Unenhanced MR Imaging in adults with clinically suspected acute appendicitis

Purpose

The purpose of the study was to evaluate unenhanced Magnetic Resonance Imaging (MRI) for the diagnosis of appendicitis or another surgery-requiring condition in an adult population scheduled for emergency appendectomy based on a clinical diagnosis of suspected acute appendicitis.

Materials and methods

The prospective study included 48 consecutive patients (29 female, 19 male, 18-70 years old, mean age = 37.1 years). MRI examination was designed to be comfortable and fast; no contrast was administered. The sequences were performed during quiet respiration. The MRI findings were reviewed by two radiologists and one surgeon independent of each other and compared with surgical and pathological records.

Results

According to the surgical and histopathological findings 30 of 48 patients (63%) had acute appendicitis. Of the remaining 18 patients, 4 patients had no reasons for the clinical symptoms and 14 patients had other pathology.For the three reviewers the performance of MRI in the diagnosis of acute appendicitis showed the following sensitivity, specificity and accuracy ranges: 83-93%, 50-83% and 77-83%. Moderate (κ = 0.51) and fair (κ = 0.31) interobserver agreements in the MR diagnosis of acute appendicitis were found between the reviewers. Sensitivity, specificity and accuracy values for overall performance of MRI in detecting pelvic abnormalities were 100%, 75% (3 of 4 healthy patients were identified by MRI) and 98%, respectively.

Conclusion

Unenhanced fast MRI is feasible as an additional fast screening before the appendectomy. It may prevent unnecessary surgeries. The fast MRI examination can be adequately performed on an MRI unit of broad range of field strengths.     

Urokinase plasminogen activator in injured adventitia increases the number of myofibroblasts and augments early proliferation

Myofibroblasts are involved in vessel remodeling during the development of hypertension as well as after angioplasty and aortocoronary grafting, but the mechanisms of myofibroblastic phenotypic modulation are not fully elucidated. We assessed the role of urokinase plasminogen activator (uPA) and its proteolytic activity in myofibroblast differentiation and the early proliferation following mechanical injury of the rat carotid adventitia. The effects of perivascular application of recombinant uPA (r-uPA), proteolytically inactive r-uPA(H/Q) and uPA neutralizing antibody were evaluated 4 days after surgical injury to the adventitia. The phenotype of adventitial cells was assessed using anti-alpha-smooth muscle actin (alpha-SM actin) antibody, anti-SM heavy chain myosin, anti-high-molecular-weight caldesmon, anti-smoothelin and anti-ED-1 antibodies, proliferation by the expression of proliferating cell nuclear antigen, and the size of the adventitia by quantitative morphometry. Four days after injury, the intensive immunostaining for urokinase appeared in the rat carotid artery adventitia. At the same time, the frequency of alpha-SM actin-positive adventitial cells was 1.8+/-1.1% in uninjured arteries and 25.2+/-5.4% in injured arteries (p<0.05), and the respective frequency of ED-1-positive cells 1.5+/-1.1 and 25.0+/-5.2%. The application of exogenous r-uPA doubled the numbers of alpha-SM actin-positive adventitial cells to 55.7+/-6.8% (p<0.05). ED-1-positive cells and proliferating cell nuclear antigen-positive cells as well as the size of the adventitia were also significantly increased after r-uPA compared with injury alone. In contrast, the proteolytically inactive r-uPA(H/Q) did not affect any parameters. The application of uPA neutralizing antibody attenuated the frequency of alpha-SM actin-positive cells to 12.6+/-3.5% (p<0.05), the frequency of ED-1-positive cells, and the numbers of adventitial cells. r-uPA stimulation of cultured human skin fibroblasts significantly increased the alpha-SM actin content in a concentration-dependent manner. In contrast, r-uPAH/Q did not induce changes in alpha-SM actin content. We conclude that uPA, which is upregulated in the injured adventitia, can augment adventitial cell accumulation, including myofibroblasts, and adventitia growth early after injury of the rat carotid artery adventitia by mechanisms involving proteolysis.     

Viral protease cleavage of inhibitor of kappaBalpha triggers host cell apoptosis

Apoptosis is an innate immune response to viral infection that limits viral replication. However, the mechanisms by which cells detect viral infection and activate apoptosis are not completely understood. We now show that during Coxsackievirus infection, the viral protease 3C(pro) cleaves inhibitor of kappaBalpha (IkappaBalpha). A proteolytic fragment of IkappaBalpha then forms a stable complex with NF-kappaB, translocates to the nucleus, and inhibits NF-kappaB transactivation, increasing apoptosis and decreasing viral replication. In contrast, cells with reduced IkappaBalpha expression are more susceptible to viral infection, with less apoptosis and more viral replication. IkappaBalpha thus acts as a sensor of viral infection. Cleavage of host proteins by pathogen proteases is a novel mechanism by which the host recognizes and responds to viral infection.     

Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile

We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.     

Profiles of sleep changes during the COVID‐19 pandemic: Demographic,behavioural and psychological factors

This study aimed to evaluate changes in sleep during the COVID‐19 outbreak, and used data‐driven approaches to identify distinct profiles of changes in sleep‐related behaviours. Demographic, behavioural and psychological factors associated with sleep changes were also investigated. An online population survey assessing sleep and mental health was distributed between 3 April and 24 June 2020. Retrospective questions were used to estimate temporal changes from before to during the outbreak. In 5,525 Canadian respondents (67.1% females, 16–95 years old: Mean ± SD = 55.6 ± 16.3 years), wake‐up times were significantly delayed relative to pre‐outbreak estimates (p < .001,  = 0.04). Occurrences of clinically meaningful sleep difficulties significantly increased from 36.0% before the outbreak to 50.5% during the outbreak (all p < .001, g ≥ 0.27). Three subgroups with distinct profiles of changes in sleep behaviours were identified: “Reduced Time in Bed”, “Delayed Sleep” and “Extended Time in Bed”. The “Reduced Time in Bed” and “Delayed Sleep” subgroups had more adverse sleep outcomes and psychological changes during the outbreak. The emergence of new sleep difficulties was independently associated with female sex, chronic illnesses, being employed, family responsibilities, earlier wake‐up times, higher stress levels, as well as heavier alcohol use and television exposure. The heterogeneity of sleep changes in response to the pandemic highlights the need for tailored interventions to address sleep problems.     

Diversity,novelty, antimicrobial activity,and new antibiotics of cultivable endophytic actinobacteria isolated from psammophytes collected from Taklamakan Desert

Three hundred and twenty endophytic actinobacterial strains were isolated from psammophytes collected from Taklamakan Desert and identified. Among them, three strains already had been identified as new species of two genera and sixteen isolates showed relatively low 16S rRNA similarities < 98.6% to validly described species. Seventy-five of the isolates were selected as representative strains to screen antibacterial activity and mechanism. Forty-seven strains showed antagonistic activity against at least one of the indicator bacteria. Two Streptomyces strains produced bioactive compounds inducing DNA damage, and two Streptomyces strains produced bioactive compounds with inhibitory activity on protein biosynthesis. Notably, the strain Streptomyces sp. 8P21H-1 that demonstrated both strong antibacterial activity and inhibitory activity on protein biosynthesis was prioritized for exploring new antibiotics. Under the strategy of integrating genetics-based discovery program and MS/MS-based molecular networking, two new streptogramin-type antibiotics, i.e., acetyl-griseoviridin and desulphurizing griseoviridin, along with known griseoviridin, were isolated from the culture broth of strain 8P21H-1. Their chemical structures were determined by HR-MS, and 1D and 2D NMR. Desulphurizing griseoviridin and griseoviridin exhibited antibacterial activities by inhibiting translation.     

Circulating tumor cells and circulating tumor DNA in colon cancer

It is known that tumor cells have the ability to penetrate into the bloodstream. The identification of such circulating tumor cells (CTC) determines the prognosis in several tumors, including colon cancer. Tumor DNA (ctDNA), which is only a part of the total circulating DNA obtained from the blood of cancer patients, is also further separated from plasma. This separation of the neoplastic derivatives of the primary tumor and metastases (CTC, ctDNA, RNA, proteome) in plasma is called “liquid biopsy.” CTC increasingly represents the pool of tumor cells that can initiate the growth of metastatic lesions, while the ctDNA provides the information about the whole tumor mass. Traditional tissue biopsy gives information based only on one small section of the primary tumor or metastasis, often retrieved before the start of treatment; however, liquid biopsy provides real-time information about the molecular disorders for the whole tumor mass and allows us to estimate the dynamics of the evolutionary tumor changes, the heterogeneity of the disease, and the effect of chemotherapy. With the possibility of obtaining multiple blood samples for analysis during the therapy, in contrast to traditional biopsy, it also allows us to evaluate the mechanisms of resistance to treatment, which in the future will perhaps lead to modification of the treatment in accordance with the detected molecular defects in tumors. Thus, this would facilitate implementing the principles of personalized therapy. In this literature review, we concentrate on liquid biopsy in patients with colon cancer.