Functions and Interrelationships of Leukocytes in Inflammation as Elucidated by the Rebuck Skin Window Technique

This article provides an overview of the functions of human leukocytes in inflammation as elucidated by the Rebuck skin window technique. The migration sequence of various leukocytes into the field of inflammation is described, as well as cytologic, cytochemical, and transformational changes, and the interrelationships of responding leukocytes. Since it was introduced in 1955, the Rebuck skin window technique has provided an excellent means of studying in vivo inflammatory response to different phlogistic agents in normal individuals and in various disease states. This simple technique continues to prove fruitful to further study and to monitoring of many disease states

Effect of chronic treatment with a cyclooxygenase inhibitor on reproductive parameters in male rat

BACKGROUND: Indomethacin is a member of non-steroidal anti-inflammatory drugs (NSAIDs) commonly used for treatment of gout, arthritis, and other inflammatory conditions. It has been shown to inhibit ovarian prostaglandins synthesis in mammals, birds, fish and reptiles. However, the effects of its chronic administration on male reproductive functions remain largely unknown. Using rat as a model, we studied the effect of chronic treatment with indomethacin on the male reproductive system. METHODS: Testosterone was measured in the serum, testicular tissue, and testicular interstitial fluid by radioimmunoassay. Moreover, we also studied the direct effect of indomethacin in vitro on luteinizing hormone stimulated testosterone secretion from the Leydig cells isolated from various treatment groups. RESULTS: Indomethacin treatment for 50 days caused a significant but reversible decrease in prostate weight, epididymal sperm reserves and sperm motility score compared with control rats (p \u3c 0.05). In vitro stimulation of Leydig cells isolated from treated rat\u27s testes with luteinizing hormone (250 microIU) produced significantly reduced testosterone compared with cells from control groups (p \u3c 0.05). Furthermore, stimulatory effect of luteinizing hormone on the control Leydig cells was significantly reduced when these cells were challenged with luteinizing hormone in the presence of indomethacin, (p \u3c 0.05). Testosterone concentration in the testicular tissue and testicular interstitial fluid reduced after indomethacin treatment (p \u3c 0.05). CONCLUSION: Due to its significant inhibition of key reproductive hormones, indomethacin effectively inhibits reproductive functions if used on a long-term basis. In his study, we have identified potential risks in the long-term use ofcyclooxygenase inhibitors

MCMC Marginalisation Bias and Λ\LambdaCDM tensions

Hubble tension is a problem in one-dimensional (1D) posteriors, since local $H_0$ determinations are only sensitive to a single parameter. Projected 1D posteriors for $\Lambda$CDM cosmological parameters become more non-Gaussian with increasing effective redshift when the model is fitted to redshift binned data in the late Universe. We explain mathematically why this non-Gaussianity arises and show using observational Hubble data (OHD) that Markov Chain Monte Carlo (MCMC) marginalisation leads to 1D posteriors that fail to track the $\chi^2$ minimum at $68\%$ confidence level in high redshift bins. To remedy this limitation of MCMC, we resort to profile distributions as a complementary technique. Doing so, we observe that $z \gtrsim 1$ cosmic chronometer (CC) data currently prefers a non-evolving (constant) Hubble parameter over a Planck-$\Lambda$CDM cosmology at $\sim 2 \sigma$. Within the Hubble tension debate, it is imperative that subsamples of data sets with differing redshifts yield similar $H_0$ values. In addition, we confirm that MCMC degeneracies observed in 2D posteriors are not due to curves of constant $\chi^2$. Finally, on the assumption that the Planck-$\Lambda$CDM cosmological model is correct, using profile distributions we confirm a $>2 \sigma$ discrepancy with Planck-$\Lambda$CDM in a combination of CC and baryon acoustic oscillations (BAO) data beyond $z \sim 1.5$. This confirms a discrepancy reported earlier with fresh methodology.Comment: 22 pages, 11 figures; v2 presentation improved, figures adde

Unusual Lymphomas Developing in Chronic Lymphocytic Leukemia

We report three patients with chronic lymphocytic leukemia (CLL) who developed malignant lymphomas of unusual character and modes of presentation. Two of the patients had received low doses of chlorambucil for several years before they developed malignant lymphoma, diffuse, large cell type (LCL). In one of these patients LCL manifested as a grossly evident osteolytic lesion. In the second patient LCL developed initially as a localized lesion in the iliac bone. Both patients died within a few weeks after LCL was diagnosed. The third patient, who was found to have CLL during a routine examination, did not receive any therapy for the leukemia. Within six months the patient developed diffuse malignant lymphoma, mixed small and large cell type, with total extinction of the leukemic component. The disease responded favorably to chemotherapy for lymphoma, and the patient is alive with minimal residual disease at this time. Immunohistochemical studies in all three patients suggested transformation or dedifferentiation of the original neoplastic lymphoid clone rather than de novo appearance of another neoplasm

On Redshift Evolution & Negative Dark Energy Density in Pantheon+ Supernovae

Within the Friedmann-Lema\^itre-Robertson-Walker (FLRW) framework, the Hubble constant $H_0$ is an integration constant. Thus, consistency of the model demands observational constancy of $H_0$. We demonstrate redshift evolution of best fit $\Lambda$CDM parameters $(H_0, \Omega_{m})$ in Pantheon+ supernove (SNe). Redshift evolution of best fit cosmological parameters is a prerequisite to finding a statistically significant evolution as well as identifying alternative models that are competitive with $\Lambda$CDM in a Bayesian model comparison. To assess statistical significance, we employ three different methods: i) Bayesian model comparison, ii) mock simulations and iii) profile distributions. The first shows a marginal preference for the vanilla $\Lambda$CDM model over an ad hoc model with 3 additional parameters and an unphysical jump in cosmological parameters at $z=1$. From mock simulations, we estimate the statistical significance of redshift evolution of best fit parameters and negative dark energy density ($\Omega_m > 1$) to be in the $1-2 \sigma$ range, depending on the criteria employed. Importantly, in direct comparison to the same analysis with the earlier Pantheon sample we find that statistical significance of redshift evolution of best fit parameters has increased, as expected for a physical effect. Our profile distribution analysis demonstrates a shift in $(H_0, \Omega_m)$ in excess of $95\%$ confidence level for SNe with redshifts $z > 1$ and also shows that a degeneracy in MCMC posteriors is not equivalent to a curve of constant $\chi^2$. Our findings can be interpreted as a statistical fluctuation or unexplored systematics in Pantheon+ or $\Lambda$CDM model breakdown. The first two possibilities are disfavoured by similar trends in independent probes.Comment: 6 pages, 5 figures; v2 mock simulation and profile distribution analysis added, conclusions unchanged; v3 to appear in EPJ

S8S_8 increases with effective redshift in Λ\LambdaCDM cosmology

Hubble constant $H_0$ and weighted amplitude of matter fluctuations $S_8$ determinations are biased to higher and lower values, respectively, in the late Universe with respect to early Universe values inferred by the Planck collaboration within flat $\Lambda$CDM cosmology. If these anomalies are physical, i.e. not due to systematics, they naively suggest that $H_0$ decreases and $S_8$ increases with effective redshift. Here, subjecting matter density today $\Omega_{m}$ to a prior, corresponding to a combination of Planck CMB and BAO data, we perform a consistency test of the Planck-$\Lambda$CDM cosmology and show that $S_8$ determinations from $f \sigma_8(z)$ constraints increase with effective redshift. Due to the redshift evolution, a $\sim 3 \sigma$ tension in the $S_8$ parameter with Planck at lower redshifts remarkably becomes consistent with Planck within $1 \sigma$ at high redshifts. This provides corroborating support for an $S_8$ discrepancy that is physical in origin. We further confirm that the flat $\Lambda$CDM model is preferred over a theoretically ad hoc model with a jump in $S_8$ at a given redshift. In the absence of the CMB+BAO $\Omega_m$ prior, we find that $> 3 \sigma$ tensions with Planck in low redshift data are ameliorated by shifts in the parameters in high redshift data. Results here and elsewhere suggest that the $\Lambda$CDM cosmological parameters are redshift dependent. Fitting parameters that evolve with redshift is a recognisable hallmark of model breakdown.Comment: 4 pages, 6 figures; v2 references updated, discussion on complementary weak and CMB lensing observations added; v3 added plots and discussion, accepted at MNRAS letter

Origanum majorana L. polyphenols: in vivo antiepileptic effect, in silico evaluation of their bioavailability, and interaction with the NMDA receptor

Introduction: Epilepsy is a chronic brain disease characterized by repeated seizures and caused by excessive glutamate receptor activation. Many plants are traditionally used in the treatment of this disease. This study aimed to evaluate the bioavailability of a polyphenolic extract obtained from Origanum majorana L. (OMP) leaves, as well as its antiepileptic activity and its potential mechanism of action.Methods: We have developed and validated a simple, rapid, and accurate stability-indicating reversed-phase liquid chromatographic method for the simultaneous determination of caffeine and quercetin in rat plasma. The OMP antiepileptic effect was evaluated with pilocarpine-induced seizures, and a docking method was used to determine the possible interaction between caffeic acid and quercetin with the N-methyl-D-aspartate (NMDA) receptor.Results and Discussion: Both compounds tested showed low bioavailability in unchanged form. However, the tested extract showed an anticonvulsant effect due to the considerably delayed onset of seizures in the pilocarpine model at a dose of 100 mg/kg. The molecular docking proved a high-affinity interaction between the caffeic acid and quercetin with the NMDA receptor. Taken together, OLP polyphenols demonstrated good antiepileptic activity, probably due to the interaction of quercetin, caffeic acid, or their metabolites with the NMDA receptor

Firm performance, corporate governance and executive compensation in Pakistan

yesThis study examines the effects of firm performance and corporate governance on chief executive officer (CEO) compensation in an emerging market, Pakistan. Using a more robust Generalized Method of Moments (GMM) estimation approach for a sample of non-financial firms listed at Karachi Stock Exchange (KSE) over the period 2005 to 2012, we find that both current and previous year accounting performance has positive influence on CEO compensation. However, stock market performance does not appear to have a positive impact on executive compensation. We further find that ownership concentration is positively related with CEO compensation, indicating some kind of collusion between management and largest shareholder to get personal benefits. Inconsistent with agency theory, CEO duality appears to have a negative influence, while board size and board independence have no convincing relationship with CEO compensation, indicating board ineffectiveness in reducing CEO entrenchment. The results of dynamic GMM model suggest that CEO pay is highly persistent and takes time to adjust to long-run equilibrium

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI