Application of CMO (capacity, motivation, and opportunity) methodology in pharmaceutical care to optimize the pharmacotherapy in older people living with HIV. DISPIMDINAC project.

OBJECTIVE: To determine the effectiveness of a pharmaceutical intervention, based on the CMO methodology (capacity, motivation and opportunity), to decrease the prevalence of the PIMDINAC concept (potentially inappropriate medication+drug interactions+non-adherence to concomitant medication) in people living with HIV infection. METHODS: Longitudinal prospective multicenter study, conducted between October 2021 and October 2022. Patients living with HIV older than 65 years, on antiretroviral treatment and concomitant drug prescription were included. Demographic, clinical, and pharmacotherapeutic variables were collected. Pharmaceutical care was provided for6 months according to the CMO model in each patient. The main variable was the percentage of patients who simultaneously fulfilled the PIMDINAC concept, comparing the baseline value with the same value at the end of the study. In addition, the percentage of patient's adherent to concomitant and antiretroviral treatment and the percentage of patients meeting the pharmacotherapeutic targets established for the prescribed medicationat 24 weeks of follow-up were compared. RESULTS: Sixty-eight patients were included. Seventy-two percent were men, with a median age of 68 years. The median number of concomitant drugs was 7. A 60.6% of the patients had polypharmacy. The prevalence of the presence of the PIMDINAC concept decreased significantly (10.3 vs. 0%). In isolation, each of the aspects also decreased significantly (p<0.031). The percentage of patients who met the objectives improved significantly from 48,5 at baseline to 88.2 (p<0.001). CONCLUSIONS: The pharmaceutical intervention based onarmaceutical intervention based on the CMO methodology significantly decreased the prevalence of the PIMDINAC concept and increased the number of patients who achieved the objectives, optimising their pharmacotherapy.

Beliefs and attitudes about deprescription in older HIV-infected patients: ICARD Project.

OBJECTIVE: HIV population is aging at an earlier age than those uninfected, requiring more non-HIV medications to treat noncommunicable diseases. In the context of chronic HIV infection, the next therapeutic change would be the polymedication control. This paper has the purpose of explore the attitudes of older people living with HIV toward deprescribing. METHODS: This was an observational, prospective and multicenter study conducted from March-April, 2018. People living with HIV (PLWH) on highly active antiretroviral therapy and older than 65 years were included. In addition to demographic and pharmacotherapeutic data, attitudes regarding deprescribing were collected through the "Revised Patients' Attitudes Towards Deprescribing Questionnaire". RESULTS: A total of 42 patients were included in this study. Regarding their attitudes in relation to deprescription, there were three statements with the most consensuses. The first ("I have a good understanding of the reasons I was prescribed each of my medicines") had 91.9% consensus. The second and third questions showed 89.2% consensus in both cases; "Overall, I am satisfied with my current medicines" and "I like to be involved in making decisions about my medicines with my doctors". CONCLUSIONS: This study is the first to explore the beliefs and attitudes of older PLWH in relation to deprescription process. There are positive attitudes regarding medication knowledge but there also is a percentage of patients who had a negative opinion regarding deprescription. We must study and go deeper in our knowledge of techniques that could help us to better understand their preferences, in order to establish effective and successful deprescription strategies.

Determination of a cutoff value for medication regimen complexity index to predict polypharmacy in HIV+ older patient.

OBJECTIVE: HIV+ patients have increased their life expectancy with a parallel increase in age-associated co-morbidities and pharmacotherapeutic complexity. The aim of this study was to determine an optimal cutoff value for Medication regimen complexity index (MRCI) to predict polypharmacy in HIV+ older patients. METHODS: A transversal observational single cohort study was conducted at a tertiary Hospital in Spain, between January 1st up to December 31st, 2014. Patients included were HIV patients over 50 years of age on active antiretroviral treatment. Prevalence of polypharmacy and it pattern were analyzed. The pharmacotherapy complexity value was calculated through the MRCI. Receiver operating characteristic curve analyses were used to calculate the area under the curve (AUC) for the MRCI value medications to determine the best cutoff value for identifying outcomes including polypharmacy. Sensitivity and specificity were also calculated. RESULTS: A total of 223 patients were included. A 56.1% of patients had polypharmacy, being extreme polypharmacy in 9.4% of cases. Regarding the pattern of polypharmacy, 78.0% had a cardio-metabolic pattern, 12.0% depressive-psychogeriatric, 8.0% mixed and 2.0% mechanical-thyroidal. The ROC curve demonstrated that a value of medication complexity index of 11.25 point was the best cutoff for predict polypharmacy (AUC=0.931; sensitivity= 77.6%; specificity=91.8%). CONCLUSIONS: A cut-off value of 11.25 for MRCI is proposed to determine if a patient reaches the criterion of polypharmacy. In conclusion, the concept of polypharmacy should include not only the number of prescribed drugs but also the complexity of them.

Oestrus synchronization treatment induces histomorphological changes on the uterine tube epithelium of the gilt.

The aim of this study was to determine the histomorphological changes that occurred in response to two treatments for oestrus synchronization in three different regions of the gilt's uterine tubes epithelium: the ampulla (AMP), ampulla-isthmic junction (AIJ) and isthmus (IST). Nine prepuberal gilts were divided into three groups (n = 3): (1) eCG 400 IU and hCG 200 IU (eCG/hCG), (2) progesterone agonist (P4) and (3) control group. The number of secretory cells (stained with periodic acid-Schiff reaction or PAS-positive cells) decreased in the AMP in the P4 treated group when compared to the control group, whereas, no difference was observed in the number of PAS-negative cells in the AMP of the three groups. A significant decrease in the number of PAS-positive cells was observed in the AIJ and IST of the P4 treated group when compared to the eCG/hCG and control groups. An increase in the number of PAS-negative cells was observed in the AIJ and IST in the P4 treated group. The epithelium height in the AMP and AIJ was increased in the eCG/hCG group when compared to the control and P4 groups. In this last group, we observed a reduced height compared with the other two groups for the AIJ. In the IST, there were no significant changes in the epithelium height of the control or the other two groups (eCG/hCG and P4). The epithelial cells of the P4 treated group had the least amount of cytoplasmic granules and the lowest intensity of PAS staining in the AMP, AIJ and IST. Animals treated with eCG/hCG showed an intermediate number of cytoplasmic granules and intensity in all regions evaluated. These data show that P4 treatment for synchronization induces a significant (P < 0.001) decrease of PAS-positive cells and staining intensity of cytoplasmic granules in the different regions studied and an increased number of PAS-negative cells in the AIJ and IST epithelium. Moreover, eCG/hCG treatment increased the height of the epithelium in the AMP and AIJ, while in this last region, the P4 treatment decreased the epithelium height. These results show that synchronization treatments with P4 and in a smaller proportion with eCG/hCG can modify the amount of PAS-positive and PAS-negative cells, and the epithelium height. This has influence in the secretory activity of the epithelium and possibly alters the fluid microenvironment of the gilt's uterine tube. The biological impact of regional variations in the epithelial cells of the gilt's uterine tube needs further investigation to understand the implications that the reproductive processes can have in the uterine tube.

Ube2l3 gene expression is modulated by activation of the aryl hydrocarbon receptor: implications for p53 ubiquitination.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a halogenated aromatic hydrocarbon and environmental contaminant, results in several deleterious effects, including fetal malformation and cancer. These effects are mediated by the aryl hydrocarbon receptor (AhR), a ligand-activated receptor that regulates the expression of genes encoding xenobiotic-metabolizing enzymes. Several reports suggest that AhR function is beyond the adaptive chemical response. In the present study, we analyzed and compared gene expression profiles of C57BL/6N wild-type (WT) and Ahr-null mice. DNA microarray and quantitative RT-PCR analyses revealed changes in the expression of genes involved in the ubiquitin-proteasome system (UPS). UPS has an important role in cellular homeostasis control and dysfunction of this pathway has been implicated in the development of several human pathologies. Protein ubiquitination is a multi-step enzymatic process that regulates the stability, function, and/or localization of the modified proteins. This system is highly regulated post-translationally by covalent modifications. However, little information regarding the transcriptional regulation of the genes encoding ubiquitin (Ub) proteins is available. Therefore, we investigated the role of the AhR in modulation of the UPS and regulation of Ube2l3 transcription, an E2 ubiquitin-conjugating enzyme, as well as the effects on p53 degradation. Our results indicate that AhR inactivation decreases on liver proteasome activity, probably due to a down-regulation on the expression of several proteasome subunits. On the other hand, AhR activation increases Ube2l3 mRNA and protein levels by controlling Ube2l3 gene expression, resulting in increased p53 ubiquitination and degradation. In agreement with this, induction of apoptosis was attenuated by the AhR activation.

Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/S progression in prostate cancer cells through the regulation of components of the cell-cycle machinery.

SHP-1, a haematopoietic cell-specific tyrosine phosphatase, is also expressed in human prostate. In this study, we report that SHP-1 depletion in PC-3 cells induced by small interfering RNAs causes G1 phase cell-cycle arrest accompanied by changes in some components of the cell-cycle machinery. SHP-1 knockdown increases p27(Kip1) (p27) protein stability, its nuclear localization and p27 gene transcription. These effects could be mediated by PI3K-AKT pathway as SHP-1 interacts with PI3K regulating its activity and p110 catalytic subunit phosphorylation. The increase in p27 protein stability could also because of reduced cyclin-dependent kinase (CDK2) activity. SHP-1 knockdown decreases the CDK6 levels, inducing retinoblastoma protein hypophosphorylation, downregulation of cyclin E and thereby a decrease in the CDK2 activity. However, the codepletion of SHP-1 and p27 does not produce re-entry into the cycle, implying that p27 is not required to maintain cell-cycle arrest induced by SHP-1 depletion. The maintenance of the PC-3 cell anti-proliferative response after p27 loss could be because of mislocalization of CDK2 induced by SHP-1 knockdown. This study shows that SHP-1 depletion promotes cell-cycle arrest by modulating the activity of cell-cycle regulators and suggests that SHP-1 may be required for the proper functioning of events governing cell-cycle progression.

Refractory anemia with ringed sideroblasts associated with thrombocytosis: comparative analysis of marked with non-marked thrombocytosis, and relationship with JAK2 V617F mutational status.

The World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues (2001) defined a provisional entity named refractory anemia with ringed sideroblasts associated to marked thrombocytosis (RARS-MT). Diagnosis of RARS-MT requires more than 15% of ringed sideroblasts in bone marrow aspirate and the existence of a thrombocytosis in blood, with a platelet count above 600 x 10(9)/L. Nevertheless, controversy exists regarding this platelet count "cut-off" value and, when RARS-MT was defined, the JAK2 mutation and its importance in the study of myeloproliferative disorders was unknown. We present the results of a Spanish retrospective multicentric study, which includes 76 cases of RARS with associated thrombocytosis (platelet count above 400 x 10(9)/L) at diagnosis (RARS-T), 36 of them with a platelet count above 600 x 10(9)/L. Our aim was to analyze their clinical, analytical and morphological characteristics, and to establish correlations with the JAK2 mutational status.

CD16+ and CD16- human blood monocyte subsets differentiate in vitro to dendritic cells with different abilities to stimulate CD4+ T cells.

Experimental protocols for cancer immunotherapy include the utilization of autologous monocyte-derived dendritic cells (moDC) pulsed with tumor antigens. However, disease can alter the characteristics of monocyte precursors and some patients have increased numbers (up to 40%) of the minor CD16(+) monocyte subpopulation, which in healthy individuals represent 10% of blood monocytes. At the present, the capacity of CD16(+) monocytes to differentiate into DC has not been evaluated. Here, we investigated the ability of CD16(+) monocytes cultured with granulocyte- macrophage colony-stimulating factor, IL-4 and tumor necrosis factor-alpha to generate DC in vitro, and we compared them to DC derived from regular CD16(-) monocytes. Both monocyte subsets gave rise to cells with DC characteristics. They internalized soluble and particulate antigens similarly, and both were able to stimulate T cell proliferation in autologous and allogeneic cultures. Nevertheless, CD16(+) moDC expressed higher levels of CD86, CD11a and CD11c, and showed lower expression of CD1a and CD32 compared to CD16(-) moDC. Lipopolysaccharide-stimulated CD16(-) moDC expressed increased levels of IL-12 p40 mRNA and secreted greater amounts of IL-12 p70 than CD16(+) moDC, whereas levels of transforming growth factor-beta1 mRNA were higher on CD16(+) moDC. Moreover, CD4(+) T cells stimulated with CD16(+) moDC secreted increased amounts of IL-4 compared to those stimulated by CD16(-) moDC. These data demonstrate that both moDC are not equivalent, suggesting either that they reach different stages of maturation during the culture or that the starting monocytes belong to cell lineages with distinct differentiation capabilities.

Autologous peripheral blood stem cell transplantation in a patient with previous invasive middle ear mucormycosis.

A 52-year-old male diagnosed with acute myeloid leukemia (AML) developed an invasive middle-ear mucormycosis during the neutropenic period after consolidation chemotherapy which resolved successfully with surgery and antifungal therapy. The patient underwent autologous peripheral blood stem cell transplantation (APBSCT) in first complete remission with antifungal prophylaxis with liposomal amphotericin B (AmB). There was no clinical, radiological or microbiological data of mycotic reactivation. This is the first reported stem cell transplantation (SCT) in a patient with prior invasive mucormycosis.

Estradiol and progesterone endometrial receptors and body fat distribution in obese women.

The content of endometrial receptors for estradiol (ER) and progesterone (PR) was determined in three groups (10 women each) classified with respect to body fat distribution: (1) normal, nonobese; (2) lower body segment obesity and (3) upper body segment obesity. The ER in group 3 were significantly (p < 0.05) higher than those of group 1. As regards PR, no statistical differences were found among the three groups. These findings demonstrate different endometrial ER concentrations in obese women according to body fat distribution, greater in upper segment obesity. Probably the lack of progesterone as well as other factors in the endocrine milieu of these patients may determine the differences found; therefore, future research on this matter should be carried out.