Ceftazidime-Avibactam Combination Therapy Compared to Ceftazidime-Avibactam Monotherapy for the Treatment of Severe Infections Due to Carbapenem-Resistant Pathogens: A Systematic Review and Network Meta-Analysis

Ceftazidime-avibactam (CZA) is a novel beta-lactam beta-lactamase inhibitor combination approved for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and for hospital-acquired/ventilator-associated pneumonia. The aim of this systematic review (PROSPERO registration number: CRD42019128927) was to evaluate the effectiveness of CZA combination therapy versus CZA monotherapy in the treatment of severe infections. The databases included in the search, until February 12th, 2020, were MEDLINE by PubMed, EMBASE, and The Cochrane Central Register of Controlled Trials. We included both randomized controlled trials (RCTs) and non-randomized studies published in peer-reviewed journals and in the English language. The primary outcome was all-cause mortality (longest follow-up) evaluated in patients with the diagnosis of infection with at least one pathogen; secondary outcomes were clinical and microbiological improvement/cure. Thirteen studies were included in the qualitative synthesis: 7 RCTs and 6 retrospective studies All the six retrospective studies identified carbapenamase-producing Enterobacteriaceae (CRE) as the cause of infection and for this reason were included in the network meta-analysis (NMA); the quality of the studies, assessed using the New Castle-Ottawa Scale, was moderate-high. In all the six retrospective studies included in the NMA, CZA was used in large part for off-label indications (mostly blood stream infections: 80-100% of patients included). No difference in mortality rate was observed in patients undergoing CZA combination therapy compared to CZA monotherapy [n = 503 patients, direct evidence OR: 0.96, 95% CI: 0.65-1.41]

A molecular model of the interaction between vitamin D binding protein-derived macrophage activating factor and vitamin D receptor

We previously demonstrated that the response of human monocytes to vitamin D binding protein-derived macrophage activating factor (DBP-MAF) is dependent on vitamin D receptor (VDR) polymorphisms [1]. Therefore, in order to verify the type of molecular interaction between DBP-MAF and VDR, we compared the amino acid sequences at their respective vitamin D binding sites. There are 23 hydrophobic amino acids (aa) near the amino terminus of DBP-MAF, and 23 aa near the carboxyl terminus of VDR. When these two sequence are aligned, it is possible to observe not only that in both proteins there is a long stretch (13-14) of hydrophobic aa, but that 4 hydrophobic aa are identical and 11 aa have similar functional valence. According to this model, the last 23 hydrophobic aa of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic aa of the DBP-MAF located at the external part of the plasma membrane, with vitamin D sandwiched in between the two vitamin D-binding proteins. Oleic acid, taken as an example of an unsaturated fatty acid bound to DBP-MAF, could stabilize the complex at the level of the plasma membrane. Therefore, it can be hypothesized that DBP-MAF and VDR have multiple sites of interaction at the level of the plasma membrane. Further studies will elucidate whether this interaction occurs only in the presence of vitamin D or whether the hydrophobic profile of the two proteins allows direct interaction without the need for vitamin D

Distal motor neuropathy associated with novel EMILIN1 mutation

Abstract Elastin microfibril interface-located proteins (EMILINs) are extracellular matrix glycoproteins implicated in elastogenesis and cell proliferation. Recently, a missense mutation in the EMILIN1 gene has been associated with autosomal dominant connective tissue disorder and motor-sensory neuropathy in a single family. We identified by whole exome sequencing a novel heterozygous EMILIN1 mutation c.748C>T [p.R250C] located in the coiled coil forming region of the protein, in four affected members of an autosomal dominant family presenting a distal motor neuropathy phenotype. In affected patient a sensory nerve biopsy showed slight and unspecific changes in the number and morphology of myelinated fibers. Immunofluorescence study of a motor nerve within a muscle biopsy documented the presence of EMILIN-1 in nerve structures. Skin section and skin derived fibroblasts displayed a reduced extracellular deposition of EMILIN-1 protein with a disorganized network of poorly ramified fibers in comparison with controls. Downregulation of emilin1a in zebrafish displayed developmental delay, locomotion defects, and abnormal axonal arborization from spinal cord motor neurons. The phenotype was complemented by wild-type zebrafish emilin1a, and partially the human wild-type EMILIN1 cRNA, but not by the cRNA harboring the novel c.748C>T [p.R250C]. These data suggest a role of EMILIN-1 in the pathogenesis of diseases affecting the peripheral nervous system

Vitamin D binding protein-derived macrophage activating factor stimulates proliferation and signalling in a human neuronal cell line

Vitamin D (vitD), vitD binding protein-derived macrophage activating factor (DBP-MAF), and vitD receptor (VDR) are essential for adult neurogenesis [1], and this effect could be responsible for the recently reported effects of DBP-MAF on autism spectrum disorders (ASD) [2]. In order to test this hypothesis, we challenged a human neuronal cell line (SH-SY5Y, IZSLER) with DBP-MAF (Immuno Biotech), and we studied cAMP formation (cAMP EIA kit, Abnova), cell proliferation (MTT assay, Sigma Aldrich), apoptosis (human caspase 3 act, Invitrogen) and cell morphology. SH-SY5Y cells represent a validated in vitro model of human neurons in neurodegenerative diseases [3]. DBP-MAF induced rapid (15 min) formation of cAMP in a dose-dependent manner (0.4-40 ng/ml) as well as increase in cell proliferation at 24-48 and 72 h. Cell morphology was consistent with neurogenesis and an increase in the number of cells with high synthetic activity was observed. No apoptosis following DBP-MAF treatment was observed. Our results open the way to exploit these newly described effects to treat neurodegenerative disorders from Parkinson’s and Alzheimer’s diseases to Myalgic Encephalomyelitis and ASD

Transcranial sonography: a technique for the study of the temporal lobes of the human and non-human primate brain

We developed a modified transcranial sonography technique to study the morphology of the temporal lobe, a brain region involved in language, memory and social functions in humans that can be visualized in correspondence of the acoustic window of the temporal squama. Previous studies raise the possibility that a unique derived feature of Homo sapiens is a relatively larger temporal lobe compared to those of other hominins and apes. Such a brain reorganization might have contributed to the evolution of various “higher” cognitive functions of Homo sapiens, including language. Hence, the importance of further comparative analyses of the temporal region. With the technique that we developed we were able to study the meninges, the subarachnoidal space and the cortex of the human temporal lobe. The spatial resolution and the ability to visualize structures of 200-300 μm size led us to hypothesize that the linear structures parallel to the subarachnoidal space might be referred to the neuronal layers of the cortex. The low cost, simplicity and safety of the procedure suggest that this technique may have a significant potential in the comparative study of the primate temporal lobe. Furthermore, the procedure described here can also be used for the study of vascularization of the meninges, in order to better understand the evolutionary relationships between the neurocranial shape and the middle meningeal vessels in living and fossil human species

NGC 2992: The interplay between the multiphase disk, wind and radio bubbles

We present an analysis of the gas kinematics in NGC 2992, based on VLT/MUSE, ALMA and VLA data, aimed at characterising the disk, the wind and their interplay in the cold molecular and warm ionised phases. CO(2-1) and H$\rm \alpha~$ arise from a multiphase disk with inclination 80 deg and radii 1.5 and 1.8 kpc, respectively. We find that the velocity dispersion of the cold molecular phase is consistent with that of star forming galaxies at the same redshift, except in the inner 600 pc region, and in the region between the cone walls and the disk. This suggests that a disk-wind interaction locally boosts the gas turbulence. We detect a clumpy ionised wind distributed in two wide opening angle ionisation cones reaching scales of 7 kpc. The [O III] wind expands with velocity exceeding -1000 km/s in the inner 600 pc, a factor of 5 larger than the previously reported wind velocity. Based on spatially resolved electron density and ionisation parameter maps, we infer an ionised outflow mass of $M_{\rm of,ion} = (3.2 \pm 0.3) \times \, 10^7 \, M_{\odot}$, and a total ionised outflow rate of $\dot M_{\rm of,ion}=13.5\pm1$ \sfr. We detected clumps of cold molecular gas located above and below the disk reaching maximum projected distances and velocities of 1.7 kpc and 200 km/s, respectively. On these scales, the wind is multiphase, with a fast ionised component and a slower molecular one, and a total mass of $M_{\rm of, ion+mol}= 5.8 \times 10^7 \, M_{\odot}$, of which the molecular component carries the bulk of the mass. The dusty molecular outflowing clumps and the turbulent ionised gas are located at the edges of the radio bubbles, suggesting that the bubbles interact with the surrounding medium through shocks. We detect a dust reservoir co-spatial with the molecular disk, with a cold dust mass $M_{\rm dust} = (4.04 \pm 0.03) \times \, 10^{6} \, M_{\odot}$.Comment: 19 pages, 17 figures, 6 tables; Accepted by A&

Metopic suture and RUNX2, a key transcription factor in osseous morphogenesis with possible important implications for human brain evolution

Background. Overall, the comparative data available on the timing of metopic suture closure in present-day and fossil members of human lineage, as well as great apes, seem to indicate that human brain evolution occurred within a complex network of fetopelvic constraints, which required modification of frontal neurocranial ossification patterns, involving delayed fusion of the metopic suture. It is very interesting that the recent sequencing of the Neanderthal genome has revealed signs of positive selection in the modern human variant of the RUNX2 gene, which is known to affect metopic suture fusion in addition to being essential for osteoblast development and proper bone formation. It is possible that an evolutionary change in RUNX2, affecting aspects of the morphology of the upper body and cranium, was of importance in the origin of modern humans. Thus, to contribute to a better understanding of the molecular evolution of this gene probably implicated in human evolution, we performed a comparative bioinformatic analysis of the coding sequences of RUNX2 in Homo sapiens and other non-human Primates.Results. We found amino-acid sequence differences between RUNX2 protein isoforms of Homo sapiens and the other Primates examined, that might have important implications for the timing of metopic suture closure. Conclusions. Further studies are needed to clear the potential distinct developmental roles of different species-specific RUNX2 N-terminal isoforms. Meantime, our bioinformatic analysis, regarding expression of the RUNX2 gene in Homo sapiens and other non-human Primates, has provided a contribution to this important issue of human evolution

The bnt162b2 vaccine induces humoral and cellular immune memory to sars-cov-2 Wuhan strain and the Omicron variant in children 5 to 11 years of age

SARS-CoV-2 mRNA vaccines prevent severe COVID-19 by generating immune memory, comprising specific antibodies and memory B and T cells. Although children are at low risk of severe COVID-19, the spreading of highly transmissible variants has led to increasing in COVID-19 cases and hospitalizations also in the youngest, but vaccine coverage remains low. Immunogenicity to mRNA vaccines has not been extensively studied in children 5 to 11 years old. In particular, cellular immunity to the wild-type strain (Wuhan) and the cross-reactive response to the Omicron variant of concern has not been investigated. We assessed the humoral and cellular immune response to the SARS-CoV-2 BNT162b2 vaccine in 27 healthy children. We demonstrated that vaccination induced a potent humoral and cellular immune response in all vaccinees. By using spike-specific memory B cells as a measurable imprint of a previous infection, we found that 50% of the children had signs of a past, undiagnosed infection before vaccination. Children with pre-existent immune memory generated significantly increased levels of specific antibodies, and memory T and B cells, directed against not only the wild type virus but also the omicron variant

CPX-351 and allogeneic stem cell transplant for a therapy-related acute myeloid leukemia that developed after treatment of acute promyelocytic leukemia: a case report and review of the literature

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression

Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K+ flux through the human ether-\ue0-gogo- related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the \u3b21 integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the \u3b21 integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with \u3b21 integrins as did closed channels, current flow through hERG1 channelswas necessary to activate the integrin-dependent phosphorylation of Tyr397 in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K+ flow, whereas metastasis of breast cancer cells was reduced when the hERG1/\u3b21 integrin interaction was disrupted. We conclude that the interaction of \u3b21 integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression