Mild cognitive impairment and early Alzheimer's disease eligibility for disease modification therapies in a tertiary centre for cognitive disorders: A simultaneous real-word study on aducanumab and lecanemab.

BACKGROUND AND PURPOSE: The Food and Drug Administration approved two disease-modifying treatments (DMTs) for Alzheimer's disease (AD), aducanumab and lecanemab, with limited clinical impact but significant biomarker changes. Identifying suitable candidates for these DMTs outside randomized clinical trials (RCTs) remains uncertain. METHODS: This cross-sectional study, conducted in an Italian tertiary centre for cognitive disorders, aimed to evaluate how the RCT eligibility criteria for DMT treatments applies to participants with early AD. The broader Cummings et al. (Journal of Prevention of Alzheimer's Disease, 2021, 2023) criteria and the clinical differences between DMT candidates were also assessed. RESULTS: The study involved 408 participants (mean age 71.1 ± 8.5 years, 48% male) with a clinical diagnosis of mild cognitive impairment (161/408, 39.5%) or mild dementia (247/408, 60.5%). Amongst them, 169 individuals (41%) showed positive AD pathology biomarkers. Eligibility RCT assessment revealed 14 patients eligible for aducanumab (3.43% of 408) and 28 for lecanemab (6.86% of 408). Following Cummings' real-world criteria, aducanumab eligibility increased to 9.56%, whereas lecanemab eligibility rose to 8.33%. Applying selection criteria to only the amyloid positive (169 out of 408), the selection for DMTs was 8.3% for aducanumab and 16.5% for lecanemab. CONCLUSION: Amongst subjects diagnosed with mild AD and mild cognitive impairment in a tertiary centre for cognitive disorders, only a small percentage of patients using RCT diagnostic criteria are eligible for DMT. The application of Cummings criteria strongly increased the DMT candidates. Nevertheless, the majority of patients with cognitive disorders have been excluded from DMTs approved so far.

Discovery of a small molecule insulin mimetic with antidiabetic activity in mice.

Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.

Maintenance of a laboratory colony of Cimex lectularius (Hemiptera: Cimicidae) using an artificial feeding technique.

The in vitro maintenance technique described in this article has been used successfully to rear Cimex lectularius (L.) by feeding for >2 yr all nymphal stages and adults through parafilm "M" sealing film on different types of blood. Using this feeding technique, the subsequent egg production of female bedbugs was remarkably high. The blood was maintained at 37 degrees C to enhance the attachment of the bugs. The effect of anticoagulation methods for the blood meal was investigated, and heparinized blood was found the most suitable for feeding bugs. All stages of the bugs fed weekly on blood in the artificial feeding system remained attached for up to 0.5-1.0 h, until completion of their blood meals, and all reached engorged weights. More than 90% of the bugs fed artificially on whole blood, and they molted or laid eggs successfully.

Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK.

A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.

Inhibitors of farnesylation of Ras from a microbial natural products screening program.

Mutant ras oncogenes are associated with various human tumors such as pancreas, colon, lung, thyroid, bladder and several types of leukemia. Prenylation of Ras proteins plays a major role in cell proliferation of both normal and cancerous cells. Normal and oncogenic Ras proteins are posttranslationally modified by a farnesyl group that promotes membrane binding. Inhibitors of farnesyl protein transferase (FPTase), the enzyme that catalyzes the prenylation of Ras proteins, inhibit growth of tumor cells. In an effort to identify structurally diverse and unique inhibitors of FPTase, a program devoted to screening of natural products was initiated. This effort led to the identification of 10 different families of compounds, all of which selectively inhibit FPTase with a variety of mechanisms that are reviewed in this manuscript. These compounds originated from the fermentations of a number of microorganisms, either actinomycetes or fungi, isolated from different substrates collected in tropical and temperate areas. A chemotaxonomic discussion on the distribution of each compound among single or different types of microorganisms, either phylogenetically related or unrelated species, is included.

Actuación de enfermería en la prevención y control del riesgo reproductivo preconcepcional / Nursing Performance in Prevention and Control of Preconception Reproductive Health

RESUMEN Introducción: La prevención de la enfermedad y la muerte durante el proceso de reproducción es uno de los pilares fundamentales para el desarrollo de la salud reproductiva, donde el rol de la enfermera juega un papel primordial en el empoderamiento del autocuidado de la mujer en edad fértil. Objetivo: Sistematizar la actuación de enfermería en la prevención y control del riesgo reproductivo preconcepcional. Métodos: Revisión bibliográfica sistemática para realizar análisis crítico reflexivo del contenido de artículos originales y de revisión publicados en español entre 2005 y 2015. La búsqueda fue realizada en las bases de datos Medline EMBASE, Current Contents, Science Citation Index, de enero a marzo de 2016, las palabras clave utilizadas fueron "riesgo preconcepcional", "práctica de enfermería", y "atención de enfermería al riesgo preconcepcional". Tras la identificación de los estudios pre-seleccionados se llevó a cabo la lectura de los títulos, resumen y palabras clave, comprobando la pertinencia con el estudio. Conclusión: Un adecuado conocimiento de la mujer en edad fértil sobre el riesgo preconcepcional permite mantener un estado de salud óptimo para asumir un embarazo con resultados finales satisfactorios. El déficit de conocimientos en la mujer sobre padecimientos o hábitos de riesgo para su salud y para asumir un embarazo satisfactorio, a ello se suma insuficiente trabajo de enfermería en la prevención del riesgo preconcepcional(AU)

ABSTRACT Introduction: Preventing disease and death during the reproduction process is one of the fundamental pillars for the development of reproductive health, in which the nurse plays a key role in empowering the self-care of women at childbearing age. Objective: To systematize the nursing action in prevention and control of preconception reproductive risk. Methods: Systematic bibliographic review to carry out a reflexive critical analysis of the content of original and review articles published in Spanish between 2005 and 2015. The search was carried out in the databases Medline EMBASE, Current Contents, and Science Citation Index, from January to March 2016; the key words used were riesgo preconcepcional [preconception risk], práctica de enfermería [nursing practice], y atención de enfermería al riesgo preconcepcional [nursing care over preconception risk]. After the identification of the pre-selected studies, the titles, summary and key words were read, verifying the relevance with the study. Conclusion: An adequate knowledge of women of childbearing age on preconception risk allows maintaining an optimal state of health to assume a pregnancy with satisfactory final results. The lack of knowledge in women about conditions or habits of risk for their health and for assuming a satisfactory pregnancy, to which insufficient nursing work is added in the prevention of preconception risk(AU)

Oreganic acid, a potent inhibitor of ras farnesyl-protein transferase.

A sulfated tricarboxylic acid fungal metabolite is an inhibitor of human farnesyl-protein transferase (FPTase). The compound, designated as oreganic acid, has a molecular weight of 494, an empirical formula of C22H38O10S and inhibits FPTase with an IC50 value of 14 nM. Oreganic acid is a selective inhibitor of FPTase because it does not inhibit human geranylgeranyl-protein transferase type I (GGPTase-I). It is not a time-dependent inhibitor, reversibly inhibits FPTase, is competitive with respect to farnesyl diphosphate and non-competitive with respect to the Ras acceptor peptide. The structure of oreganic acid resembles that of farnesyl diphosphate and most likely inhibits FPTase by mimicking farnesyl diphosphate at the active site of the enzyme.

Clavaric acid: a triterpenoid inhibitor of farnesyl-protein transferase from Clavariadelphus truncatus.

Farnesyl-protein transferase (FPTase) catalyses the specific transfer of farnesyl to Ras-peptides that is essential for oncogenic activity in oncogene-mediated tumors. Specific inhibition of FPTase activity has been shown to reduce tumor development in nude mice challenged with oncogenic forms of ras, thereby establishing FPTase as a viable therapeutic target. Our continued efforts to discover inhibitors of FPTase has led to the discovery of a triterpenoidal inhibitor, clavaric acid (1). This compound inhibits rHFPTase with an IC50 value of 1.3 microM. Structure elucidation, structure modifications, and biological activity of clavaric acid are herein described.

The complestatins as HIV-1 integrase inhibitors. Efficient isolation, structure elucidation, and inhibitory activities of isocomplestatin, chloropeptin I, new complestatins, A and B, and acid-hydrolysis products of chloropeptin I.

From the screening of a microbial extract library, isocomplestatin (1), a new axial-chiral isomer of complestatin (2) which is a known rigid bicyclic hexapeptide, was identified as a potent natural product inhibitor of HIV-1 integrase, a unique enzyme responsible for viral replication. Isocomplestatin showed inhibitory activities (IC(50)) in coupled 3'-end processing/strand transfer (200 nM), strand transfer (4 microM), and HIV-1 replication (200 nM) in virus-infected cells. Attempted large-scale isolation of 1 by the literature method, used for the isolation of complestatin, led to lower yield and limited availability. We have developed several new, two-step, high-yielding absorption/elution methods of isolation based on reverse-phase chromatography at pH 8 that are applicable to scales from one gram to potential industrial quantities. We have also discovered and determined the structure of two new congeners of 1, namely, complestatins A (4) and B (5), with almost equal HIV-1 integrase activity. They differ from 1 at C2' and C3' of the tryptophan moiety (residue F). Selective acid hydrolysis of chloropeptin I (3), itself a known acid-catalyzed rearranged isomer of 1 and 2 (8'- vs 7'-substitution in tryptophan residue F, respectively), an isomer of complestatin, and isocomplestatin resulted in a number of fragments (6-10) with retention of most of the HIV-1 integrase activity. The structure-activity relationship as revealed by these compounds could possibly lead to the design of better inhibitors or understanding of the HIV-1 integrase target.