Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells.

Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced numbers of microtubules prior to mitosis. This causes cells to undergo centrosome de-clustering, prolonged multipolar mitosis, and cell death. 3D-organotypic invasion assays reveal that CCB02 has broad anti-invasive activity in various cancer models, including tyrosine kinase inhibitor (TKI)-resistant EGFR-mutant non-small-cell lung cancers. Thus, we have identified a vulnerability of cancer cells to activation of extra centrosomes, which may serve as a global approach to target various tumors, including drug-resistant cancers exhibiting high incidence of centrosome amplification.

The inhibition of glucose uptake to erythrocytes: microwave dielectric response.

Dielectric spectroscopy has been used in the study and development of non-invasive glucose monitoring (NIGM) sensors, including the range of microwave frequencies. Dielectric relaxation of red blood cell (RBC) cytosolic water in the microwave frequency band has been shown to be sensitive to variations in the glucose concentration of RBC suspensions. It has been hypothesized that this sensitivity stems from the utilization of D-glucose by RBCs. To verify this proposition, RBCs were pretreated with inhibitors of D-glucose uptake (cytochalasin B and forskolin). Then their suspensions were exposed to different D-glucose concentrations as measured by microwave dielectric spectroscopy (MDS) in the 500 MHz-40 GHz frequency band. After incubation of RBCs with either inhibitor, the dielectric response of water in the cytoplasm, and specifically its relaxation time, demonstrated minimal sensitivity to the change of D-glucose concentration in the medium. This result allows us to conclude that the sensitivity of MDS to glucose uptake is associated with variations in the balance of bulk and bound RBC cytosolic water due to intracellular D-glucose metabolism, verifying the correctness of the initial hypothesis. These findings represent a further argument to establish the dielectric response of water as a marker of glucose variation in RBCs.

Continuing versus withholding angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) combination tablets during perioperative periods in patients undergoing minor surgery: a single-blinded randomized controlled trial.

PURPOSE: This trial was conducted to compare effects of continuing versus withholding single-pill combination tablets consisting of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) on perioperative hemodynamics and clinical outcomes. METHODS: Patients undergoing minor abdominal or urological surgery (n = 106) were randomly assigned to Group C, in which ARB/CCB combination tablets were continued until surgery, or Group W, in which they were withheld within 24 h of surgery. Perioperative hemodynamics and clinical outcomes were compared between the Groups. RESULTS: The incidence of hypotension during anesthesia requiring repeated treatment with vasoconstrictors was higher in Group C than Group W (p = 0.0052). Blood pressure during anesthesia was generally lower in Group C than Group W (p < 0.05) despite significantly more doses of ephedrine and phenylephrine administrated in Group C (p = 0.0246 and p = 0.0327, respectively). The incidence of postoperative hypertension did not differ between Groups (p = 0.3793). Estimated glomerular filtration rate (eGFR) on the preoperative day did not differ between Groups (p = 0.7045), while eGFR was slightly lower in Group C than Group W on the first and third postoperative days (p = 0.0400 and p = 0.0088, respectively), although clinically relevant acute kidney injury did not develop. CONCLUSIONS: Continuing ARB/CCB combination tablets preoperatively in patients undergoing minor surgery increased the incidence of hypotension during anesthesia, increased requirements of vasoconstrictors to treat hypotension, and might deteriorate postoperative renal function, albeit slightly. These results suggest that withholding ARB/CCB tablets preoperatively is preferable to continuing them. CLINICAL TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials (jRCT) at Japanese Ministry of Health, Labour, and Welfare (Trial ID: jRCT1031190027).

Comparative Effectiveness of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in Individuals With Advanced CKD: A Nationwide Observational Cohort Study.

RATIONALE & OBJECTIVE: It is unknown whether initiating renin-angiotensin system (RAS) inhibitor therapy in patients with advanced chronic kidney disease (CKD) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs). We compared the risks for kidney replacement therapy (KRT), mortality, and major adverse cardiovascular events (MACE) in patients with advanced CKD in routine nephrology practice who were initiating either RAS inhibitor or CCB therapy. STUDY DESIGN: Observational study in the Swedish Renal Registry, 2007 to 2017. SETTINGS & PARTICIPANTS: 2,458 new users of RAS inhibitors and 2,345 CCB users with estimated glomerular filtration rates<30mL/min/1.73m2 (CKD G4-G5 without KRT) who were being followed up by a nephrologist. As a positive control cohort, new users of the same drugs with CKD G3 (estimated glomerular filtration rate, 30-60mL/min/1.73m2) were evaluated. EXPOSURES: RAS inhibitor versus CCB therapy initiation. OUTCOME: Initiation of KRT (maintenance dialysis or transplantation), all-cause mortality, and MACE (composite of cardiovascular death, myocardial infarction, or stroke). ANALYTICAL APPROACH: HRs with 95% CIs were estimated using propensity score-weighted Cox proportional hazards regression adjusting for demographic, clinical, and laboratory covariates. RESULTS: Median age was 74 years, 38% were women, and median follow-up was 4.1 years. After propensity score weighting, there was significantly lower risk for KRT after new use of RAS inhibitors compared with new use of CCBs (adjusted HR, 0.79 [95% CI, 0.69-0.89]) but similar risks for mortality (adjusted HR, 0.97 [95% CI, 0.88-1.07]) and MACE (adjusted HR, 1.00 [95% CI, 0.88-1.15]). Results were consistent across subgroups and in as-treated analyses. The positive control cohort of patients with CKD G3 showed similar KRT risk reduction (adjusted HR, 0.67 [95% CI, 0.56-0.80]) with RAS inhibitor therapy compared with CCBs. LIMITATIONS: Potential confounding by indication. CONCLUSIONS: Our findings provide evidence from real-world clinical practice that initiation of RAS inhibitor therapy compared with CCBs may confer kidney benefits among patients with advanced CKD, with similar cardiovascular protection.

Synthesis of novel calcium channel blockers with ACE2 inhibition and dual antihypertensive/anti-inflammatory effects: A possible therapeutic tool for COVID-19.

Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2:SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition.

Pharmacogenomics of Hypertension Treatment.

Hypertension is one of the strongest modifiable cardiovascular risk factors, affecting an increasing number of people worldwide. Apart from poor medication adherence, the low efficacy of some therapies could also be related to inter-individual genetic variability. Genetic studies of families revealed that heritability accounts for 30% to 50% of inter-individual variation in blood pressure (BP). Genetic factors not only affect blood pressure (BP) elevation but also contribute to inter-individual variability in response to antihypertensive treatment. This article reviews the recent pharmacogenomics literature concerning the key classes of antihypertensive drugs currently in use (i.e., diuretics, ß-blockers, ACE inhibitors, ARB, and CCB). Due to the numerous studies on this topic and the sometimes-contradictory results within them, the presented data are limited to several selected SNPs that alter drug response. Genetic polymorphisms can influence drug responses through genes engaged in the pathogenesis of hypertension that are able to modify the effects of drugs, modifications in drug-gene mechanistic interactions, polymorphisms within drug-metabolizing enzymes, genes related to drug transporters, and genes participating in complex cascades and metabolic reactions. The results of numerous studies confirm that genotype-based antihypertension therapies are the most effective and may help to avoid the occurrence of major adverse events, as well as decrease the costs of treatment. However, the genetic heritability of drug response phenotypes seems to remain hidden in multigenic and multifactorial complex traits. Therefore, further studies are required to analyze all associations and formulate final genome-based treatment recommendations.

KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline.

Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality and reduction of elevated blood pressure (BP) remains an important intervention for slowing kidney disease progression. Over the past decade, the most appropriate BP target for initiation and titration of BP-lowering medications has been an area of intense research and debate within the clinical community. In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) in conjunction with several other professional societies released new hypertension guidelines based on data from a systematic review of clinical trials and observational data. While many of the recommendations in the ACC/AHA hypertension guideline are relevant to nephrology practice, BP targets and management strategies for patients receiving dialysis are not discussed. This Kidney Disease Outcomes Quality Initiative (KDOQI) commentary focuses largely on recommendations from the ACC/AHA hypertension guidelines that are pertinent to individuals at risk of chronic kidney disease or with non-dialysis-dependent chronic kidney disease. This KDOQI commentary also includes a brief discussion of the consensus statement regarding hypertension diagnosis and management for adults receiving maintenance dialysis published by the European Renal and Cardiovascular Medicine Working Group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension. Overall, we support the vast majority of the ACC/AHA recommendations and highlight select areas in which best diagnosis and treatment options remain controversial.

Comparison of real-world effectiveness between valsartan and non-RAS inhibitor monotherapy on the incidence of new diabetes in Chinese hypertensive patients: An electronic health recording system based study.

This study aimed to compare the real-world effectiveness of valsartan and non renin-angiotensin system (non-RAS) agent monotherapy on the incidence of new on-set diabetes (NOD) in Chinese hypertensive patients. It was based on an electronic Health Recording System database from Minhang District of Shanghai. Hypertensive patients aged ≥18 years continuously taking either valsartan or non-RAS agent monotherapy for >12 months were included. Hazard ratios (HR) of NOD events were estimated using propensity score matching method and multivariate regression. Of 29295 patients, there were 2107 in valsartan group, 21397 in CCB group, 4094 in ß-blockers group and 1697 in diuretics group. Two-year follow-up revealed NOD rates of 11.09 and 14.22 per 100 persons per year in valsartan and non-RAS inhibitor groups (HR = 0.77, 95% confidence interval 0.65-0.93, P = 0.006), respectively. Among non-RAS agents, CCB group had the highest incidence of NOD (21.72 per 100 persons per year). Comparisons between CCB sub-groups revealed the highest NOD incidence for nifedipine, followed by amlodipine and felodipine. NOD incidences in ß-blockers and diuretics groups (11.70 and 10.50 per 100 persons per year, respectively) were not significantly different from valsartan group. Compared with non-RAS inhibitors, particularly CCBs, valsartan could significantly reduce the incidence of NOD.

Large-scale integrated assessment of soil carbon and organic matter-related nitrogen fluxes in Saxony (Germany).

Changes in land-use, agricultural management and climate affect the turnover and storage of organic carbon in soils (SOC) as well as the nitrogen mobilization from soil organic matter (SOM), with potential side effects on nitrogen availability and leaching. When addressing the requests for increased carbon storage in soil as well as for the reduction of nitrogen losses, integrated approaches on regional scales are required that take into account the actual changes in agricultural management and climate. This study investigated the arable land (7345 km2) of Saxony (Germany) with regard to the following: (1) the trends of SOC storage and organic matter-related nitrogen fluxes, including their subregional and annual dynamics, (2) changes in the carbon input to arable soils and the turnover of organic matter, and (3) the contribution of different drivers (climate, crop production and fertilization, tillage system) to the simulated SOM changes for the period 1998-2014 on a 500 m grid. The model CANDY carbon balance (CCB) was specifically adapted for large-scale simulations of SOM turnover to link spatial data on soils and climate with regional statistics on agricultural management. This new 'regional mode' of CCB has been validated using data from 391 plots across different European locations. The initial SOC levels for Saxony assumed steady state conditions at the beginning of the simulation period and have been validated using data from 667 monitoring sites. The results showed an increase in the SOC stocks of the arable soils of Saxony of 785 × 103 t C (1.24‰ annually) during the simulation period. At the same time, the model simulated an average increase in organic nitrogen stored in SOM of approximately 7.5 kg N ha-1 a-1, with considerable differences between individual years and subregions. Both the increase in carbon inputs to soil (+8%) and the reduction of carbon turnover rates (-10%) had positive effects on SOC storage. While the increased use of conservation tillage was the most important driver for the overall increase in SOM storage in Saxony, climate variability and crop production and fertilization had the largest effect on its annual dynamics.

Changes in left ventricular geometry during antihypertensive treatment.

The reduction of echocardiographic left ventricular (LV) mass and the change toward a less concentric geometry during antihypertensive treatment are independently associated with a better prognosis. Blood pressure-lowering treatment may reduce cardiac hypertrophy, although different effect on changes of LV mass have been reported among antihypertensive drug classes, while changes in echocardiographic evaluated LV geometry have not been systemically evaluated. It is not yet clear whether antihypertensive drugs may influence LV geometry. Our aim was to compare the effects of diuretics (D), beta-blockers (BB), calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACE-I), and angiotensin receptor blockers (ARBS) on relative wall thickness (RWT) in patients with hypertension on the basis of prospective, randomized comparative studies. METHODS: MEDLINE, and the ISI Web of Sciences were searched for randomized clinical trials evaluating LV mass and geometry at baseline and end follow-up. We have performed a pooled pairwise comparisons of the effect of the 5 major drug classes on relative wall thickness changes, and of each drug class versus other classes statistically combined. RESULTS: We selected 53 publications involving 7684 patients. A significant correlation was observed between percent changes from baseline to end of treatment in LV mass and those in systolic BP (r = 0.44, p < 0.001). Reduction of LV mass was significantly greater with CCB than with BB (P <  0.02) without other significant differences between drug classes. Percent changes in RWT were related to percent changes in LV mass/LVmass index (r = 0.68, p = 0.016) and of SBP (r = 0.64 p < 0.033). RWT decreased during treatment with all classes of drugs, except the combination of BB and D; the decrease of RWT was less with diuretics and sympatholytic drugs. CONCLUSIONS: In studies evaluating the effect of different classes of antihypertensive drugs on LV mass, the reduction of relative wall thickness seems to be less during treatment with diuretics.

Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers.

We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 µmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 µmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60-<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.

A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension.

PURPOSE: Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). MATERIALS AND METHODS: The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long-term safety and BP (office and home), respectively. RESULTS: Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. CONCLUSIONS: The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension.

Impact of Seasonal Hypoxia on Activity and Community Structure of Chemolithoautotrophic Bacteria in a Coastal Sediment.

Seasonal hypoxia in coastal systems drastically changes the availability of electron acceptors in bottom water, which alters the sedimentary reoxidation of reduced compounds. However, the effect of seasonal hypoxia on the chemolithoautotrophic community that catalyzes these reoxidation reactions is rarely studied. Here, we examine the changes in activity and structure of the sedimentary chemolithoautotrophic bacterial community of a seasonally hypoxic saline basin under oxic (spring) and hypoxic (summer) conditions. Combined 16S rRNA gene amplicon sequencing and analysis of phospholipid-derived fatty acids indicated a major temporal shift in community structure. Aerobic sulfur-oxidizing Gammaproteobacteria (Thiotrichales) and Epsilonproteobacteria (Campylobacterales) were prevalent during spring, whereas Deltaproteobacteria (Desulfobacterales) related to sulfate-reducing bacteria prevailed during summer hypoxia. Chemolithoautotrophy rates in the surface sediment were three times higher in spring than in summer. The depth distribution of chemolithoautotrophy was linked to the distinct sulfur oxidation mechanisms identified through microsensor profiling, i.e., canonical sulfur oxidation, electrogenic sulfur oxidation by cable bacteria, and sulfide oxidation coupled to nitrate reduction by Beggiatoaceae The metabolic diversity of the sulfur-oxidizing bacterial community suggests a complex niche partitioning within the sediment, probably driven by the availability of reduced sulfur compounds (H2S, S0, and S2O32-) and electron acceptors (O2 and NO3-) regulated by seasonal hypoxia.IMPORTANCE Chemolithoautotrophic microbes in the seafloor are dependent on electron acceptors, like oxygen and nitrate, that diffuse from the overlying water. Seasonal hypoxia, however, drastically changes the availability of these electron acceptors in the bottom water; hence, one expects a strong impact of seasonal hypoxia on sedimentary chemolithoautotrophy. A multidisciplinary investigation of the sediments in a seasonally hypoxic coastal basin confirms this hypothesis. Our data show that bacterial community structure and chemolithoautotrophic activity varied with the seasonal depletion of oxygen. Unexpectedly, the dark carbon fixation was also dependent on the dominant microbial pathway of sulfur oxidation occurring in the sediment (i.e., canonical sulfur oxidation, electrogenic sulfur oxidation by cable bacteria, and sulfide oxidation coupled to nitrate reduction by Beggiatoaceae). These results suggest that a complex niche partitioning within the sulfur-oxidizing bacterial community additionally affects the chemolithoautotrophic community of seasonally hypoxic sediments.

Dissolved organic carbon and relationship with bacterioplankton community composition in 3 lake regions of Lake Taihu, China.

To clarify the relationships between dissolved organic carbon (DOC) and bacterioplankton community composition (BCC), a 1-year survey (June 2009 - May 2010) was conducted in 3 regions of Lake Taihu (Meiliang Bay, Lake Center, and Eastern Taihu), China. Polymerase chain reaction - denaturing gradient gel electrophoresis was used to analyze the composition and heterogeneity of the bacterioplankton community. Canonical correspondence analysis was used to explore the relationships between DOC concentration and BCC. We found a significant negative correlation between DOC concentration and bacterioplankton community diversity (as measured by the Shannon-Wiener index (H')). The results show that spatial variation in the bacterioplankton population was stronger than the seasonal variation and that DOC concentration influences BCC in Lake Taihu. DOC concentration, followed by macrophyte biomass, water turbidity, and phytoplankton biomass were the most influential factors that account for BCC changes in Lake Taihu. More detailed studies on the relationship between DOC concentration and BCC should focus on differences in DOC concentrations and quality among these lake regions. DOC had a significant impact on BCC in Meiliang Bay. The relationship between DOC and BCC in the 2 other regions studied (Lake Center and Eastern Taihu) was weaker. The results of this study add to our understanding of the BCC in eutrophic lakes, especially regarding the role of the microbial loop in lake ecosystems.

Association between types of antihypertensive medication and the risk of atrial fibrillation: a nationwide population study.

Background: Patients with hypertension are at a high risk of atrial fibrillation (AF). Recent research has indicated the varying effects of antihypertensive medications on developing AF. Objectives: We investigated the relationship between different types of antihypertensive medications and the risk of AF occurrence. Methods: We analyzed data from 113,582 subjects with national health screening examinations between 2009 and 2014. The study population was categorized according to antihypertensive medication type. The primary outcome was the incidence of AF. Results: Among 113,582 subjects (mean age 59.4 ± 12.0 years, 46.7% men), 93,557 received monotherapy [angiotensin receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEi), beta-blockers, calcium channel blockers (CCB), or diuretics], while 34,590 received combination therapy (ARB/beta-blockers, ARB/CCB, ARB/diuretics, or ARB/CCB/diuretics). During a mean follow-up duration of 7.6 ± 2.1 years, 3.9% of patients were newly diagnosed with AF. In monotherapy, ACEi and CCB had similar AF risks as ARB, while beta-blockers and diuretics showed higher AF risks than ARB. In combination therapy, ARBs/CCBs and ARBs/diuretics had the lowest AF risk, whereas ARBs/beta-blockers had the highest compared to ARB/CCB. Among the specific ARBs, the AF risk varied insignificantly, except for telmisartan and candesartan. Conclusions: In hypertensive patients receiving monotherapy, ACEi and CCB showed a similar AF risk as ARBs, while beta-blockers and diuretics were associated with a higher risk. Among those receiving combination therapy, ARBs/CCBs and ARBs/diuretics had the lowest AF risk, whereas ARBs/beta-blockers showed the highest risk. Various types of ARBs have different associations with AF risk.

Human brain atlas for automated region of interest selection in quantitative susceptibility mapping: application to determine iron content in deep gray matter structures.

The purpose of this paper is to extend the single-subject Eve atlas from Johns Hopkins University, which currently contains diffusion tensor and T1-weighted anatomical maps, by including contrast based on quantitative susceptibility mapping. The new atlas combines a "deep gray matter parcellation map" (DGMPM) derived from a single-subject quantitative susceptibility map with the previously established "white matter parcellation map" (WMPM) from the same subject's T1-weighted and diffusion tensor imaging data into an MNI coordinate map named the "Everything Parcellation Map in Eve Space," also known as the "EvePM." It allows automated segmentation of gray matter and white matter structures. Quantitative susceptibility maps from five healthy male volunteers (30 to 33 years of age) were coregistered to the Eve Atlas with AIR and Large Deformation Diffeomorphic Metric Mapping (LDDMM), and the transformation matrices were applied to the EvePM to produce automated parcellation in subject space. Parcellation accuracy was measured with a kappa analysis for the left and right structures of six deep gray matter regions. For multi-orientation QSM images, the Kappa statistic was 0.85 between automated and manual segmentation, with the inter-rater reproducibility Kappa being 0.89 for the human raters, suggesting "almost perfect" agreement between all segmentation methods. Segmentation seemed slightly more difficult for human raters on single-orientation QSM images, with the Kappa statistic being 0.88 between automated and manual segmentation, and 0.85 and 0.86 between human raters. Overall, this atlas provides a time-efficient tool for automated coregistration and segmentation of quantitative susceptibility data to analyze many regions of interest. These data were used to establish a baseline for normal magnetic susceptibility measurements for over 60 brain structures of 30- to 33-year-old males. Correlating the average susceptibility with age-based iron concentrations in gray matter structures measured by Hallgren and Sourander (1958) allowed interpolation of the average iron concentration of several deep gray matter regions delineated in the EvePM.

Proteomic analysis for testis of mice exposed to carbon ion radiation.

This paper investigates the mechanism of action of heavy ion radiation (HIR) on mouse testes. The testes of male mice subjected to whole body irradiation with carbon ion beam (0.5 and 4Gy) were analyzed at 7days after irradiation. A two-dimensional gel electrophoresis approach was employed to investigate the alteration of protein expression in the testes. Spot detection and matching were performed using the PDQuest 8.0 software. A difference of more than threefold in protein quantity (normalized spot volume) is the standard for detecting differentially expressed protein spots. A total of 11 differentially expressed proteins were found. Protein identification was performed using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-TOF). Nine specific proteins were identified by searching the protein sequence database of the National Center for Biotechnology Information. These proteins were found involved in molecular chaperones, metabolic enzymes, oxidative stress, sperm function, and spermatogenic cell proliferation. HIR decreased glutathione activity and increased malondialdehyde content in the testes. Given that Pin1 is related to the cell cycle and that proliferation is affected by spermatogenesis, we analyzed testicular histological changes and Pin1 protein expression through immunoblotting and immunofluorescence. Alterations of multiple pathways may be associated with HIR toxicity to the testes. Our findings are essential for studies on the development, biology, and pathology of mouse testes after HIR in space or radiotherapy.

Association of antihypertensive drugs with COVID-19 outcomes: a drug-target Mendelian randomization study.

Background: Observational investigations have provided conflicting results regarding the effect of antihypertensive drugs on the risk of COVID-19 outcomes. We intended to assess the causal effect of antihypertensive drugs on COVID-19 outcomes using drug-target Mendelian randomization (MR), mainly including angiotensin-converting enzyme inhibitors (ACEIs), ß-blockers (BBs) and calcium channel blockers (CCBs). Methods: We used the genetic variants (minor allele frequency >1%, r 2 < 0.30) located within 100 k bases of each drug target gene and associated with lower systolic blood pressure (p < 5 × 10-8) as genetic proxies for antihypertensive drugs. COVID-19 outcomes included COVID-19 susceptibility (122,616 cases and 2,475,240 controls), hospitalization (32,519 cases and 206,2805 controls), and severe illness (13,769 cases and 1,072,442 controls). All studies were conducted on populations of European ancestry. MR estimates were generated using an inverse variance weighted (IVW) model. Results: IVW-MR analysis observed a weak causality between CCBs and COVID-19 susceptibility (OR: 0.993, 95% CI: 0.988-0.999, p = 0.012). Sensitivity analysis suggested that this result was robust. No evidence was found for a link between other antihypertensive drugs and COVID-19 outcomes. Conclusion: The present study suggests that CCBs may reduce COVID-19 susceptibility in European populations.

Unique Case of Cardiogenic Shock in the Setting of Cumulative Calcium Channel Blocker Toxicity.

Calcium channel blockers (CCBs) are the most prescribed medications in clinical practice. These drugs treat many conditions, including migraine headaches, vasospasms, abnormal heart rhythms, and hypertension. This widespread use, however, has also been linked with the increased incidence of CCB toxicity cases. CCB toxicity may be from accidental ingestion or iatrogenic. Patients may show signs of cardiovascular toxicity such as hypotension, bradyarrhythmia, coma, or even death. The treatment includes discontinuing the offending medication, securing the airway, and raising blood pressure. Herein, we report a rare case of a 40-year-old male with a history of uncontrolled hypertension and advanced kidney disease who experienced iatrogenic cumulative calcium channel blocker toxicity while switching CCB classes due to a hypertensive emergency with concomitant atrial flutter. Although uncommon in clinical practice, iatrogenic CCB toxicity is possible and equally lethal. Clinicians must be cautious when initiating these drugs, switching between oral and intravenous formulations, or switching from one class to another to avoid overdoses.

Diabetes or calcium channel blocker contribute to cerebral hemodynamics after bypass surgery in adult patients with moyamoya disease.

Background: Moyamoya disease (MMD) is a teratogenic and lethal disease. However, existing studies do not sufficiently indicate the impact factors. Therefore, we investigated the different impact factors on cerebral hemodynamics after revascularization in patients with MMD. Methods: We retrospectively collected the clinical data of 233 adult patients with MMD who underwent revascularization surgery in the Department of Neurosurgery, Renmin Hospital of Wuhan University, from January 2015 to June 2021 for this retrospective cohort study. We analyzed the effects on hemodynamic improvement of age, sex, stroke type, early symptoms, Suzuki stage, history of hypertension, history of diabetes, and history of hyperlipidemia in patients with MMD. We also evaluated the efficacy of different revascularization strategies and we verified the effect of computed tomography perfusion (CTP) in evaluating cerebral hemodynamics. Results: The CTP values demonstrated that δ cerebral blood volume (CBV) values were significantly higher in the combined group [1.01 (0.87-1.75)] relative to those in the indirect group [1.34 (1.01-1.63); P=0.027]. There was no statistical significance in the improvement of clinical symptoms and clinical prognosis between the indirect and combined groups. Patients with MMD with diabetes [δ mean transit time (MTT), 0.49 (0.35-0.70) vs. 0.72 (0.52-0.87); P<0.001] or calcium channel blocker (CCB) [δCBV, 1.46 (1.10-1.83) vs. 1.12 (0.93-1.54); P=0.001] had better cerebral hemodynamics than patients in non-diabetic group or non-CCB group after revascularization. Conclusions: We didn't find differences in clinical outcome between indirect and combined revascularization in patients with MMD. we demonstrated that CTP values can be used as a way to detect postoperative cerebral hemodynamic changes in MMD patients. Interestingly, we found that MMD patients with diabetes or CCB showed better cerebral perfusion after revascularization.