Molecularly imprinted ‘traps’ for sulfonylureas prepared using polymerisable ion pairs

A novel approach towards recognition of sulfonylureas based on a polymerisable ion pair is presented. A solution association constant >10⁵ M⁻¹ between the model target glibenclamide and 4-vinylbenzyltrimethylammonium methacrylate is measured, and the formation of 1 : 1 complexes verified. Subsequently prepared stoichiometrically imprinted polymers exhibit exceptionally high affinity and binding capacity for glibenclamide, owing to synergistic binding of both the neutral and deprotonated form of the drug by the ion pair monomer. The polymers are applied to the selective extraction of glibenclamide from blood serum samples, achieving recoveries of up to 98% and demonstrating excellent long-term stability, negating the need for regular sorbent regeneration.

Polymerisable ion pair captures both neutral and anionic form of acidic sulfonylurea drug in stoichiometrically imprinted polymer.     

Quantitative assessment of the effects of 6 months of adapted physical activity on gait in people with multiple sclerosis: a randomized controlled trial

Purpose: The purpose of this study is to quantitatively assess the effect of 6 months of supervised adapted physical activity (APA i.e. physical activity designed for people with special needs) on spatio-temporal and kinematic parameters of gait in persons with Multiple Sclerosis (pwMS).

Methods: Twenty-two pwMS with Expanded Disability Status Scale scores ranging from 1.5 to 5.5 were randomly assigned either to the intervention group (APA, n?=?11) or the control group (CG, n?=?11). The former underwent 6 months of APA consisting of 3 weekly 60-min sessions of aerobic and strength training, while CG participants were engaged in no structured PA program. Gait patterns were analyzed before and after the training using three-dimensional gait analysis by calculating spatio-temporal parameters and concise indexes of gait kinematics (Gait Profile Score – GPS and Gait Variable Score – GVS) as well as dynamic Range of Motion (ROM) of hip, knee, and ankle joints.

Results: The training originated significant improvements in stride length, gait speed and cadence in the APA group, while GPS and GVS scores remained practically unchanged. A trend of improvement was also observed as regard the dynamic ROM of hip, knee, and ankle joints. No significant changes were observed in the CG for any of the parameters considered.

Conclusions: The quantitative analysis of gait supplied mixed evidence about the actual impact of 6 months of APA on pwMS. Although some improvements have been observed, the substantial constancy of kinematic patterns of gait suggests that the full transferability of the administered training on the ambulation function may require more specific exercises.

• Implications for rehabilitation

• Adapted Physical Activity (APA) is effective in improving spatio-temporal parameters of gait, but not kinematics, in people with multiple sclerosis.

• Dynamic range of motion during gait is increased after APA.

• The full transferability of APA on the ambulation function may require specific exercises rather than generic lower limbs strength/flexibility training.

     

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

Nuclear receptor coactivator 4 (NCOA4) promotes ferritin degradation and Ncoa4-ko mice in a C57BL/6 background show microcytosis and mild anemia, aggravated by iron deficiency. To understand tissue-specific contributions of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich Sv129/J strain. Increased body iron content protects these mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nevertheless, when fed a low-iron diet they develop a more severe anemia compared to that of wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Reconstitution of erythropoiesis with normalization of red blood count and hemoglobin concentration occurred at the same rate in transplanted animals independently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, erythropoietin administration failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematologic phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.     

Association between vitamin D deficiency and serum Homocysteine levels and its relationship with coronary artery disease

Journal of Thrombosis and Thrombolysis - Homocysteine (Hcy) elevation and vitamin D deficiency have emerged as potential markers of coronary artery disease (CAD). However, even tough...     

Evaluation of acromegaly treatment direct costs with respect to biochemical control and follow-up length

Purpose

Acromegaly is a severe chronic endocrine disease. Achieving biochemical control often needs a multimodal treatment approach, including prolonged medical treatment. Aim of the study is to evaluate the burden of treatment direct costs with respect to the different therapeutic strategies, disease control, and follow-up length.

Methods

Single center retrospective study on 73 acromegaly patients. Costs of acromegaly treatments were computed based on a detailed revision of patients’ clinical charts.

Results

Median total treatment cost/patient was €47,343 during the entire follow-up (8 years), while median treatment cost/patient/year was €6811. The majority of patients received medical therapy (71/73, 97.3%). Median cost for first-line medical treatment (first-generation somatostatin receptor ligands) was lower compared to second-line treatments (pegvisomant monotherapy or combination therapies), considering both total (€22,824 vs €76,140; p?<?0.001), and yearly cost/patient (€4927 vs €9161; p?<?0.001). Sixty patients (82.2%) reached biochemical control at last follow-up (IGF-1?≤?1 xULN). The percentage of patients treated with first- or second-line medical therapies was comparable between controlled and uncontrolled patients (p?=?1.000), and the yearly cost/patient did not significantly differ between the two groups (€6936 vs €6680; p?=?0.829). Follow-up duration was significantly longer in controlled patients compared to the uncontrolled ones (8.7 vs 3.5 years; p?=?0.019).

Conclusions

Direct costs for the management of acromegaly have a significant burden on the healthcare systems. However, more than 80% of our patients reached biochemical control using multimodal approaches. Treatment modalities and yearly costs did not significantly differ between controlled and uncontrolled patients, while follow-up length represented a major determinant of biochemical outcome.

     

Sex-related differences in diabetic kidney disease: A review on the mechanisms and potential therapeutic implications

Sexual dimorphism may play a key role in the pathogenesis of diabetic kidney disease (DKD) and explain differences observed in disease phenotypes, responses to interventions, and disease progression between men and women with diabetes. Therefore, omitting the consideration of sex as a biological factor may result in delayed diagnoses and suboptimal therapies. This review will summarize the effects of sexual dimorphism on putative metabolic and molecular mechanisms underlying DKD, and the potential implications of these differences on therapeutic interventions. To successfully implement precision medicine, we require a better understanding of sexual dimorphism in the pathophysiologic progression of DKD. Such insights can unveil sex-specific therapeutic targets that have the potential to maximize efficacy while minimizing adverse events.     

High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency

We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri–immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient’s CD4⁺ αβ T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4⁺ αβ T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4⁺ αβ T lymphocytes.