The Association of Tacrolimus Formulation on Cerebral Blood Flow and Cognitive Function.

Calcineurin inhibitors are inherent vasoconstrictors. Cerebral vasoconstriction can reduce cerebral blood flow (CBF), and negatively impact cerebrovascular response (CVR) to exercise, and cognitive function. The once-daily extended-release (LCP) tacrolimus has fewer side effects than the immediate-release (IR) tacrolimus. The role of calcineurin inhibitors on CBF and the impact of specific formulations of tacrolimus on CBF, CVR, and cognitive function are unknown. In this pilot study, we evaluated whether changing from IR tacrolimus to LCP tacrolimus modulates CBF, CVR, or cognitive function in kidney transplant (KT) recipients. Methods: We randomized (2:1) 30 stable KT recipients on IR tacrolimus to intervention (switch to LCP tacrolimus) and control (continue IR tacrolimus) arms. We measured CBF, CVR, and cognitive function at baseline and at 12 wk. We used ANCOVA to evaluate changes in outcome variables, with baseline values and study arm as covariates. We used descriptive statistics with mean changes in outcome variables to compare the 2 groups. Results: Participants were 51 ± 13 y old. There was no difference in plasma tacrolimus levels at baseline and at 12 wk in the 2 arms. The changes in CBF, resting middle cerebral artery velocity, CVR, and cognitive function were more favorable in the intervention arm than in the control group. Conclusions: Changing IR tacrolimus to LCP tacrolimus may improve CBF, cerebrovascular dynamics, and cognitive function in KT recipients. Larger studies are needed to confirm these results.

Pre-transplant cognitive screening is a poor predictor of post-transplant cognitive status.

INTRODUCTION: Transplant centers hesitate to transplant patients with cognitive impairment. It is unclear if pre-kidney transplant (KT) cognitive screening can predict post-KT cognitive function. METHODS: We evaluated pre- to post-KT cognitive function with the Montreal Cognitive Assessment (MoCA) in a cohort of 108 patients. We used an adjusted logistic regression model to assess pre- to post-KT changes in cognitive status (continuous variable) and a linear mixed model to assess changes in MoCA scores (categorical variable) pre- to post- KT. RESULTS: The average pre- and post-KT MoCA scores were 25.3 ± 3.0 and 26.4 ± 2.8, respectively. Final pre-KT score did not predict post-KT cognitive status (OR = 1.08; 95% CI: .92-1.26; P = .35). 32% of the patients with a final pre-KT score ≥26 had at least one post-KT score < 26. Conversely, 61% of the patients with a final pre-KT score < 26 had at least one post KT score ≥26. In the linear mixed model analysis, the final pre-KT score was associated with a small, clinically insignificant (ß = .34; 95% CI: .19-.49; P < .001) effect on the post-KT score. CONCLUSION: A low pre-KT MoCA score is not a strong independent predictor of post-KT cognitive function and should not preclude patients from receiving a KT.

Assessment of Atherosclerosis in Sle Patients by Measuring Carotid Intima Media Thickness: A Cross Sectional Study.

SLE patients have an increased burden of atherosclerosis leading to adverse cardiovascular events.Alterations in endothelial function, dysregulated immune system and increased oxidative stress are implicated in their development and progression. Carotid Artery Ultrasound has been recommended by the AHA/ACC to assess and follow progression of subclinical atherosclerosis & correlate with traditional /non traditional CV risk factors in SLE. To study the correlation between Carotid Intima Media Thickness, traditional/non traditional CV risk factors in SLE. MATERIAL: Hospital based descriptive, cross sectional study.Patients with Systemic Lupus Erythematosus, diagnosed by SLICC 2012 criteria, aged > 12 years, irrespective of therapy status, between April 2019 to August 2020, were recruited by consecutive sampling. Non consenting patients, individuals with preexisting cardiovascular disease, history of MACE, hypothyroidism (detected prior to diagnosis of SLE/disease onset), smokers, PLHIV,individuals with neck surgical, radiation, were excluded. OBSERVATION: 55 SLE patients were observed. No individuals were lost to follow up. Subgroup analysis was performed between SLE with Nephritis (36) and those without Nephritis (19) as presenting features. The mean age of the study subjects is 33 years with mean disease duration of 4.6 years.SLE nephritis patients had longer disease duration,younger age of disease onset & longer duration of steroid usage.The mean Systolic BP is 134+/-20mmHg, observed to be significantly higher in SLE nephritis patients. Framingham Risk scores were positively correlated with duration of SLE disease & SLEDAI 2K scores & duration of steroid therapy. The mean CIMT of the study population is 0.91mm with 10.9% plaque prevalence whereas Mean CIMT of Lupus nephritis patients is 1.02+/- 0.27mm; but no statistically significant difference in CIMT was observed between two subgroups. Carotid Intima Media thickness was positively correlated in bivariate analysis with anti DSDNA ab levels, Framingham Risk Scores,anaemia, SLE Disease activity scores, 24hr urine proteinuria,duration of steroid usage, Serum Creatinine & CRP. No correlation between CIMT and age of subjects,FPG,TG,serum homocysteine was observed. CONCLUSION: SLE patients have a high atherosclerosis burden and are at increased risk of adverse cardiovascular events. Carotid intima media thickness measurement by USG doppler is a reliable, non invasive, inexpensive tool which helps to detect subclinical atherosclerosis and plaques in SLE patients. In this study,Lupus Nephritis patients, Neuropsychiatric SLE and SLE with secondary APS, early age of lupus onset, longer disease duration with prolonged steroid therapy,significant proteinuria, higher antiDSDNA ab levels and hypocomplementemia are observed to have higher mean CIMT and plaque formation.

GABAA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability. FXS is caused by functional loss of the Fragile X Protein (FXP), also known as Fragile X Mental Retardation Protein (FMRP). In humans and animal models, loss of FXP leads to sensory hypersensitivity, increased susceptibility to seizures and cortical hyperactivity. Several components of the GABAergic system, the major inhibitory system in the brain, are dysregulated in FXS, and thus modulation of GABAergic transmission was suggested and tested as a treatment strategy. However, so far, clinical trials using broad spectrum GABAA or GABAB receptor-specific agonists have not yielded broad improvement of FXS phenotypes in humans. Here, we tested a more selective strategy in Fmr1 knockout (KO) mice using the experimental drug BAER-101, which is a selective GABAA α2/α3 agonist. Our results suggest that BAER-101 reduces hyperexcitability of cortical circuits, partially corrects increased frequency-specific baseline cortical EEG power, reduces susceptibility to audiogenic seizures and improves novel object memory. Other Fmr1 KO-specific phenotypes were not improved by the drug, such as increased hippocampal dendritic spine density, open field activity and marble burying. Overall, this work shows that BAER-101 improves select phenotypes in Fmr1 KO mice and encourages further studies into the efficacy of GABAA-receptor subunit-selective agonists for the treatment of FXS.

Decoding Directing Groups and Their Pivotal Role in C-H Activation.

Synthetic organic chemistry has witnessed a plethora of functionalization and defunctionalization strategies. In this regard, C-H functionalization has been at the forefront due to the multifarious applications in the development of simple to complex molecular architectures and holds a brilliant prospect in drug development and discovery. Despite been explored tremendously by chemists, this functionalization strategy still enjoys the employment of novel metal catalysts as well metal-free organic ligands. Moreover, the switch to photo- and electrochemistry has widened our understanding of the alternative pathways via which a reaction can proceed and these strategies have garnered prominence when applied to C-H activation. Synthetic chemists have been foraging for new directing groups and templates for the selective activation of C-H bonds from a myriad of carbon-hydrogen bonds in aromatic as well as aliphatic systems. As a matter of fact, by varying the templates and directing groups, scientists found the answer to the challenge of distal C-H bond activation which remained an obstacle for a very long time. These templates have been frequently harnessed for selectively activating C-H bonds of natural products, drugs, and macromolecules decorated with multiple C-H bonds. This itself was a challenge before the commencement of this field as functionalization of a site other than the targeted site could modify and hamper the biological activity of the pharmacophore. Total synthesis and pharmacophore development often faces the difficulty of superfluous reaction steps towards selective functionalization. This obstacle has been solved by late-stage functionalization simply by harnessing C-H bond activation. Moreover, green chemistry and metal-free reaction conditions have seen light in the past few decades due to the rising concern about environmental issues. Therefore, metal-free catalysts or the usage of non-toxic metals have been recently showcased in a number of elegant works. Also, research groups across the world are developing rational strategies for directing group free or non-directed protocols that are just guided by ligands. This review encapsulates the research works pertinent to C-H bond activation and discusses the science devoted to it at the fundamental level. This review gives the readers a broad understanding of how these strategies work, the execution of various metal catalysts, and directing groups. This not only helps a budding scientist towards the commencement of his/her research but also helps a matured mind searching out for selective functionalization. A detailed picture of this field and its progress with time has been portrayed in lucid scientific language with a motive to inculcate and educate scientific minds about this beautiful strategy with an overview of the most relevant and significant works of this era. The unique trait of this review is the detailed description and classification of various directing groups and their utility over a wide substrate scope. This allows an experimental chemist to understand the applicability of this domain and employ it over any targeted substrate.

An expeditious click approach towards the synthesis of galactose coated novel glyco-dendrimers and dentromers utilizing a double stage convergent method.

The primary motive behind this article is to bring to the forefront a unique kind of dendrimer which has remained a dark horse since its discovery, namely dentromer. We herein report the synthesis of glycodendrimers and glycodentromers crowned with galactose units by harnessing an expeditious synthesis of dendrimer core 18 and dentromer core 19, divergently with branching directionality (1 → 2) and (1 → 3), respectively. A competent, double stage convergent synthetic path was chosen to facilitate ease of refining and spectroscopic elucidations. By exploiting a Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction strategy, we successfully developed a new series of galactosylated dendrimers 20, 21, 22, and 24 containing 6, 12, 18, and 18 peripheral galactose units, respectively. We are first to report the practical synthesis of 9-peripheral galactose coated glycodentromer 23 (0th generation) and 27-peripheral galactose coated glycodentromer 25 (1st generation). These synthesized scaffolds were characterized by spectral studies such as 1H, 13C NMR, FT-IR, MALDI-TOF MS, HRMS and SEC analysis. Additionally, gel permeation chromatography depicted the regular progression in size from 6 to 27-peripheral galactose coated glycodendrimers along with glycodentromers, with their high monodispersity. Also, the glyco-dendrimers and dentromers synthesized from two different hypercore units i.e. dendrimers core (18) and dentromer core (19), have been supported by their UV-visible absorbance and emission spectroscopy.

Evaluation of the Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Inadequately Controlled With First-Generation Somatostatin Analogs.

Introduction: Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 µg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36-72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 µg/L and IGF-I 2.5 µg/L. For patients who entered the extension, 14.8% (95% CI: 8.1-23.9), 12.5% (95% CI: 6.4-21.3), 14.8% (95% CI: 8.1-23.9) and 11.4% (95% CI: 5.6-19.9) had mGH <1 µg/L and IGF-I

Efficacy and Safety of Patiromer in Hyperkalemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients at the highest risk of hyperkalemia are those with chronic kidney disease (CKD) stages 3 and 4. OBJECTIVE: To evaluate the efficacy and safety of patiromer in hyperkalemia in patients with heart failure or CKD. METHODS: The Cochrane Renal Group's Specialized Register was searched through contact with the Trials' Search Coordinator. We aimed at including randomized controlled trials with patiromer in patients with developed or risks of developing hyperkalemia, comparing against an active comparator or placebo. Three studies matched our inclusion and exclusion criteria, which we included in the meta-analysis. All-cause mortality, reduction in hospitalization, episodes of hypokalemia or hyperkalemia, and cardiovascular and gastrointestinal adverse events during the treatment period were our primary outcomes. Serial change in serum potassium (K+) until end of treatment or follow-up during the trial period and all other reported adverse reactions during the treatment period were our secondary outcomes. Meta-analysis (RevMan version 5.3.5) and descriptive statistics were used. RESULTS: There was a non-significant improvement in all-cause mortality and serious cardiovascular events with patiromer than placebo. Hospitalization data were unavailable. Although serious gastrointestinal events were more common with placebo, there was a significant reduction ( P = .02) in the risk of non-serious gastrointestinal events with placebo. Patiromer lowered serum K+ more than placebo, and there were more patients developing hyperkalemia with placebo. High-dose patiromer was associated with better efficacy in some parameters but with more adverse events. CONCLUSION: Although patiromer seems promising, more trials with active comparator are essential to finalize its indication and use in hyperkalemia.