Protective effect of prostacyclin on postischemic acute renal failure in the rat

Protective effect of prostacyclin on postischemic acute renal failure in the rat. Infusion of prostacyclin (PGI2) reportedly attenuates renal ischemic injury in the dog and the rat. In the dog, PGI2 is a potent renal vasodilator; in the rat a direct action on the renal vasculature is not always apparent. To determine whether or not the protective effect of PGI2 on postichemic ARF was hemodynamically mediated, studies were performed in uninephrectomized Sprague–Dawley rats before and after a 40 minute period of complete renal artery occlusion. In response to the preischemic infusion of PGI2 for 30 minutes at 160 ng/kg body wt/min i.v. (N = 7), MAP and RBF fell to 86 ± 7% (P < 0.0001) and 84 ± 9% (P < 0.05) of baseline values, respectively. RVR initially declined to 81 ± 9% of baseline values (P < 0.025) but returned to 102 ± 13% of baseline values prior to the period of ischemia. Following the period of ischemia, reflow of blood in the rats receiving PGI2 was delayed when compared to rats not receiving PGI2 (N = 1). RBF returned to only 76 ± 19% of the initial values in PGI2-treated rats (P < 0.01) but to 90 ± 12% of the initial values in rats receiving buffer alone (NS). Observations made during the ensuing 48 hours in animals treated with either 80 (N = 8) or 160 ng/kg/body wt/min (N = 7) for 30 minutes before and four hours after the period of ischemia indicated that renal function improved to a greater extent in the PGI2-treated animals than in buffer–treated animals (N = 15) as judged by significantly–greater mean values of V, UOsm, UCr and CCr. On the second day after ischemia, CInwas significantly greater in PGI2-treated animals than in the postischemic animals receiving buffer alone (77 ± 45 vs. 33 ± 20 µl/min/100 g body wt; P < 0.05) despite the fact that no differences were found in the mean values of RBF (3.59 ± 1.08 vs. 3.43 ± 0.32 ml/min/100 body wt. Blinded analysis of the histological sections revealed significantly less evidence of tublar epithelial cell necrosis in the PGI2-treated animals (P < 0.005). The data indicate that the protective effect of PGI2 on the renal response to ischemic injury in the Sprague–Dawley rat is not related to changes in RBF or RVR. Instead, the beneficial effect of PGI2may be a result of cytoprotective properties as has been demonstrated in other tissues

Multiple Access Protocols for Data Communications via VSAT Networks

One of the most significant advantages of VSAT Networks is the ability to link together many terminals at remote sites under a single manageable network and to adapt the performance characteristics of the network to the requirements of the type of data traffic presented to the network

Human T Regulatory Cells Can Use the Perforin Pathway to Cause Autologous Target Cell Death

AbstractCytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells. Mutations in genes important for this pathway are associated with several human diseases. CD4+ T regulatory (Treg) cells have emerged as important in the control of immunopathological processes. We have previously shown that human adaptive Treg cells preferentially express granzyme B and can kill allogeneic target cells in a perforin-dependent manner. Here, we demonstrate that activated human CD4+CD25+ natural Treg cells express granzyme A but very little granzyme B. Furthermore, both Treg subtypes display perforin-dependent cytotoxicity against autologous target cells, including activated CD4+ and CD8+ T cells, CD14+ monocytes, and both immature and mature dendritic cells. This cytotoxicity is dependent on CD18 adhesive interactions but is independent of Fas/FasL. Our findings suggest that the perforin/granzyme pathway is one of the mechanisms that Treg cells can use to control immune responses

Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR

© 2020 The Authors Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:PpqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation

Memory Phenotype CD4 T Cells Undergoing Rapid, Nonburst-Like, Cytokine-Driven Proliferation Can Be Distinguished from Antigen-Experienced Memory Cells

Contrary to the current paradigm that nearly all memory T cells proliferate in response to antigenic stimulation, this paper shows that an important population of CD4 T lymphocytes achieves memory/effector status independent of antigenic stimulation

Criteria for the diagnosis of corticobasal degeneration

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed

The pacing stress test: Thallium-201 myocardial imaging after atrial pacing. Diagnostic value in detecting coronary artery disease compared with exercise testing

Many patients suspected of having coronary artery disease are unable to undergo adequate exercise testing. An alternate stress, pacing tachycardia, has been shown to produce electrocardiographic changes that are as sensitive and specific as those observed during exercise testing. To compare thallium-201 imaging after atrial pacing stress with thallium imaging after exercise stress, 22 patients undergoing cardiac catheterization were studied with both standard exercise thallium imaging and pacing thallium imaging.Positive ischemic electrocardiographic changes (> 1 mm ST segment depression) were noted in 11 of 16 patients with coronary artery disease during exercise, and in 15 of the 16 patients during atrial pacing. One of six patients with normal or trivial coronary artery disease had a positive electrocardiogram with each test. Exercise thallium imaging was positive in 13 of 16 patients with coronary artery disease compared with 15 of 16 patients during atrial pacing. Three of six patients without coronary artery disease had a positive scan with exercise testing, and two of these same patients developed a positive scan with atrial pacing. Of those patients with coronary artery disease and an abnormal scan, 85% showed redistribution with exercise testing compared with 87% during atrial pacing. Segment by segment comparison of thallium imaging after either atrial pacing or exercise showed that there was a good correlation of the location and severity of the thallium defects (r = 0.83, p = 0.0001, Spearman rank correlation).It is concluded that the location and presence of both fixed and transient thallium defects after atrial pacing are closely correlated with the findings after exercise testing. Thus, atrial pacing may be used as a stress for myocardial perfusion scintigraphy in patients unable to complete a satisfactory exercise test

Screening for Gynecologic Conditions With Pelvic Examination US Preventive Services Task Force Recommendation Statement

IMPORTANCE Many conditions that can affect women\u27s health are often evaluated through pelvic examination. Although the pelvic examination is a common part of the physical examination, it is unclear whether performing screening pelvic examinations in asymptomatic women has a significant effect on disease morbidity and mortality. OBJECTIVE To issue a new US Preventive Services Task Force(USPSTF) recommendation on screening for gynecologic conditions with pelvic examination for conditions other than cervical cancer, gonorrhea, and chlamydia, for which the USPSTF has already made specific recommendations. EVIDENCE REVIEW The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of performing screening pelvic examinations in asymptomatic, nonpregnant adult women 18 years and older who are not at increased risk for any specific gynecologic condition. FINDINGS Overall, the USPSTF found inadequate evidence on screening pelvic examinations for the early detection and treatment of a range of gynecologic conditions in asymptomatic, nonpregnant adult women. CONCLUSIONS AND RECOMMENDATION The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of performing screening pelvic examinations in asymptomatic, nonpregnant adult women. (I statement) This statement does not apply to specific disorders for which the USPSTF already recommends screening (ie, screening for cervical cancer with a Papanicolaou smear, screening for gonorrhea and chlamydia)

Dirac Leptogenesis with a Non-anomalous U(1)′U(1)^{\prime} Family Symmetry

We propose a model for Dirac leptogenesis based on a non-anomalous $U(1)^{\prime}$ gauged family symmetry. The anomaly cancellation conditions are satisfied with no new chiral fermions other than the three right-handed neutrinos, giving rise to stringent constraints among the charges. Realistic masses and mixing angles are obtained for all fermions. The model predicts neutrinos of the Dirac type with naturally suppressed masses. Dirac leptogenesis is achieved through the decay of the flavon fields. The cascade decays of the vector-like heavy fermions in the Froggatt-Nielsen mechanism play a crucial role in the separation of the primodial lepton numbers. We find that a large region of parameter space of the model gives rise to a sufficient cosmological baryon number asymmetry through Dirac leptogenesis.Comment: 8 pages, 8 figures, version to appear in JHE