Tuberculosis (TB) is a bacterial infectious disease caused by the obligate human pathogen, Mycobacterium tuberculosis. Mycobacteria are a distinctive rod-shaped bacteria that share a common property ...of a lipid-rich cell wall that avidly retains Carbol fuchsin dye even in the presence of acidic alcohol (acid fast staining). Despite longstanding intense efforts to control this disease, Tuberculosis remains an expanding global health crisis that mandates new therapeutic and preventative strategies. Although a wealth of information has been gathered about M. tuberculosis over many decades of research into the bacteriology, cell biology, biochemistry, and immunology of this infection, investigation of this bacterial pathogen has lacked the multidisciplinary approach that has evolved from the investigation of genetically tractable and fast growing bacterial pathogens such as Salmonella, Yersinia, Shigella, and Listeria. These organisms, among others, have given rise to the integrated discipline of microbial pathogenesis, also known as cellular microbiology. This discipline probes the molecular interactions between specific microbial products and the host cell, predominantly through the examination of defined bacterial mutants. Until recently, this type of analysis has not been possible with M. tuberculosis, mostly because of our inability to genetically manipulate this organism and the consequent lack of defined mutants with specific phenotypes. These barriers have been surmounted such that multidisciplinary investigation into M. tuberculosis pathogenesis is now possible, an enterprise that has accelerated dramatically due to the completion of the genome sequence of M. tuberculosis. This review will outline present efforts to understand the pathogenesis of this unique bacterial infection, focusing primarily on insights gained from recently isolated M. tuberculosis mutants with altered growth kinetics in experimental animals. This review is not intended to comprehensively detail the incredible breadth of the mycobacterial literature, but rather to highlight and interpret recent advances and to point to future directions.
Endothelin Receptor Antagonists in Kidney Disease Martínez-Díaz, Irene; Martos, Nerea; Llorens-Cebrià, Carmen ...
International journal of molecular sciences,
02/2023, Letnik:
24, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the ...endothelin receptor type A (ET
) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ET
receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.
Objective
To assess the determinants of patients' (PTGL) and physicians' (MDGL) global assessment of rheumatoid arthritis (RA) activity and factors associated with discordance among them.
Methods
A ...total of 7,028 patients in the Quantitative Standard Monitoring of Patients with RA study had PTGL and MDGL assessed at the same clinic visit on a 0–10‐cm visual analog scale (VAS). Three patient groups were defined: concordant rating group (PTGL and MDGL within ±2 cm), higher patient rating group (PTGL exceeding MDGL by >2 cm), and lower patient rating group (PTGL less than MDGL by >2 cm). Multivariable regression analysis was used to identify determinants of PTGL and MDGL and their discordance.
Results
The mean ± SD VAS scores for PTGL and MDGL were 4.01 ± 2.70 and 2.91 ± 2.37, respectively. Pain was overwhelmingly the single most important determinant of PTGL, followed by fatigue. In contrast, MDGL was most influenced by swollen joint count (SJC), followed by erythrocyte sedimentation rate (ESR) and tender joint count (TJC). A total of 4,454 (63.4%), 2,106 (30%), and 468 (6.6%) patients were in the concordant, higher, and lower patient rating groups, respectively. Odds of higher patient rating increased with higher pain, fatigue, psychological distress, age, and morning stiffness, and decreased with higher SJC, TJC, and ESR. Lower patient rating odds increased with higher SJC, TJC, and ESR, and decreased with lower fatigue levels.
Conclusion
Nearly 36% of patients had discordance in RA activity assessment from their physicians. Sensitivity to the “disease experience” of patients, particularly pain and fatigue, is warranted for effective care of RA.
Background. Changes in serotype prevalence among pneumococcal populations result from both serotype replacement and serotype (capsular) switching. Temporal changes in serotype distributions are well ...documented, but the contribution of capsular switching to such changes is unknown. Furthermore, it is unclear to what extent vaccine-induced selective pressures drive capsular switching. Methods. Serotype and multilocus sequence typing data for 426 pneumococci dated from 1937 through 2007 were analyzed. Whole-genome sequence data for a subset of isolates were used to investigate capsular switching events. Results. We identified 36 independent capsular switch events, 18 of which were explored in detail with wholegenome sequence data. Recombination fragment lengths were estimated for 11 events and ranged from approximately 19.0 kb to > 58.2 kb. Two events took place no later than 1960, and the imported DNA included the capsular locus and the nearby penicillin-binding protein genes pbp2x and pbpla. Conclusions. Capsular switching has been a regular occurrence among pneumococcal populations throughout the past 7 decades. Recombination of large DNA fragments (> 30 kb), sometimes including the capsular locus and penicillin-binding protein genes, predated both vaccine introduction and widespread antibiotic use. This type of recombination has likely been an intrinsic feature throughout the history of pneumococcal evolution.
Stress at encoding affects memory processes, typically enhancing, or preserving, memory for emotional information. These effects have interesting implications for eyewitness accounts, which in ...real-world contexts typically involve encoding an aversive event under stressful conditions followed by potential exposure to misinformation. The present study investigated memory for a negative event encoded under stress and subsequent misinformation endorsement. Healthy young adults participated in a between-groups design with three experimental sessions conducted 48h apart. Session one consisted of a psychosocial stress induction (or control task) followed by incidental encoding of a negative slideshow. During session two, participants were asked questions about the slideshow, during which a random subgroup was exposed to misinformation. Memory for the slideshow was tested during the third session. Assessment of memory accuracy across stress and no-stress groups revealed that stress induced just prior to encoding led to significantly better memory for the slideshow overall. The classic misinformation effect was also observed – participants exposed to misinformation were significantly more likely to endorse false information during memory testing. In the stress group, however, memory accuracy and misinformation effects were moderated by arousal experienced during encoding of the negative event. Misinformed-stress group participants who reported that the negative slideshow elicited high arousal during encoding were less likely to endorse misinformation for the most aversive phase of the story. Furthermore, these individuals showed better memory for components of the aversive slideshow phase that had been directly misinformed. Results from the current study provide evidence that stress and high subjective arousal elicited by a negative event act concomitantly during encoding to enhance emotional memory such that the most aversive aspects of the event are well remembered and subsequently more resistant to misinformation effects.
We demonstrate strong-to-perfect absorption across a wide range of mid-infrared wavelengths (5-12µm) using a two-layer system consisting of heavily-doped silicon and a thin high-index germanium ...dielectric layer. We demonstrate spectral control of the absorption resonance by varying the thickness of the dielectric layer. The absorption resonance is shown to be largely polarization-independent and angle-invariant. Upon heating, we observe selective thermal emission from our materials. Experimental data is compared to an analytical model of our structures with strong agreement.
Independent effects of changes in biologic risk factors on type 2 diabetes incidence remain unclear. The authors examined whether associations between changes in biologic risk factors and diabetes ...risk are driven by initial or attained risk factor levels. Biologic risk factors were measured at baseline and at each 5-year interval follow-up (rounds 2, 3, and 4) among 4,204 initially healthy men and women, aged 20-59 years, participating in the Dutch Doetinchem Cohort Study (1987-2007). Time-dependent Cox regression analyses were used to analyze associations between changes in waist circumference, blood pressure, and high density lipoprotein cholesterol (HDL cholesterol) and incident diabetes, adjusted for initial or attained levels; 130 diabetes cases occurred during 9 years of follow-up. Five-year increases in waist circumference and blood pressure and decreases in HDL cholesterol were positively associated with risk of diabetes after adjustment for initial levels but no longer after adjustment for attained levels: waist circumference (hazard ratio (HR) = 0.86, 95% confidence interval (CI): 0.69, 1.07), systolic blood pressure (HR = 0.96, 95% CI: 0.84, 1.10), diastolic blood pressure (HR = 0.96, 95% CI: 0.87, 1.06), and HDL cholesterol (HR = 0.91, 95% CI: 0.81, 1.01). In conclusion, the associations between changes in biologic risk factors and risk of diabetes are mainly driven by the attained levels. Hence, not the prior changes, but the attained levels seem to be of importance with regard to diabetes risk.
Early growth response 1 (EGR1) is an immediate early gene and transcription factor previously found to be significantly upregulated in human astrocytoma cells infected with Venezuelan equine ...encephalitis virus (VEEV). The loss of EGR1 resulted in decreased cell death but had no significant impact on viral replication. Here, we extend these studies to determine the impacts of EGR1 on gene expression following viral infection. Inflammatory genes CXCL3, CXCL8, CXCL10, TNF, and PTGS2 were upregulated in VEEV-infected cells, which was partially dependent on EGR1. Additionally, transcription factors, including EGR1 itself, as well as ATF3, FOS, JUN, KLF4, EGR2, and EGR4 were found to be partially transcriptionally dependent on EGR1. We also examined the role of EGR1 and the changes in gene expression in response to infection with other alphaviruses, including eastern equine encephalitis virus (EEEV), Sindbis virus (SINV), and chikungunya virus (CHIKV), as well as Zika virus (ZIKV) and Rift Valley fever virus (RVFV), members of the Flaviviridae and Phenuiviridae families, respectively. EGR1 was significantly upregulated to varying degrees in EEEV-, CHIKV-, RVFV-, SINV-, and ZIKV-infected astrocytoma cells. Genes that were identified as being partially transcriptionally dependent on EGR1 in infected cells included ATF3 (EEEV, CHIKV, ZIKV), JUN (EEEV), KLF4 (SINV, ZIKV, RVFV), CXCL3 (EEEV, CHIKV, ZIKV), CXCL8 (EEEV, CHIKV, ZIKV, RVFV), CXCL10 (EEEV, RVFV), TNF-α (EEEV, ZIKV, RVFV), and PTGS2 (EEEV, CHIKV, ZIKV). Additionally, inhibition of the inflammatory gene PTGS2 with Celecoxib, a small molecule inhibitor, rescued astrocytoma cells from VEEV-induced cell death but had no impact on viral titers. Collectively, these results suggest that EGR1 induction following viral infection stimulates multiple inflammatory mediators. Managing inflammation and cell death in response to viral infection is of utmost importance, especially during VEEV infection where survivors are at-risk for neurological sequalae.
Degenerative Cervical Myelopathy (DCM) is the functional derangement of the spinal cord resulting from vertebral column spondylotic degeneration. Typical neurological symptoms of DCM include gait ...imbalance, hand/arm numbness, and upper extremity dexterity loss. Greater spinal cord compression is believed to lead to a higher rate of neurological deterioration, although clinical experience suggests a more complex mechanism involving spinal canal diameter (SCD). In this study, we utilized machine learning clustering to understand the relationship between SCD and different patterns of cord compression (i.e. compression at one disc level, two disc levels, etc.) to identify patient groups at risk of neurological deterioration. 124 MRI scans from 51 non-operative DCM patients were assessed through manual scoring of cord compression and SCD measurements. Dimensionality reduction techniques and k-means clustering established patient groups that were then defined with their unique risk criteria. We found that the compression pattern is unimportant at SCD extremes (≤14.5 mm or > 15.75 mm). Otherwise, severe spinal cord compression at two disc levels increases deterioration likelihood. Notably, if SCD is normal and cord compression is not severe at multiple levels, deterioration likelihood is relatively reduced, even if the spinal cord is experiencing compression. We elucidated five patient groups with their associated risks of deterioration, according to both SCD range and cord compression pattern. Overall, SCD and focal cord compression alone do not reliably predict an increased risk of neurological deterioration. Instead, the specific combination of narrow SCD with multi-level focal cord compression increases the likelihood of neurological deterioration in mild DCM patients.
•Focal cord compression alone cannot predict progression of mild symptoms in DCM.•Overly large/small canal diameters reduce the predictive value of focal compression.•Severe compression at multiple disc levels increases deterioration risk.•Detailed spinal canal measurement crucial for accurate neurological risk prediction.•Clustering algorithms capable of identifying DCM patients at risk of deterioration.
Abstract
Objective
To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab ...initiated in biologic-naïve patients with established RA.
Methods
In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ–Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24.
Results
Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%.
Conclusion
RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.
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