS diagnosed based on the Rome III criteria and 23 healthy people. All study participants completed a questionnaire on IBS symptoms and lactose intolerance, and they underwent a hydrogen breath test (HBT) with lactose. In the group of patients with positive results of HBT, the polymorphism C/T -13910 and G/A -22018 in the promoter of the LCT gene encoding lactase was determined. Results: Lactase deficiency was diagnosed in HBT in 34 (60.7%) patients with IBS and in the control group - in 10 (43.5%). Primary adult type hypolactasia was confirmed in 78.9% (n = 30; 79.3% in the study group; 77.8% in the control group). There were no statistically significant differences in the occurrence of LCT gene polymorphisms in particular IBS subtypes. Adult type hypolactasia was significantly more common in patients with severe than moderate and mild enzyme deficiency in HBT (p < 0.05). Conclusions: The incidence of lactase deficiency in IBS patients is not different from that found in healthy subjects. Nevertheless, irrespective of the IBS subtype, lactose intolerance may pose additional issues in patients with IBS and requires the targeted treatment.

Non-Healing Perianal Fistulas: A Clinical Model of Tissue Senescence Impairing Both Tissue Fibrosis and Regenerative Potential.

Senescent cells and fibrosis are important components that impact the regenerative capacity of skin, particularly when considering chronic non-healing wounds. Anoderm and perianal fistulas in the setting of Crohn's disease are clinically pathophysiological extremes with consequently different healing processes which impact treatment modalities. This study describes the implications of potential senescence reversing techniques including autologous fat grafting and pharmacologic and immunomodulating agents. Given these findings, the authors propose a future direction of study involving exosomes loaded with senolytics as a method for potentially improving chronic wound healing. In conclusion, this manuscript explores the diversity of skin healing and healing outcomes which supports the future investigation of senotherapeutic agents promoting regenerative processes for non-healing wounds.

LIPID transfer proteins regulate store-operated calcium entry via control of plasma membrane phosphoinositides.

The ER-resident proteins STIM1 together with the plasma membrane (PM)-localized Orai1 channels constitute the molecular components of the store-operated Ca2+ entry (SOCE) pathway. Prepositioning of STIM1 to the peripheral ER close to the PM ensures its efficient interaction with Orai1 upon a decrease in the ER luminal Ca2+ concentration. The C-terminal polybasic domain of STIM1 has been identified as mediating the interaction with PM phosphoinositides and hence positions the molecule to ER-PM contact sites. Here we show that STIM1 requires PM phosphatidylinositol 4-phosphate (PI4P) for efficient PM interaction. Accordingly, oxysterol binding protein related proteins (ORPs) that work at ER-PM junctions and consume PI4P gradients exert important control over the Ca2+ entry process. These studies reveal an important connection between non-vesicular lipid transport at ER-PM contact sites and regulation of ER Ca2+store refilling.

Osteogenesis Modulation: Induction of Mandibular Bone Growth in Adults by Electrical Field for Aesthetic Purposes.

BACKGROUND: A new technique in plastic surgery termed Osteogenesis Modulation is described. This technique uses a surgically implanted, battery-operated medical device to deliver customized electrical pulses to produce mandibular bone growth. This device was designed to be a temporary, nonpermanent implant. The purpose of this study was to review both the safety and efficacy of Osteogenesis Modulation. METHODS: This study comprises two phases. Phase I involved experimental technology development and animal experiments. Phase II included technology development for clinical use and a clinical trial. In Phase II, four patients with a diagnosis of mandibular hypoplasia and microgenia underwent surgical implantation of the novel medical device over the chin bone. Once a satisfactory change of contour of mandibular bone was achieved, the devices were removed. In all patients, the devices were left in place for 12 months, then surgically removed under local anesthesia. Preoperative and long-term postoperative cephalometric controls were done. RESULTS: In all patients, symmetrical mandibular bone growth was observed with good-to-excellent aesthetic results. The overall follow-up period was 39 months. Cephalometric controls taken 3 to 6 months after the device removal showed an average increase in mandible length of 5.26mm (range, 2.83-7.60mm) CONCLUSIONS: Preliminary clinical results suggest that Osteogenesis Modulation is a safe, minimally invasive, and effective alternative treatment for the correction of mandibular hypoplasia in selected cases. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Marie and Irène Curie, two brilliant women who pioneered the development of nuclear chemistry, radiotherapy, and radiobiology.

OBJECTIVE: To describe the contributions of Marie Sklodowska-Curie and her daughter Irene Curie to radiation science and how these studies in physics, chemistry and medicine led to the need to study radiobiological effects. CONCLUSIONS: The seminal discoveries of Maria Sklodowska-Curie in radiation physics and chemistry provided the basis for later investigations of the effects of ionizing radiation on cells and tissues and the role of radioactivity in mutagenesis and carcinogenesis. Both Maria and Irene contributed to the development of radiotherapy and the use of x-rays and radioisotopes in medical diagnosis. Their legacy is not confined to their own generation but can be traced through grand- and great-grand-students of these pioneering women.

The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer.

The high mortality rate for pancreatic cancer (PC) is due to the lack of specific symptoms at early tumor stages and a high biological aggressiveness. Reliable biomarkers and new therapeutic targets would help to improve outlook in PC. In this study, we analyzed the expression of GNMT in a panel of pancreatic cancer cell lines and in early-stage paired patient tissue samples (normal and diseased) by quantitative reverse transcription-PCR (qRT-PCR). We also investigated the effect of 1,2,3,4,6-penta-O-galloyl-ß-d-glucopyranoside (PGG) as a therapeutic agent for PC. We find that GNMT is markedly downregulated (p < 0.05), in a majority of PC cell lines. Similar results are observed in early-stage patient tissue samples, where GNMT expression can be reduced by a 100-fold or more. We also show that PGG is a strong inhibitor of PC cell proliferation, with an IC50 value of 12 ng/mL, and PGG upregulates GNMT expression in a dose-dependent manner. In conclusion, our data show that GNMT has promise as a biomarker and as a therapeutic target for PC.

A derivative of vitamin B3 applied several days after exposure reduces lethality of severely irradiated mice.

Most, if not all, of the hitherto tested substances exert more or less pronounced pro-survival effects when applied before or immediately after the exposure to high doses of ionizing radiation. In the present study we demonstrate for the first time that 1-methyl nicotinamide (MNA), a derivative of vitamin B3, significantly (1.6 to 1.9 times) prolonged survival of BALB/c mice irradiated at LD30/30 (6.5 Gy), LD50/30 (7.0 Gy) or LD80/30 (7.5 Gy) of γ-rays when the MNA administration started as late as 7 days post irradiation. A slightly less efficient and only after the highest dose (7.5 Gy) of γ-rays was another vitamin B3 derivative, 1-methyl-3-acetylpyridine (1,3-MAP) (1.4-fold prolonged survival). These pro-survival effects did not seem to be mediated by stimulation of haematopoiesis, but might be related to anti-inflammatory and/or anti-thrombotic properties of the vitamin B3 derivatives. Our results show that MNA may represent a prototype of a radioremedial agent capable of mitigating the severity and/or progression of radiation-induced injuries when applied several hours or days after exposure to high doses of ionizing radiation.

Time to rejuvenate ultra-low dose whole-body radiotherapy of cancer.

The results of clinical trials performed from the 1930s until the end of the 20th century in which total-body ultra-low level ionizing radiation (TB-LLR) was used demonstrate that this form of treatment can be equal or superior to other systemic anti-neoplastic modalities in terms of the rates of remissions, toxicity, and side effects. In this review, we provide the rationale for TB-LLR and analyze the results of reliable clinical trials in patients with predominantly lymphoproliferative disorders but also advanced solid cancers. The doses used in these trials did not exceed 0.1-0.2 Gy per fraction and cumulative totals ranged from 1 to 4 Gy. Based on the reviewed results we conclude that it is appropriate to revive interest in and resume clinical investigations of TB-LLR in order to refine and improve the effectiveness of such treatment, whether employed alone or in combination with other anticancer strategies.

Metabolic fingerprinting of the Antarctic cyanolichen Leptogium puberulum-associated bacterial community (Western Shore of Admiralty Bay, King George Island, Maritime Antarctica).

Lichens are presently regarded as stable biotopes, small ecosystems providing a safe haven for the development of a diverse and numerous microbiome. In this study, we conducted a functional diversity assessment of the microbial community residing on the surface and within the thalli of Leptogium puberulum, a eurytopic cyanolichen endemic to Antarctica, employing the widely used Biolog EcoPlates which test the catabolism of 31 carbon compounds in a colorimetric respiration assay. Lichen thalli occupying moraine ridges of differing age within a proglacial chronosequence, as well as those growing in sites of contrasting nutrient concentrations, were procured from the diverse landscape of the western shore of Admiralty Bay in Maritime Antarctica. The L. puberulum bacterial community catabolized photobiont- (glucose-containing carbohydrates) and mycobiont-specific carbon compounds (D-Mannitol). The bacteria also had the ability to process degradation products of lichen thalli components (D-cellobiose and N-acetyl-D-glucosamine). Lichen thalli growth site characteristics had an impact on metabolic diversity and respiration intensity of the bacterial communities. While high nutrient contents in lichen specimens from "young" proglacial locations and in those from nitrogen enriched sites stimulated bacterial catabolic activity, in old proglacial locations and in nutrient-lacking sites, a metabolic activity restriction was apparent, presumably due to lichen-specific microbial control mechanisms.

Endovascular treatment of chronic aortic dissection with fenestrated and branched stent grafts.

OBJECTIVE: Chronic aortic dissection with aneurysm development that includes the aortic arch and/or thoracoabdominal aorta (TAAA) is traditionally treated with open or hybrid surgery. Total endovascular treatment with fenestrated and branched aortic repair (F/B-EVAR) has recently been introduced as a less invasive alternative. The aim was to report the short- and midterm outcomes from a single tertiary vascular center. METHODS: All patients with chronic aortic dissection treated with F/B-EVAR from 2010 to 2019 at Uppsala University Hospital were identified. Perioperative and postoperative parameters were analyzed, with focus on short- (<30 days) and midterm survival, complication, and reintervention rates. RESULTS: F/B-EVAR was performed on 26 patients (median age, 63 years; range, 33-87 years; 18 men; median aortic diameter, 70 mm; range, 50-98 mm); with a median follow-up of 23 months (range, 0.5-118.0 months). One patient underwent both arch and TAAA repair. Overall, 13 arch repairs (arch group) after type A (n = 8) and type B (n = 5) dissection (all elective) were performed, and 14 TAAA repairs (TAAA group) after type A (n = 5) and type B (n = 9) dissection (one rupture). A total of 72 aortic branches were targeted (22 arch, 50 TAAA). Short-term technical success was achieved in 24 of 27 procedures (89%). Failures were related to one intraoperative retrograde type A dissection (RTAD) requiring open conversion (arch group), one persistent type IC endoleak on completion angiography (arch group), and one persistent type III endoleak (TAAA group). Mortality was 4% (n = 1) at 30 days and related to a second RTAD that occurred after discharge and was found on autopsy. Both RTADs occurred in patients with chronic type B dissection undergoing fenestrated arch repair. Paraplegia occurred in three cases (two arch, one TAAA) (11%), none permanent, and stroke in three cases (one arch, one TAAA) (11%); one was permanent. In the midterm, endoleaks were detected in 12 patients (44%); persistent false lumen flow (n = 3), type IB (n = 1), type IC (n = 3), type II (n = 7), and type IIIC (n = 2). The 3-year survival (Kaplan-Meier) of the arch repair was 75% and for the TAAA, 93%. Freedom from reintervention at 3 years were 100% for arch repairs and 48% for TAAA. In patients with a follow-up of more than 6 months (n = 23), all had stable or decreased aortic diameters and complete false lumen thrombosis at the level of stent graft was present in 65% (n = 15). CONCLUSIONS: Endovascular treatment of postdissection aneurysms is feasible, with acceptable short-term and midterm outcomes. RTAD after fenestrated and branched endovascular arch repair warrants caution when performed on patients with native ascending aortas, and reinterventions are frequent in TAAA repair.

Subclinical Infection of the Silicone Breast Implant Surface as a Possible Cause of Capsular Contracture.

In order to reexamine the possible association between bacterial presence and capsular contracture, 55 silicone devices (mammary implants or tissue expanders) were cultured at the time of their removal from 40 patients. Special culture techniques were used in an attempt to recover bacteria adhering to the smooth-surfaced implant and encased in glycocalyx biofilm. Bacteria were detected on 56% (15 of 27) of implants surrounded by contracted capsules and on 18% (5 of 28) of those without capsular contracture (p < 0.05). Only three implants tested positive using routine plating techniques. The predominant isolate was Staphylococcus epidermidis. The concept that capsular contracture is associated with subclinical infection of silicone implants is supported by this study. With changes in the microbiological technique, bacterial recovery and growth occurs at a frequency greater than previously thought.

Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a key receptor in the angiogenesis process. The VEGFR2 expression is upregulated in many cancers so this receptor is an important target for anticancer agents. In the present paper, we analyse interactions of several dimeric indazoles, previously investigated for anticancer activity, with the amino acids present in the VEGFR2 binding pocket. Using the docking method and MD simulations as well as theoretical computations (SAPT0, PIEDA, semi-empirical PM7), we confirmed that these azoles can efficiently bind into the kinase pocket and their poses can be stabilised by the formation of hydrogen bonds, π-π stacking, π-cation, and hybrid interactions with some amino acids of the kinase cavity like Ala866, Lys868, Glu885, Thr916, Glu917, and Phe918.

Polish adaptation and validation of the hip disability and osteoarthritis outcome score (HOOS) in osteoarthritis patients undergoing total hip replacement.

BACKGROUND: The Hip disability and Osteoarthritis Outcome Score (HOOS) is a frequently used patient-reported outcome measure (PROM) for assessment of hip disorders and treatment effects following hip surgery. The objective of the study was to translate and adapt the Hip disability and Osteoarthritis Outcome Score (HOOS) into Polish and to investigate the psychometric properties of the HOOS in patients with osteoarthritis undergoing total hip replacement (THR). MATERIALS AND METHODS: The Polish version of the HOOS was developed according to current guidelines. Patients completed the HOOS, Short Form 36 Health Survey (SF-36), the visual analogue scale (VAS) for pain and the global perceived effect (GPE) scale. Psychometric properties including interpretability (floor/ceiling effects), internal consistency (Cronbach's alpha), test-retest reliability (intra-class correlation coefficient, ICC), convergent construct validity (a priori hypothesized Spearman's correlations between the HOOS subscales, the generic SF-36 measure and the VAS for pain) and responsiveness (effect size, association between the HOOS and GPE scores) were analyzed. RESULTS: The study included 157 patients (mean age 66.8 years, 54% women). Floor effects were found prior to THR for the HOOS subscales Sports and Recreation and Quality of Life. The Cronbach's alpha was over 0.7 for all subscales indicating satisfactory internal consistency. The test-retest reliability was good for the HOOS subscale Pain (0.82) and excellent for all other subscales with ICCs ranging from 0.91 to 0.96. The minimal detectable change ranged from 12.0 to 26.2 on an individual level and from 1.4 to 3.0 on a group level. Seven out of eight a priori hypotheses were confirmed indicating good construct validity. Responsiveness was high since the expected pattern of effect sizes in all subscales was found. CONCLUSIONS: The Polish version of the HOOS demonstrated good reliability, validity and responsiveness for use in patient groups having THR.

Selected arylsulphonyl pyrazole derivatives as potential Chk1 kinase ligands-computational investigations.

Protein kinases control diversity of biochemical processes in human organism. Checkpoint 1 kinase (Chk1) is an important element of the checkpoint signalling pathways and is responsible for DNA damage repair. Hence, this kinase plays an essential role in cancer cells survival and has become an important target for anticancer agents. Our previous investigations showed that some arylsulphonyl indazole derivatives displayed anticancer effect in vitro. In the present study, in order to verify possibility of interactions of pyrazole and indazole derivatives with Chk1, we focused on the docking of selected tosyl derivatives of indazole and condensed pyrazole 1-7 to the Chk1 pocket, analysis of interactions involving optimized ligand-protein system using DFT formalism, and estimation of the interaction enthalpy of the ligand-protein complex by applying the PM7 method. The estimation of binding affinity seems to indicate that the indazole 5-substituted with 3,5-dimethylpyrazole 4 and condensed pyrazoloquinoline derivative 7 fit the best to the Chk1-binding pocket. The values of the energy of interaction, i.e. the enthalpy change (ΔHint), were between - 85.06 and - 124.04 kcal mol-1 for the optimized ligand-Chk1 complexes. The relaxation of the ligands within the complexes azole-protein as well as the distribution of hydrogen contacts between the ligands and kinase pocket amino acids was also analysed using molecular dynamics as a supporting method. Graphical Abstract Presentation of methods used to describe the interactions between arylsulphonyl pyrazole derivatives and Chk1 kinase.

Bringing Radiation Exposures and Associated Health Risks into Perspective-Development of an App.

The NATO HFM 291 research task group (RTG) on "Ionizing Radiation Bioeffects and Countermeasures" represents a group of scientists from military and civilian academic and scientific institutions primarily working in the field of radiobiology. Among other tasks, the RTG intends to extend their work on risk estimation and communication to bridge the gap in appropriate judgment of health risks given a certain radiation exposure. The group has no explicit psychological background but an expertise in radiobiology and risk assessment. The group believes that, as one of the essential first steps in risk communication, it is required to put radiation risk into perspective. Radiation risk requires a weight in comparison to already-known risks. What we envision is to Compare Radiation exposure-associated health Risks (CRRis App) with daily life health risks caused by other common exposures such as cigarette smoking, driving a car, etc. Within this paper, we provide (1) an overview of health risks after radiation exposure, (2) an explanation of the task and concept of an envisioned CRRis App, (3) an overview of existing software tools related to this issue, (4) a summary of inputs and discussions with experts in the field of radiation protection and risk communication during the ConRad conference, and finally, (5) identification of the next steps in the development of the App.

Erector spinae plane versus paravertebral nerve blocks for postoperative analgesia after breast surgery: a randomized clinical trial.

BACKGROUND: Paravertebral nerve blocks (PVBs) are frequently used to treat pain during and following breast surgery, but have various undesirable risks such as pneumothorax. The erector spinae plane block (ESPB) also provides perioperative breast analgesia, but is purported to be easier to administer with a favorable safety profile. However, it remains unknown if the new ESPB provides comparable analgesia as the decades-old PVB technique. METHODS: Subjects undergoing unilateral or bilateral non-mastectomy breast surgery were randomized to a single-injection ESPB or PVB in a subject-blinded fashion (ropivacaine 0.5% with epinephrine; 20 mL unilateral or 16 mL/side for bilateral). We hypothesized that (1) analgesia would be non-inferior in the recovery room as measured on a Numeric Rating Scale (NRS) with ESPB, and (2) opioid consumption would be non-inferior in the operating and recovery rooms with ESPB. RESULTS: Both pain scores and opioid consumption were higher in subjects with ESPBs (n=50) than PVBs (n=50; median NRS 3.0 vs 0; 95% CI -3.0 to 0; p=0.0011; and median morphine equivalents 2.0 vs 1.5 mg; 95% CI -1.2 to -0.1; p=0.0043). No block-related adverse events occurred in either group. CONCLUSIONS: PVBs provided superior analgesia and reduced opioid requirements following non-mastectomy breast surgery. To compare the relatively rare complications between the techniques will require a sample size 1-2 orders of magnitude greater than the current investigation; however, without a dramatic improvement in safety profile for ESPBs, it appears that PVBs are superior to ESPBs for postoperative analgesia after non-mastectomy breast surgery. TRIAL REGISTRATION NUMBER: NCT03549234.