Autologous hematopoietic stem cell transplantation (HSCT) has been recognized as treatment alternative for patients with severe, refractory autoimmune rheumatic diseases (ARDs). Usually, ...anti-thymocyte globulin (ATG)-containing conditioning regimens are employed; however, ATG is unavailable in some developing nations. We report our 15-year clinical experience autografting patients with ARDs with an ATG-free conditioning regimen and a brief assessment of patient-reported outcomes post-HSCT. All patients had active disease and were resistant to multiple lines of treatment. Event-free survival (EFS) was assessed using the Kaplan-Meier method. Eight patients underwent autologous HSCT. Diagnoses included juvenile idiopathic arthritis (
n
= 3), systemic lupus erythematosus (
n
= 2), systemic sclerosis (
n
= 2), and rheumatoid arthritis (
n
= 1). Median time from diagnosis to HSCT was 3 years (0.75–19). Hematological recovery was documented in all recipients, and 4 patients (50%) completed the procedure in a completely ambulatory setting. Five (62.5%) patients achieved complete response and 3 (37.5%) partial response. The median EFS was 7 months (95% CI, 4.97–9.02), and the 1-year EFS rate was 21.9% (95% CI, 18.25–25.76). Transplant-related mortality was 0%, and 1 recipient died 8 years post-HSCT due to chronic kidney disease. Six (75%) patients presented steroid dosage reduction post-HSCT, and 2 (25%) perceived improvement in functionality despite having relapsed. HSCT is a viable treatment alternative for selected patients with severe therapy-resistant ARDs, as an improvement in disease management and quality of life was documented. The need remains to elucidate the characteristics of the optimal HSCT candidate, as well as the adequate conditioning regimen when ATG is not available.
Key Points
• Despite advances in the treatment of autoimmune rheumatic diseases, some patients remain refractory. In this context, autologous hematopoietic stem cell transplantation (HSCT) rises as a viable alternative.
• Of 8 HSCT recipients with autoimmune rheumatic diseases, 5 (62.5%) patients achieved complete response and 3 (37.5%) partial response, with a 1-year event-free survival of 21.9%.
• Transplant-related mortality was 0%, with 4 (50%) patients autografted in a completely outpatient setting.
• Even when relapse presented, patients reported an improvement in functionality and quality of life; also, a better response to DMARDs and a reduction in steroid dependency post-HSCT were documented.
A computational procedure based on the numerical integration of the Michaelis‐Menten model of enzyme action, free of any restrictions of steady‐state conditions and substrate/enzyme ratios is ...proposed. The original Michaelis‐Menten data for invertase (Michaelis and Menten, 1913, Biochem Z. 49:333‐369) were reanalyzed. The surface and contour plots that were generated for substrate, free enzyme, complex, and product confirmed the model's usefulness. All energy potentials G and the “conformational drift parameter” δ involved in the enzymatic reactions were determined. Our findings indicate that at so = 0.0052 M the enzyme‐substrate (ES) complex present an energy of dissociation of GE + S➔ES = 15.0 kJ/mol and as so increases to 0.333 M, the GE + S➔ES value decreases to 5.0 kJ/mol, thereby decreasing its presence in solution. Overall, the ability to determine G and δ for each transition suggests a relationship between kinetics and thermodynamics. The analysis proposed here can be directly applied to chemical and biological situations, as well as industrial processes.
A new approach for analyzing the simple Michaelis‐Menten original data is described using a computational/numerical integration approach yielding a complete Michaelis‐Menten solution. The system is free of steady‐state restrictions/enzyme‐substrate ratio limitations, and the method yields the Michaelis‐Menten kinetic constants k+1, k‐1 and k2 values. Free energy G and mass‐action coefficient suggest a kinetic‐thermodynamic link.
Agroindustrial potato (Solanum tuberosum L.) waste mainly includes peel and pulp; however, potatoes of low industrial quality are also discarded by industry. A viable alternative to give added value ...to these byproducts is the use of these as seeds, as well as the use of starch. The objective of this work was to evaluate the physiological quality (germination and vigor), starch content and relationship between these variables in discarded tubers from the industry through chemical-structural analyses to better understand their influence on starch composition. The physiological quality of the potatoes was evaluated through germination and vigor tests; likewise, starch was extracted, and the yield was determined. Physicochemical characterization of the starches was carried out through proximal and structural analysis using nuclear magnetic resonance (NMR). The results showed that the tubers had 100.00% germination and 98.66% vigor and were suitable for use as seeds. The starch yield did not significantly differ. However, characterization of the starch revealed significant differences (p less than or equal to 0.05) in moisture, ash, carbohydrate and amylose contents, which were influenced by the storage temperature (4 degreesC) of the tubers subjected to a vigor test, which interferes with enzymatic activity. During germination, the NMR results showed type B crystallinity, which is typical of tubers, indicating that the viability tests did not promote changes in the type of crystallinity. The results obtained can help us understand the effect of germination on the composition of starch and, accordingly, choose the most appropriate applications for this starch, whether food or nonfood. Key words: NMR, physiological quality, seed tuber, Solanum tuberosum, starch.
This article describes a design optimization method based on variable conversion applied to low-voltage (LV) CMOS analog integrated circuits. For supply voltages in the range of 0.3 to 0.6 V, ...traditional design variables (e.g., transistor channel width <inline-formula> <tex-math notation="LaTeX">W </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">\text {gm}/I_{D} </tex-math></inline-formula>) are not suitable for exploring the design space, leading to impractical design solutions. We show that it is more efficient to convert the design variables into current <inline-formula> <tex-math notation="LaTeX">I_{D} </tex-math></inline-formula> and channel length <inline-formula> <tex-math notation="LaTeX">L </tex-math></inline-formula>, since these parameters are directly related to circuit performance for LV applications. The proposed optimization algorithm explores the design space to obtain solutions that satisfy the design constraints while analyzing the effects of process, voltage, and temperature variations (PVT). We apply the proposed method for design optimization in terms of area and power consumption of a fourth-order LV active filter preceded by a programmable gain amplifier (PGA), in 130 nm CMOS technology. A fully differential 0.6 V operational amplifier (OTA) is designed as a building block and used in the filter in a bottom-up approach. Measurements of a prototype chip validate the proposed method and resulted in a 0.784 mW, 0.066 mm2 active low-pass filter with a cutoff frequency of 2.5 MHz and attenuation that meet the requirements of the IEEE 802.15.4 technical standard for 2.4 GHz receivers.
Abstract
α-Synuclein (αS), the causative protein of Parkinson’s disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer ...(HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.
•Hispanics with ALL have increased risk of relapse and complications.•Intensive pediatric-inspired regimens are the standard of care for B-ALL in adolescents and young adults.•Administering a ...modified, low-cost regimen focused on outpatient administration was safe, feasible and effective in a patient cohort in Mexico.•Outcomes are still limited by treatment adherence and affordability.
B-cell acute lymphoblastic leukemia is frequent in Hispanic adolescents and young adults. Outcomes of implementation of pediatric-inspired regimens in low-and middle-income countries are not well known.
In this study we treated 94 adolescents and young adults with a local BFM regimen designed to be affordable with the use of native L-asparaginase and mitoxantrone administered in an outpatient fashion, and the of BCR/ABL and measurable residual disease (MRD) determined by high sensitivity flow cytometry for risk stratification.
Induction mortality was 11%; 25% of patients had to abandon treatment or be transferred to another health system. Two-year overall (OS) and event free survival (EFS) were 61.5% and 49.8%, MRD-negative patients had a 24-month OS of 85.6% vs. 69.6% (p = .024) and EFS of 76% vs. 45.5% (p = .004). Patients older than 40 years and those who abandoned treatment had worse EFS. Overall drug costs in our regimen were 52% lower than those of CALGB10403.
The treatment of AYAs with ALL with an outpatient focus was implemented successfully at a reduced cost. Genetic risk assessment, treatment abandonment and lack of access to novel therapies remain major barriers for improving outcomes.
This study originated due to the need of more efficient, cost-effective, and ambulatory regimens for adolescents and AYAs with ALL. Patients received a modified pediatric inspired regimen adjusted for maximum affordability. We have treated 94 patients this treatment with an outpatient focus has shown the possibility to implement low-cost treatment strategies for LLA in young patients in middle and low-income countries.
Autologous stem cell transplantation (ASCT) is commonly an in-patient procedure. However, outpatient ASCT grows as a cost-effective and feasible option for patients with lymphoma and reports ...assessing it after reduced-intensity conditioning (RIC) are sparse. We report the outcome of 102 patients with lymphoma who underwent ASCT on a full outpatient basis in a single-center transplant program between 2010 and 2020. Forty-two percent of the cohort required transfusion support, 36.3% experienced a neutropenic fever episode, 25.5% mucositis, and 9.8% developed severe infection. At a median time of 5 days (range 1-28), only 22.5% of the cohort required admission within the first 100 days after the autograft, median length of hospital stay was 0 days (range 0-14) and neutropenic fever was the most common reason for hospitalization. Non-relapse mortality at 1 year was 5%. ASCT in a completely outpatient setting is feasible, safe, and highly effective to treat lymphoma patients.
The study aims to investigate the vitamin B6 levels in Parkinson's disease (PD) patients and their association with liver enzymes and evaluate how much dysregulation is associated with levodopa dose. ...Furthermore, to evaluate the effect of Opicapone, a catechol‐o‐methyl‐transferase inhibitor, on vitamin B6 levels by monitoring the AST and ALT levels in patients treated with Levodopa–Carbidopa Intestinal Gel Infusion (LCIG). For these aims, serum vitamin B6 levels were measured (PD, n = 72 and controls, n = 31). The vitamin B6 level was compared with the total levodopa dose, clinical parameters, and blood homocysteine, albumin, and hemoglobin levels in PD patients. Correlations between vitamin B6 levels and AST and ALT levels, as well as the ratio ALT/AST, were analyzed. Changes in the AST and ALT levels and ALT/AST were analyzed in the patients treated with LCIG before and after the therapy (n = 24) and in the patients treated with LCIG + Opicapone before and after Opicapone treatment (n = 12). We found vitamin B6 levels were significantly lower in PD patients. Total levodopa dose and albumin levels were independently associated with vitamin B6 levels. Decreased vitamin B6 levels appeared as lower AST and ALT levels and ALT/AS. Treatment with LCIG decreased the AST and ALT levels and ALT/AST. Adjunctive therapy with Opicapone to LCIG ameliorated the decreased ALT and ALT/AST. We conclude that the ALT and ALT/AST can be useful parameters for monitoring vitamin B6 levels and Opicapone can ameliorate the dysregulated vitamin B6 in PD patients.
Serum vitamin B6 level was strongly correlated with total levodopa dose in PD patients.
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