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Cancers May 2024Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may...
Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, 100 males) with HCC with advanced PVTT (Vp3 or Vp4) who received PBT from April 2008 to March 2018. Of these patients, 63 received PBT as definitive treatment and 53 as palliative treatment. The representative dose was 72.6 Gy (RBE) in 22 fractions. Eight patients died in follow-up, including 72 due to tumor progression. The 5-year overall survival (OS) rate was 18.0% (95% CI 9.8-26.2%) and the 5-year local control (LC) rate was 86.1% (74.9-97.3%). In multivariate analyses, performance status and treatment strategy were significantly associated with OS. The median follow-up period for survivors with definitive treatment was 33.5 (2-129) months, and the 5-year OS rate was 25.1% (12.9-37.3%) in these cases. The median survival time after definitive irradiation was >20 months. The 5-year OS rate was 9.1% (0-19.7%) for palliative irradiation. These results compare favorably with those of other therapies and suggest that PBT is a useful option for cases of HCC with advanced PVTT that cannot undergo surgery, with an expected survival benefit and good local control. Determining the optimal indication for this treatment is a future challenge.
PubMed: 38893169
DOI: 10.3390/cancers16112050 -
Journal of Clinical Medicine May 2024: To define if the use of proton pump inhibitors (PPI) is associated with PDF prevalence and characteristics and with time of recovery after dialysis in patients on...
: To define if the use of proton pump inhibitors (PPI) is associated with PDF prevalence and characteristics and with time of recovery after dialysis in patients on maintenance hemodialysis. : Patients were defined as experiencing PDF if they spontaneously offered this complaint when asked the open-ended question: "Do you feel fatigued after dialysis?". Time of recovery after dialysis (TIRD) was also assessed for each patient. Each patient was invited to rate the intensity, duration and frequency of PDF from 1 to 5. We defined if patients used PPI (no PPI use or PPI use), the type of used PPI, the dose of used PPI, and the duration of the use of PPI (<1 year or ≥1 year). : A total of 346 patients were studied: 259 used PPI (55 used omeprazole, 63 esomeprazole, 54 pantoprazole, 87 lansoprazole, and 7 rabeprazole) and 87 did not. Two hundred and thirty-two patients declared PDF and 114 did not. The median [min-max] TIRD was 210 min [0-1440]. The prevalence of PDF in PPI users and PPI non-users was 67% and 68%, respectively ( = 0.878). The median [min-max] TIRD did not differ significantly between PPI users and PPI non-users (180 [0-1440] and 240 [0-1440], respectively; = 0.871). Median PDF intensity, duration, frequency, and severity did not differ significantly between PPI use and no use. The prevalence of PDF was similar among the different types of PPI use and did not differ with respect to PPI non-users. Duration of PPI exposure was <1 year in 40 patients and ≥1 year in 219 patients. The prevalence of PDF did not differ between the two exposures. The correlation matrix between PPI equivalent dose, PPI treatment duration and PDF frequency, PDF characteristics, and TIRD showed whether there was statistical significance. : The use of PPI is not associated with PDF and time of recovery after dialysis in patients on maintenance hemodialysis.
PubMed: 38892950
DOI: 10.3390/jcm13113241 -
Journal of Clinical Medicine May 2024Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection...
Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI.
PubMed: 38892766
DOI: 10.3390/jcm13113056 -
Nutrients May 2024The relation of vitamin C with Alzheimer's disease (AD) is equivocal. The aim of this study was to assess the relation of serum vitamin C levels with AD-related...
The relation of vitamin C with Alzheimer's disease (AD) is equivocal. The aim of this study was to assess the relation of serum vitamin C levels with AD-related mortality, and to evaluate the threshold beyond which the potential benefits of higher serum concentrations of vitamin C for AD mortality ceases. The cohort consisted of 4504 adults aged ≥60 years enrolled in the National Health and Nutrition Examination Survey who had serum measures of vitamin C and no cognitive impairment at baseline (1988-1994) and were followed-up for mortality until 2019. Vitamin C was assayed from fasting blood samples using isocratic high-performance liquid chromatography. At baseline, the mean age of participants was 70 years, with 42.7% being men. At the end of follow-up (median: 15 years), the AD mortality rate was 2.4 per 1000 person-years. In the Cox regression models, compared to participants in the lowest tertile of serum vitamin C (<0.56 mg/dL), those in the highest tertile (>0.98 mg/dL) had a lower risk of AD mortality (hazard ratio: 0.44, 95% confidence intervals: 0.25-0.77) after adjusting for sociodemographic factors, behavior/lifestyle factors, prevalent health conditions, and dietary vitamin C intake. In dose-response analysis using restricted cubic splines, vitamin C concentrations beyond 2.3 mg/dL were associated with the elevated risk of AD-related mortality. The findings from this national sample of community-dwelling elderly adults suggest that higher levels of serum vitamin C are associated with slower AD disease progression, although levels beyond the normal reference values were associated with a higher risk of AD mortality.
Topics: Humans; Alzheimer Disease; Male; Female; Ascorbic Acid; Aged; Independent Living; Middle Aged; Nutrition Surveys; Cohort Studies; Proportional Hazards Models; Aged, 80 and over; Risk Factors
PubMed: 38892605
DOI: 10.3390/nu16111672 -
Nutrients May 2024The relative availability of the essential amino acid tryptophan in the brain, as indicated by the tryptophan index, which is the ratio of tryptophan to its competing...
BACKGROUND
The relative availability of the essential amino acid tryptophan in the brain, as indicated by the tryptophan index, which is the ratio of tryptophan to its competing amino acids (CAAs) in circulation, has been related to major depression. However, it remains unknown whether tryptophan availability is involved in the pathogenesis of ischemic stroke.
AIMS
We aimed to investigate the relationship between the tryptophan index and the risk of ischemic stroke.
METHODS
We performed a nested case-control study within a community-based cohort in eastern China over the period 2013 to 2018. The analysis included 321 cases of ischemic stroke and 321 controls matched by sex and date of birth. The plasma levels of tryptophan and CAAs, including tyrosine, valine, phenylalanine, leucine, and isoleucine, were measured by ultra-high-performance liquid chromatography-tandem mass spectrometry. Conditional logistic regression analyses were employed to determine incidence rate ratios (IRRs) and their 95% confidence intervals (CIs).
RESULTS
After adjustment for body mass index, current smoking status, educational attainment, physical activity, family history of stroke, hypertension, diabetes, hyperlipidemia, and estimated glomerular filtration rate, an elevated tryptophan index was significantly associated with a reduced risk of ischemic stroke in a dose-response manner (IRR, 0.76; 95% CI, 0.63-0.93, per standard deviation increment). The plasma tryptophan or CAAs were not separately associated with the risk of ischemic stroke.
CONCLUSIONS
The tryptophan index was inversely associated with the risk of ischemic stroke. Our novel observations suggest that the availability of the essential amino acid tryptophan in the brain is involved in the pathogenesis of ischemic stroke.
Topics: Humans; Case-Control Studies; Female; Male; Tryptophan; Middle Aged; Ischemic Stroke; Aged; Risk Factors; China
PubMed: 38892478
DOI: 10.3390/nu16111544 -
International Journal of Molecular... Jun 2024An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a...
An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.
Topics: Animals; Dogs; Neprilysin; Hemodynamics; Angiotensin Receptor Antagonists; Kidney; Valsartan; Male; Aminobutyrates; Blood Pressure; Atrial Natriuretic Factor; Glomerular Filtration Rate; Female; Drug Combinations; Biphenyl Compounds; Tetrazoles; Renal Circulation
PubMed: 38892356
DOI: 10.3390/ijms25116169 -
International Journal of Molecular... May 2024A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in...
Differential Roles of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, and Prefrontal Cortex in Regulating Response to Methylphenidate: Insights from Neuronal and Behavioral Studies in Freely Behaving Rats.
A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose-response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals' behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied-the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)-responds significantly ( < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals' behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area's role in response to the drug.
Topics: Animals; Methylphenidate; Prefrontal Cortex; Rats; Neurons; Caudate Nucleus; Male; Ventral Tegmental Area; Nucleus Accumbens; Behavior, Animal; Locus Coeruleus; Rats, Sprague-Dawley; Dorsal Raphe Nucleus; Central Nervous System Stimulants
PubMed: 38892125
DOI: 10.3390/ijms25115938 -
International Journal of Molecular... May 2024The kinetics and mechanism of drug binding to its target are critical to pharmacological efficacy. A high throughput (HTS) screen often results in hundreds of hits, of...
The kinetics and mechanism of drug binding to its target are critical to pharmacological efficacy. A high throughput (HTS) screen often results in hundreds of hits, of which usually only simple IC values are determined during reconfirmation. However, kinetic parameters such as residence time for reversible inhibitors and the / ratio, which is the critical measure for evaluating covalent inactivators, are early predictive measures to assess the chances of success of the hits in the clinic. Using the promising cancer target human histone deacetylase 8 as an example, we present a robust method that calculates concentration-dependent apparent rate constants for the inhibition or inactivation of HDAC8 from dose-response curves recorded after different pre-incubation times. With these data, hit compounds can be classified according to their mechanism of action, and the relevant kinetic parameters can be calculated in a highly parallel fashion. HDAC8 inhibitors with known modes of action were correctly assigned to their mechanism, and the binding mechanisms of some hits from an internal HDAC8 screening campaign were newly determined. The oxonitriles SVE04 and SVE27 were classified as fast reversible HDAC8 inhibitors with moderate time-constant IC values of 4.2 and 2.6 µM, respectively. The hit compound TJ-19-24 and SAH03 behave like slow two-step inactivators or reversible inhibitors, with a very low reverse isomerization rate.
Topics: Humans; Histone Deacetylases; Histone Deacetylase Inhibitors; Kinetics; Repressor Proteins; Protein Binding; High-Throughput Screening Assays
PubMed: 38891780
DOI: 10.3390/ijms25115593 -
Plants (Basel, Switzerland) Jun 2024This study explores the interplay between nitrogen doses and seeding rates on wheat yield, biomass, and protein content. Utilizing tools such as the Normalized...
This study explores the interplay between nitrogen doses and seeding rates on wheat yield, biomass, and protein content. Utilizing tools such as the Normalized Difference Vegetation Index (NDVI), Soil Plant Analysis Development (SPAD) measurements, and canopy temperature (CT), we conducted experiments over five growing seasons. The treatments included three nitrogen levels (0, 60, 120 kg/ha) and three seeding rates (300, 400, 500 seeds/m) in a split-plot design with 90 plots and two replications. Our results show that an intermediate nitrogen dose (60 kg/ha) combined with a moderate seed rate (400 seeds/m) enhances wheat yield by 22.95%. Reduced nitrogen levels increased protein content, demonstrating wheat's adaptive mechanisms under nitrogen constraints. NDVI analysis highlighted significant growth during the tillering phase with high nitrogen, emphasizing early-stage nutrient management. SPAD measurements showed that early nitrogen applications boost chlorophyll content, essential for vigorous early growth, while CT data indicate that optimal nitrogen and seed rates can effectively modulate plant stress responses. As crops mature, the predictive capacity of NDVI declines, indicating the need for adjusted nitrogen strategies. Collectively, these findings advocate for refined management of nitrogen and seeding rates, integrating NDVI, SPAD, and CT assessments to enhance yields and promote sustainable agricultural practices while minimizing environmental impacts.
PubMed: 38891382
DOI: 10.3390/plants13111574 -
Plants (Basel, Switzerland) May 2024Rare earth elements (REEs) have been intentionally used in Chinese agriculture since the 1980s to improve crop yields. Around the world, REEs are also involuntarily...
Rare earth elements (REEs) have been intentionally used in Chinese agriculture since the 1980s to improve crop yields. Around the world, REEs are also involuntarily applied to soils through phosphate fertilizers. These elements are known to alleviate damage in plants under abiotic stresses, yet there is no information on how these elements act in the physiology of plants. The REE mode of action falls within the scope of the hormesis effect, with low-dose stimulation and high-dose adverse reactions. This study aimed to verify how REEs affect rice plants' physiology to test the threshold dose at which REEs could act as biostimulants in these plants. In experiment 1, 0.411 kg ha (foliar application) of a mixture of REE (containing 41.38% Ce, 23.95% La, 13.58% Pr, and 4.32% Nd) was applied, as well as two products containing 41.38% Ce and 23.95% La separately. The characteristics of chlorophyll fluorescence, gas exchanges, SPAD index, and biomass (pot conditions) were evaluated. For experiment 2, increasing rates of the REE mix (0, 0.1, 0.225, 0.5, and 1 kg ha) (field conditions) were used to study their effect on rice grain yield and nutrient concentration of rice leaves. Adding REEs to plants increased biomass production (23% with Ce, 31% with La, and 63% with REE Mix application) due to improved photosynthetic rate (8% with Ce, 15% with La, and 27% with REE mix), favored by the higher electronic flow (photosynthetic electron transport chain) (increase of 17%) and by the higher F/F (increase of 14%) and quantum yield of photosystem II (increase of 20% with Ce and La, and 29% with REE Mix), as well as by increased stomatal conductance (increase of 36%) and SPAD index (increase of 10% with Ce, 12% with La, and 15% with REE mix). Moreover, adding REEs potentiated the photosynthetic process by increasing rice leaves' N, Mg, K, and Mn concentrations (24-46%). The dose for the higher rice grain yield (an increase of 113%) was estimated for the REE mix at 0.72 kg ha.
PubMed: 38891244
DOI: 10.3390/plants13111435