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Iron(III) complexes based on N,N´-bis(salicylidene)ethylenediamine (salene) scaffolds have demonstrated promising anticancer features like induction of ferroptosis, an iron dependent cell death. Since poor cellular uptake limits their therapeutical potential, this study aimed to enhance the lipophilic character of chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes by introducing lipophilicity improving ligands such as fluorine (X1), chlorine (X2) and bromine (X3) in 5-position in the salicylidene moieties. After detailed characterization the binding to nucleophiles, logP values and cellular uptake were determined. The complexes were further evaluated regarding their biological activity on MDA-MB 231 mammary carcinoma, the non-tumorous SV-80 fibroblast, HS-5 stroma and MCF-10A mammary gland cell lines. Stability of the complexes in aqueous and biological environments was proven by the lack of interactions with amino acids and glutathione. Cellular uptake was positively correlated with the logP values, indicating that higher lipophilicity enhanced cellular uptake. The complexes induced strong antiproliferative and antimetabolic effects on MDA-MB 231 cells, but were inactive on all non-malignant cells tested. Generation of mitochondrial reactive oxygen species, increase of lipid peroxidation and induction of both ferroptosis and necroptosis were identified as mechanisms of action. In conclusion, halogenation of chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes raises their lipophilic character resulting in improved cellular uptake., (© 2024. The Author(s).)

This multidisciplinary study examined the pharmacokinetics of nanoparticles based on albumin-DTPA-gadolinium chelates, testing the hypothesis that these nanoparticles create a stronger vessel signal than conventional gadolinium-based contrast agents and exploring if they are safe for clinical use. Nanoparticles based on human serum albumin, bearing gadolinium and designed for use in magnetic resonance imaging, were used to generate magnet resonance images (MRI) of the vascular system in rats ("blood pool imaging"). At the low nanoparticle doses used for radionuclide imaging, nanoparticle-associated metals were cleared from the blood into the liver during the first 4 h after nanoparticle application. At the higher doses required for MRI, the liver became saturated and kidney and spleen acted as additional sinks for the metals, and accounted for most processing of the nanoparticles. The multiple components of the nanoparticles were cleared independently of one another. Albumin was detected in liver, spleen, and kidneys for up to 2 days after intravenous injection. Gadolinium was retained in the liver, kidneys, and spleen in significant concentrations for much longer. Gadolinium was present as significant fractions of initial dose for longer than 2 weeks after application, and gadolinium clearance was only complete after 6 weeks. Our analysis could not account quantitatively for the full dose of gadolinium that was applied, but numerous organs were found to contain gadolinium in the collagen of their connective tissues. Multiple lines of evidence indicated intracellular processing opening the DTPA chelates and leading to gadolinium long-term storage, in particular inside lysosomes. Turnover of the stored gadolinium was found to occur in soluble form in the kidneys, the liver, and the colon for up to 3 weeks after application. Gadolinium overload poses a significant hazard due to the high toxicity of free gadolinium ions. We discuss the relevance of our findings to gadolinium-deposition diseases.

Introduction: Voiding disorders are a common problem in elderly people. The highest incidence and prevalence occurs in female patients with a high level of dependency and cognitive impairments., Aim: The aim of the study was to define the correlation between the presence of voiding disorders and age-related functional deficits in hospitalized elderly patients within the framework of a comprehensive geriatric assessment. This is of utmost importance for planning adequate further diagnostic and therapeutic measures., Methods: This study involved a retrospective cross-sectional assessment of data from 7487 hospitalized patients (74.1 % females, 25.9 % males, mean age 78.9 ± 7.2 years) evaluated by a multidimensional geriatric assessment. Items tested were symptoms of voiding disorders, activities of daily living, cognitive and emotional status, mobility, handgrip strength, need for walking aids, pain, nutritional status and visual function. Data were evaluated with respect to the prevalence of voiding disorders, patient functional status and to the relationship between these findings., Results: Among all patients 4494 (60.0 %) presented with voiding disorders. Of these 95.8 % showed additional relevant functional deficits in three or more test items. Voiding disorders were positively correlated to patient age, dependency in activities of daily living and pain scores and were negatively correlated to cognitive and emotional status, mobility, hand grip strength, nutritional status and visual function. The functional deficits were associated with the severity of voiding disorders. Female patients were more often affected by voiding disorders as well as by functional impairments in comparison to male patients., Discussion: The results showed that more than half of the elderly hospitalized patients suffered from voiding disorders. The high prevalence and correlation between the presence of voiding disorders and functional deficits indicate the need to clearly define and plan diagnostic and therapeutic measures (e. g. bladder diaries and bladder retraining) for these patients, taking the individual functional status into consideration., Conclusion: In older patients with voiding disorders, high levels of functional impairment should be considered before planning diagnostic and therapeutic measures in order to ensure the quality of implementation.

Symptoms of urinary incontinence are a common problem in elderly, multimorbid female patients. The first step in establishing optimal management is to screen patients routinely and address this pathology directly. Urinary incontinence is considered to be a geriatric syndrome. It develops as a consequence of many complex underlying and potentially synergistic factors related to ageing and disease. A multidimensional clinically based assessment of urinary incontinence should be performed using a defined multimodal method including geriatric assessment, medical history, targeted physical investigation, urinalysis, and measurement of post-void residual urine volume. The aim is to identify as many of the underlying factors and pathologies, followed by step-by-step treatment to alleviate or eliminate incontinence. With this approach, excellent therapeutic results can be achieved in practice, even in elderly patients.

Introduction and Hypothesis: The purpose of this study was to determine pelvic floor muscle (PFM) function in hospitalized elderly women with urinary incontinence (UI)., Methods: A cross-sectional study was performed using data of 704 patients, routinely collected by means of a clinical UI assessment., Results: Only 25.5% of the patients were able to perform normal PFM contractions (Oxford grading scale score ≥3); 74.5% were unable to contract their PFM or showed weak PFM activity without circular contraction or elevation of the vagina. Vulvovaginal mucosal dystrophy was noted in 84% of the patients. A significant positive correlation of PFM function was found to cognitive status (MMSE score), mobility (Tinetti performance score), and history of previous PFM training; a negative correlation of PFM function was found to patients' age and vulvovaginal mucosal dystrophy, and no significant correlation to body mass index, parity, or history of hysterectomy., Conclusions: Targeted clinical UI assessment including digital vaginal palpation should be performed in all incontinent elderly women in order to detect PFM dysfunction and to optimize therapeutic measures.

Polypharmacy as well as urinary incontinence are common geriatric problems. Possible adverse drug effects remain a matter of concern in geriatric medicine and must be considered in urinary incontinence. The occurrence or aggravation of lower urinary tract symptoms might be caused by medication, especially when the symptom is newly diagnosed. On the other hand geriatric patients are at an increased risk for adverse effects of medications, commonly used for treatment of urinary incontinence. Especially antimuscarinic drugs reveal several complex anticholinergic adverse effects. Therefore, knowledge of inappropriate medication and of possible adverse drug effects is important in the diagnostic evaluation and therapeutic considerations to prevent a cascade of symptom-related medications.

Introduction and Hypothesis: the aim of this pilot study was to demonstrate physiological movements of the muscular walls surrounding the abdominal cavity during breathing and coughing in healthy nulliparous women by means of real-time dynamic magnetic resonance imaging (MRI)., Methods: eight volunteers underwent MRI measurements in a 1.5-T whole body MR-scanner. Coronal and sagittal slices were acquired simultaneously to assess respiratory-related cranio-caudal movement of diaphragm and pelvic floor (PF) and concomitant changes in horizontal abdominal diameter., Results: respective mean amplitudes of cranio-caudal movement of the right and left diaphragmatic cupolae were 15 ± 6 and 9 ± 7 mm during quiet breathing; 32 ± 15 and 28 ± 16 mm during forceful breathing; and 32 ± 13 and 28 ± 7 mm during coughing. Both diaphragm and PF moved caudally during inspiration and cranially during expiration. Abdominal diameter decreased in all eight women consistently during the expiration phase of breathing, and in five women during coughing., Conclusions: in healthy women, real-time dynamic MRI demonstrates parallel cranio-caudal movement of the diaphragm and the PF during breathing and coughing and synchronous changes in abdominal wall diameter.

We are developing a nanoparticulate histochemical reagent designed for histochemistry in living animals (molecular imaging), which should finally be useful in clinical imaging applications. The iterative development procedure employed involves conceptual design of the reagent, synthesis and testing of the reagent, then redesign based on data from the testing; each cycle of testing and development generates a new generation of nanoparticles, and this report describes the synthesis and testing of the third generation. The nanoparticles are based on human serum albumin and the imaging modality selected is magnetic resonance imaging (MRI). Testing the second particle generation with newly introduced techniques revealed the presence of impurities in the final product, therefore we replaced dialysis with diafiltration. We introduced further testing methods including thin layer chromatography, arsenazo III as chromogenic assay for gadolinium, and several versions of polyacrylamide gel electrophoresis, for physicochemical characterisation of the nanoparticles and intermediate synthesis compounds. The high grade of chemical purity achieved by combined application of these methodologies allowed standardised particle sizes to be achieved (low dispersities), and accurate measurement of critical physicochemical parameters influencing particle size and imaging properties. Regression plots confirmed the high purity and standardisation. The good degree of quantitative physicochemical characterisation aided our understanding of the nanoparticles and allowed a conceptual model of them to be prepared. Toxicological screening demonstrated the extremely low toxicity of the particles. The high magnetic resonance relaxivities and enhanced mechanical stability of the particles make them an excellent platform for the further development of MRI molecular imaging.

To develop a platform for molecular magnetic resonance imaging, we prepared gadolinium-bearing albumin-polylactic acid nanoparticles in the size range 20-40 nm diameter. Iterative cycles of design and testing upscaled the synthesis procedures to gram amounts for physicochemical characterisation and for pharmacokinetic testing. Morphological analyses showed that the nanoparticles were spheroidal with rough surfaces. Particle sizes were measured by direct transmission electron microscopical measurements from negatively contrasted preparations, and by use of photon correlation spectroscopy; the two methods each documented nanoparticle sizes less than 100 nm and generally 10-40 nm diameter, though with significant intrabatch and interbatch variability. The particles' charge sufficed to hold them in suspension. HSA retained its tertiary structure in the particles. The nanoparticles were stable against turbulent flow conditions and against heat, though not against detergents. MRI imaging of liquid columns was possible at nanoparticle concentrations below 10 mg/ml. The particles were non-cytotoxic, non-thrombogenic and non-immunogenic in a range of assay systems developed for toxicity testing of nanoparticles. They were micellar prior to lyophilisation, but loosely structured aggregated masses after lyophilisation and subsequent resuspension. These nanoparticles provide a platform for further development, based on non-toxic materials of low immunogenicity already in clinical use, not expensive, and synthesized using methods which can be upscaled for industrial production.

Introduction and Hypothesis: The aim of this cross-sectional study was to determine correlations between pelvic floor muscle (PFM) function and expiratory function in healthy young nulliparous women., Methods: In 40 volunteers, PFM function was assessed by vaginal palpation. Forced expiration patterns were evaluated visually and by palpation of the suprapubic insertion region of the anterolateral abdominal muscles. Forced vital capacity (FVC) and forced expiratory flows (FEF) were determined by spirometry., Results: Incremental positive correlation was found between voluntary PFM contraction strength and forced expiratory flow at 25%, 50% and 75% (FEF(25%), FEF(50%), FEF(75%)) of the FVC, respectively. Positive correlation was also found between PFM contraction strength and forced expired volume in 1 s (FEV(1)). No correlation was found between PFM contraction strength and FVC or peak expiratory flow (PEF)., Conclusions: Despite some limitations of this study, the observed correlation between PFM contraction strength and forced expiratory flows may serve as theoretical background for a potential role of coordinated abdominal and PFM training in diseases with expiratory flow limitations.

Unlabelled: Not only do anatomy and function of the pelvic floor play an important role as possible causes of female urinary incontinence, they are also crucial for its therapy. The aim of this case control study of female geriatric patients with symptoms of urinary incontinence was to determine the knowledge about their pelvic floor and to assess their ability to contract pelvic floor muscles voluntarily and reflexly., Methods: A total of 377 female geriatric patients with symptoms of urinary incontinence were investigated in a Basis Assessment for Urinary incontinence. The ability to contract their pelvic floor muscles was examined by a digital vaginal palpation. The extent of the registered muscle strength was graded by the Modified Oxford Grading Scale by Laycock (1994)., Results: Of the patients, 65.5% were not aware of their pelvic floor and were not able to contract the pelvic floor muscles (Grade 0 to 1 by Laycock), 22% had an inaccurate knowledge and only performed an insufficient pelvic floor muscle contraction (Grade 2 by Laycock). Only 12.5% could contract their pelvic floor muscles properly (Grade 3 to 4 by Laycock). A subgroup of 83 patients had already absolved pelvic floor exercises in the past, 80 patients with conventional instructions, 3 patients with digital vaginal control. In this subgroup 54.2% of the patients were not able to contract the pelvic floor muscles (Grade 0 to 1 by Laycock) 25.3% only performed an insufficient contraction (Grade 2 by Laycock), while 20% were able to perform a sufficient and powerful contraction (Grade 3 to 4 by Laycock). The three patients in the past controlled by a digital vaginal palpation were part of this group and managed a pelvic floor muscle strength Grade 4 by Laycock. A high percentage of female geriatric patients with symptoms of urinary incontinence have a lack of understanding regarding the position and function of their pelvic floor. These results suggest that conventional pelvic floor muscle exercises without specific control are not an appropriate method to improve geriatric patients' ability to contract their pelvic floor muscles and to prevent urine leakage.

The physical and chemical parameters involved in the design and synthesis of biospecifically targeted nanoparticulate contrast media for magnetic resonance molecular imaging (MRMI) were explored in this pilot investigation. Latex nanoparticles 100, 400 and 900 nm in diameter were doubly derivatised, first with tomato lectin and then with gadolinium(III)-diethylenetriamine pentaacetic acid (Gd-chelates) to target them to epithelial and endothelial glycocalyceal N-glycans and to generate contrast enhancement in magnetic resonance imaging (MRI). After intravenous injection into mice, human placental cotyledons or human Vena saphena magna, contrasty images of the vascular structures were obtained in 1.5 T MRI with spatial resolution 0.1 mm in the imaging plane and 0.6 mm in the z axis, persisting >60 min and resistant to washing out by buffer rinses. Ultrastructural analysis of the nanoparticles revealed the targeting groups at the nanoparticle surfaces and the distribution of the Gd-chelates within the nanoparticles and enabled counts for use in determining relaxivity. The relaxivity values revealed were extremely high, accounting for the strong MR signals observed. Occasionally, nanoparticles larger than 100 nm were seen in close spatial association with disrupted regions of cell membrane or of collagen fibrils in the extracellular matrix. The data suggest that 100-nm nanoparticles generate adequate contrast for MRMI and cause least disruption to endothelial cell surfaces.

Mouse NIH 3T3 fibroblasts were starved by serum depletion and subsequently restimulated by addition of serum. Histone acetylation and histone synthesis were studied from the beginning of starvation to the point where most of the cells were in S-phase utilizing electrophoretic and fluorographic techniques. We found that the major part of histone acetylation and histone synthesis occurs during S-phase but that also in the absence of DNA synthesis there are significant changes in the acetylation and synthesis rates of the core histones which occur during the first 6 hours of serum stimulation of quiescent cells, and between 24 and 48 hours of serum starvation.