Sustainable Protocol for the Synthesis of 2',3'-Dideoxynucleoside and 2',3'-Didehydro-2',3'-dideoxynucleoside Derivatives.

An improved protocol for the transformation of ribonucleosides into 2',3'-dideoxynucleoside and 2',3'-didehydro-2',3'-dideoxynucleoside derivatives, including the anti-HIV drugs stavudine (d4T), zalcitabine (ddC) and didanosine (ddI), was established. The process involves radical deoxygenation of xanthate using environmentally friendly and low-cost reagents. Bromoethane or 3-bromopropanenitrile was the alkylating agent of choice to prepare the ribonucleoside 2',3'-bisxanthates. In the subsequent radical deoxygenation reaction, tris(trimethylsilyl)silane and 1,1'-azobis(cyclohexanecarbonitrile) were used to replace hazardous Bu3SnH and AIBN, respectively. In addition, TBAF was substituted for camphorsulfonic acid in the deprotection step of the 5'-O-silyl ether group, and an enzyme (adenosine deaminase) was used to transform 2',3'-dideoxyadenosine into 2',3'-dideoxyinosine (ddI) in excellent yield.

Oligonucleotides Containing 1-Aminomethyl or 1-Mercaptomethyl-2-deoxy-d-ribofuranoses: Synthesis, Purification, Characterization, and Conjugation with Fluorophores and Lipids.

Oligonucleotide conjugates are widely used as therapeutic drugs, gene analysis, and diagnostic tools. A critical step in the biologically relevant oligonucleotide conjugates is the design and synthesis of functional molecules that connect oligonucleotide with ligands. Here, we report the synthesis and application for oligonucleotide functionalization of novel tethers based on aminomethyl and mercaptomethyl sugar derivatives. Starting from a common cyano sugar precursor, three novel phosphoramidites have been prepared in the two α- and ß-anomeric forms. The mercaptomethyl sugar was protected with the S-acetyl group, while two different protecting groups have been developed for the aminomethyl sugar. These two protecting groups are orthogonal, as they can be removed independently using photolysis or ammonolysis. This combination allowed the introduction of two different ligands in a single oligonucleotide.

Imaging abusive head trauma: why use both computed tomography and magnetic resonance imaging?

Abusive head trauma is the leading cause of death in child abuse cases. The majority of victims are infants younger than 1 year old, with the average age between 3 and 8 months, although these injuries can be seen in children up to 5 years old. Many victims have a history of previous abuse and the diagnosis is frequently delayed. Neuroimaging is often crucial for establishing the diagnosis of abusive head trauma as it detects occult injury in 37% of cases. Several imaging patterns are considered to be particularly associated with abusive head trauma. The presence of subdural hematoma, especially in multiple locations, such as the interhemispheric region, over the convexity and in the posterior fossa, is significantly associated with abusive head trauma. Although CT is the recommended first-line imaging modality for suspected abusive head trauma, early MRI is increasingly used alongside CT because it provides a better estimation of shear injuries, hypoxic-ischemic insult and the timing of lesions. This article presents a review of the use and clinical indications of the most pertinent neuroimaging modalities for the diagnosis of abusive head trauma, emphasizing the newer and more sensitive techniques that may be useful to better characterize the nature and evolution of the injury.

Synthesis of 2'-O-Methyl/2'-O-MOE-L-Nucleoside Derivatives and Their Applications: Preparation of G-Quadruplexes, Their Characterization, and Stability Studies.

Nucleosides and their analogues constitute an important family of molecules with potential antiviral and antiproliferative activity. The enantiomers of natural nucleosides, l-nucleoside derivatives, which have comparable biological activity but more favorable toxicological properties and greater metabolic stability than d-nucleosides, have emerged as a new class of therapeutic agents. Furthermore, l-nucleosides can be used as a building block to prepare l-oligonucleotides, which have identical physical properties in terms of solubility, hybridization kinetics, and duplex thermal stability as d-oligonucleotides but completely orthogonal in nature. Consequently, they are resistant to nuclease degradation, nontoxic, and immunologically passive, which are desirable properties for biomedical applications. Herein, we describe the synthesis of several 2'-O-methyl/2'-O-MOE-l-nucleoside pyrimidine derivatives and their incorporation into G-rich oligonucleotides. Finally, we evaluated the stability and resistance against nucleases of these new G-quadruplexes, demonstrating the potential of the l-nucleosides described in this work in providing enhanced nuclease resistance with a minimal impact in the nucleic acid structural properties.

Utero-ovarian anastomoses and their influence on uterine fibroid embolization.

PURPOSE: To correlate clinical outcomes after uterine artery embolization (UAE) performed to treat uterine fibroids with the presence of varying types of utero-ovarian anastomoses (UOA). MATERIALS AND METHODS: A retrospective analysis was performed of all uterine angiograms from 202 patients (mean age 42 y, range 28-54 y) who underwent UAE because of heavy menstrual bleeding, dysmenorrhea, or anemia or a combination of these symptoms. UOA were classified as absent or present, unilateral or bilateral. The effects of UOA on long-term outcomes (clinical endpoints such as control of bleeding and pain) and complications (amenorrhea) were assessed statistically using Kaplan-Meier curves and χ(2) and log-rank tests. RESULTS: Of the UOA in 104 women, 38 anastomoses were bilateral, and 66 were unilateral. Type III was the most common type of anastomosis (66 cases) followed by type Ia (22 cases) and type Ib (18 cases); there were no type II anastomoses. Amenorrhea was reported in 27 (14%) women at 5-year follow-up after UAE (only 3% in women < 45 y old). There were 10 cases of clinical failure with a median follow-up of > 4 years. Bilateral or unilateral presence of UOA had no statistically significant effect on outcomes or on complications. CONCLUSIONS: Recurrence rates, clinical failure, and amenorrhea after UAE do not seem to be influenced by the presence or absence of UOA. However, further studies are needed to confirm these findings.

The evolution of an FLS in search of excellence: the experience of Gran Canaria.

We present the achievements and difficulties of our pioneering FLS within the Spanish public health system over an 8-year period. Despite implementing consolidating measures at the unit, the addition of a support nurse, the establishment of a solid alliance with primary care, the involvement of primary care nurses, and starting initial prescriptions at the hospital are pending. PURPOSE: To assess the consolidation of an FLS after its implementation as well as the problems that have arisen over time. METHODS: The program for secondary fracture prevention was implemented in 2012. Initially manned by the same staff assigned to the rheumatology department, a part-time support nurse was added in 2016. Patients were identified from the emergency registry and, more recently, from among those admitted for hip fracture and treated in a monographic osteoporosis clinic. The baseline visit consisted of a consultation with the nurse, as well as DXA and bone metabolism analytics. Patients were referred to their primary care physician to start treatment. RESULTS: Of the 2416 attended patients, 30% presented forearm fractures, 27% hip, 20% humerus, 10% spine, and 11% other fractures. In comparison with 2012, in 2019, the monthly average of patients had doubled, with an increased in the number of hip and spine fractures and an increase in the percentage of captured patients. The performance of DXA fell from 100 to 52%, and fewer patients were referred to the osteoporosis clinic. One in four patients was referred to a fall prevention school. Despite implementing consolidating measures at the unit (the addition of a support nurse and the establishment of a solid alliance with primary care), the involvement of primary care nurses and starting initial prescriptions at the hospital are pending. CONCLUSIONS: We present herein the achievements made by our FLS and the difficulties within the Spanish public health system over an 8-year period.

Novel 1'-homo-N-2'-deoxy-α-nucleosides: synthesis, characterization and biological activity.

For the first time, a series of novel 1'-homo-N-2'-deoxy-α-nucleosides containing natural nucleobases as well as 5-fluoro and 5-iodopyrimidine analogs have been synthesized in an efficient manner. Additionally, a high yield protocol for the assembly of a dimeric scaffold containing two sugar moieties linked to the N-1 and N-3 positions of a single pyrimidine base has been accomplished. The structures of the novel homonucleosides were established by a single crystal X-ray structure of 1'-homo-N-2'-deoxy-α-adenosine and NMR studies. The biological activity of these 1'-homo-N-2'-deoxy-α-nucleosides as antiviral (HIV-1 and HBV) and cytotoxic studies was measured in multiple cell systems. The unique structure and easy accessibility of these compounds may allow their use in the design of new nucleoside analogs with potential biological activity and as a scaffold for combinatorial chemistry.

Prevalence of erectile dysfunction in Spanish primary care setting and its association with cardiovascular risk factors and cardiovascular diseases. SIMETAP-ED study.

INTRODUCTION: Few studies conducted in primary care setting report about age-adjusted prevalence rates of erectile dysfunction (ED). Aims of SIMETAP-ED study were to determine crude and age-adjusted prevalence rates of ED diagnosis, to compare these rates with other similar studies, and to compare prevalence rates of cardiovascular risk factors (CVRF), cardiovascular diseases (CVD), metabolic diseases and chronic kidney disease (CKD) between populations with and without ED. METHODS: Cross-sectional observational study conducted in primary care setting. Population-based random sample: 2934 adult men. Response rate: 66%. A clinical interview was conducted to diagnose ED using a question derived from ED definition. The medical records of patients were reviewed to identify their CVRF and diseases associated with ED. The age-adjustments were standardized to Spanish population. RESULTS: The prevalence rates of metabolic diseases, CVD, CVRF, and CKD in population with ED were higher than population without ED, highlighting the CVD. The crude prevalence of ED was 17.2% (95% confidence interval: 15.8-18.6). The age-adjusted prevalence rates of ED were 0.71% in men under 40 years, 12.4% in men over 18 years, 10.8% in men aged 40-69 years, 18.9% in men over 40 years, and 48.6% in men over 70 years. CONCLUSIONS: SIMETAP-ED study showed association of ED with metabolic diseases, CKD, CVRF, and highlighting CVD. The age-adjusted prevalence of ED was 12.4% in adult men, 19% in men over 40 years, and almost 50% in men over 70 years.

Population and methodology of the SIMETAP study: Prevalence of cardiovascular risk factors, cardiovascular diseases, and related metabolic diseases. / Población y metodología del estudio SIMETAP: Prevalencia de factores de riesgo cardiovascular, enfermedades cardiovasculares y enfermedades metabólicas relacionadas.

The prevention of cardiovascular disease is based on the detection and control of cardiovascular risk factors (CVRF). In Spain there are important geographical differences both in the prevalence and in the level of control of the CVRF. In the last decade there has been an improvement in the control of hypertension and dyslipidaemia, but a worsening of cardio-metabolic risk factors related to obesity and diabetes. The SIMETAP study is a cross-sectional descriptive, observational study being conducted in 64 Primary Care Centres located at the Community of Madrid. The main objective is to determine the prevalence rates of CVRF, cardiovascular diseases, and metabolic diseases related to cardiovascular risk. A report is presented on the baseline characteristics of the population, the study methodology, and the definitions of the parameters and diseases under study. A total of 6,631 study subjects were selected using a population-based random sample. The anthropometric variables, lifestyles, blood pressure, biochemical parameters, and pharmacological treatments were determined. The highest crude prevalences were detected in smoking, physical inactivity, obesity, prediabetes, diabetes, hypertension, dyslipidaemias, and metabolic syndrome. A detailed analysis needs to be performed on the prevalence rates, stratified by age groups, and prevalence rates adjusted for age and sex to assess the true epidemiological dimension of these CVRF and diseases.

Malignant hypertension: ocular manifestations.

Malignant hypertension may be the first manifestation of systemic hypertension. We report a clinical case of a Caucasian 41-year-old man with no previous history of blood hypertension seen at casualty because of blurred vision. Fundus examination disclosed optic disk swelling, retinal hemorrhages and infarcts. The blood pressure was 220/130 mmHg. After the appropriate management of hypertension, optic disk and retinal edema resolved, leaving minor changes as mild optic disk pallor and hard exudates.

Two-step stool aerobic training for smokers.

OBJECTIVE: The aim of this study was to analyze subjective, physical, and physiologic responses to a standardized incremental 30-min two-step stool test to create an individualized 45-min maximally intensive two-step stool endurance exercise regimen for home training. DESIGN: This is a longitudinal study on 26 consecutively referred male smokers aged 39-66 yrs. Each performed the two-step stool test on two 15-cm steps at 10, 20, 30, 40, 50, and 60 climbs per minute. Exertional dyspnea, oxygen consumption per unit time, ventilation, respiratory rate, tidal volume, heart rate, capillary oxyhemoglobin saturation, physiologic cost index, and oxygen pulse were recorded and compared with those observed during incremental cycle exercise (30 W per 3 mins). Multivariate analysis for each parameter was undertaken as a mixed model. RESULTS: All subjects attained 60 climbs per minute on the two-step stool test and performed 38-42 mins of two-step stool endurance. All parameters reached 80%-96% of cycle maximum oxygen consumption. The subjects found the two-step stool endurance simple and practical to perform at home. There were no complications. CONCLUSIONS: The incremental two-step stool test is a simple, cost-effective way to establish a 45-min maximally intensive endurance exercise training program practical for use in the home.

[Management of fibroids]. / Abordaje de los miomas.

Approximately 25% of reproductive age females have fibroids; of these 50% have relevant symptoms. Abnormal menstrual bleeding, pain, pressure, infertility and repeated miscarriages are frequently associated with fibroids. Although surgery and radiological therapies are frequently used to manage these tumors, medical therapies are considered the first-line treatment for fibroids. The objective of this article is to serve as a guide for decision-making in the management of fibroids.

Bilevel exercise training and directed breathing relieves exertional dyspnea for male smokers.

OBJECTIVE: The purpose of this study was to compare the effects on exertional dyspnea and exercise capacity of square wave (bilevel) cycle ergometry endurance exercise training (SWEET) and comprehensive directed breathing vs. walking while pushing an OxCar and traditional diaphragmatic breathing for male smokers with normal spirometry but reduced exercise capacity. DESIGN: This was a prospective randomized trial of 24 unmedicated men with exertional dyspnea assigned to SWEET or OxCar groups. Exertional dyspnea was assessed using the Borg scale during four tests: incremental exercise, constant exercise at 80% of the peak work rate (PWR) (maximum tolerated for 3 mins before exhaustion), SWEET, and 6-min walk test. Both groups trained for 45 mins, 5 days a week, for 6 wks. Before, during, and after training, 32 lung function parameters were studied at ventilatory anaerobic threshold, at PWR, and during incremental exercise (30 W/3 mins). RESULTS: For the SWEET group, exertional dyspnea and the dyspnea index decreased during incremental exercise, at the ventilatory anaerobic threshold, and at PWR (P < 0.01). At the ventilatory anaerobic threshold, oxygen consumption increased by 74%; minute ventilation, 30%; tidal volume, 91%; and ventilatory efficiency and oxygen pulse (O(2)P), 25%; and breathing rate (breathing frequency) decreased by 32% (all significant at P < 0.001). At PWR, oxygen consumption increased by 30%; minute ventilation, 37%; breathing rate, 21%; and ventilatory efficiency and oxygen pulse, 25% (P < 0.01). During the full incremental test, minute ventilation, breathing frequency, and heart rate (cardiac frequency) decreased significantly (P < 0.01). In addition, there was significant improvement (P < 0.001) in SWEET intensity by 63%, constant exercise intensity at 80% of PWR by 38%, and 6-min walk test by 30%. No significant changes were observed for the OxCar group other than for the 6-min walk test, which increased by 7% (P < 0.05). CONCLUSIONS: This study suggests that the decline in exercise tolerance for male smokers can be reduced by intensive exercise training (SWEET) and comprehensive directed breathing but not by moderate training and traditional diaphragmatic breathing. Thus, some smokers can be helped despite continuing to smoke.