Facilitators and Barriers for Keeping Cool in an Urban Heat Island: Perspectives from Residents of an Environmental Justice Community.

Background: Extreme heat is a leading cause of morbidity and mortality during summer months in the United States. Risk of heat exposure and associated health outcomes are disproportionately experienced by people with lower incomes, people of color, and/or immigrant populations. Methods: As qualitative research on the experiences of residents in heat islands is limited, this community-based study examined barriers and coping strategies for keeping cool among residents of Chelsea and East Boston, Massachusetts-environmental justice (EJ) areas that experience the urban heat island effect-through semistructured interviews and qualitative content analysis. Results: Results indicate that all participants (n = 12) had air conditioning, but high energy bills contributed to low use. Eight participants were self-described heat-sensitive, with five experiencing poor health in heat. In addition, nine reported insufficient hydration due to work schedules, distaste of water, or perceptions of it being unsafe. Discussion: This research highlights the importance of understanding perceptions of residents in EJ communities to contextualize vulnerability and identify multipronged heat coping strategies and targeted interventions.

Cross-sectional study of quality of life in relation with vascular access in hemodialysis patients. Study in a hospital and a satellite center

Introduction: Vascular access for hemodialysis (HD) is essential for the patient. Even though Arteriovenous fistula (AVF) is the preferred access, in certain age groups, the central venous catheter (CVC) may provide advantages. This study aims to investigate the quality of life related to vascular access. Methods: Cross-sectional study including patients from a hospital, a home HD unit and a satellite hemodialysis center. Clinical data was collected from the patients, who went through a quality-of-life questionnaire SF12 and a Vascular Access Questionnaire (VAQ). Results: 91 patients participated, mostly male (70 %), with a mean age of 68.9 ± 16.2 years. AVF was the current vascular access in 60.4 %, the rest used a CVC. Home HD was performed in 12.1 % of patients and 76 % started it via CVC. Regarding patients who have had both AVF and CVC, 58 % prefer AVF and only 26.5 % of current CVC carriers would have a new AVF, mostly due to fear of pain (52 %). Most people (72.5 %) reported having received sufficient information, with no differences between both accesses. The SF12 results showed no differences between patients with AVF or CVC. Regarding the VAQ, patients with AVF were more satisfied with the social aspect (p = 0.036) and complications (p = 0.006). Conclusion: Patients with AVF had better outcomes than those using CVC regarding complications and social aspects. These differences are not attributable to a worse overall quality of life status of CVC patients. Most patients with CVCs refuse to go through a new AVF for fear of puncture pain.

Introducción: el acceso vascular para la hemodiálisis (HD) es esencial para el paciente. Aunque la fístula arteriovenosa (FAV) es el acceso preferido, en ciertos grupos de edad el catéter venoso central (CVC) puede aportar ventajas. Este estudio pretende investigar la calidad de vida relacionada con el acceso vascular. Métodos: el estudio transversal incluye pacientes del hospital, de una unidad de HD domiciliaria y de un centro de hemodiálisis periférico. Se recogieron datos clínicos de los pacientes que contestaron el cuestionario de calidad de vida SF12 y Cuestionario de Acceso Vascular (VAQ). Resultados: 91 pacientes, en su mayoría varones (70 %), con una edad media de 68,9 ± 16,2 años. La FAV era el acceso vascular actual en el 60,4 %. La HD domiciliaria se realizó en el 12,1 % de los pacientes y el 76 % la inició mediante CVC. En cuanto a los pacientes que han tenido tanto FAV como CVC, el 58 % prefiere la FAV y sólo el 26,5 % de los actuales portadores de CVC se sometería a una nueva FAV, sobre todo por miedo al dolor (52 %). La mayoría de las personas (72,5 %) declararon haber recibido suficiente información, sin diferencias entre ambos accesos. Los resultados del SF12 no mostraron diferencias según el acceso. En cuanto al VAQ, los pacientes con AVF estaban más satisfechos con el aspecto social y las complicaciones. Conclusión: los pacientes con FAV tuvieron mejores resultados en comparación con los que utilizaron CVC en cuanto a complicaciones y aspectos sociales, sin deberse a un peor estado general de la calidad de vida. La mayoría de los pacientes con CVC se niegan a someterse a una nueva FAV por miedo al dolor de la punción.

In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters.

AIMS: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and ß-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by ß-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.

Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity.

Arachidonic acid (AA)-derived cytochrome P450 (CYP) derivatives, epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetranoic acid (20-HETE), play a key role in kidney tubular and vascular functions and blood pressure. Altered metabolism of CYP epoxygenases and CYP hydroxylases has differentially been involved in the pathogenesis of metabolic disease-associated vascular complications, although the mechanisms responsible for the vascular injury are unclear. The present study aimed to assess whether obesity-induced changes in CYP enzymes may contribute to oxidative stress and endothelial dysfunction in kidney preglomerular arteries. Endothelial function and reactive oxygen species (ROS) production were assessed in interlobar arteries of obese Zucker rats (OZR) and their lean counterparts lean Zucker rats (LZR) and the effects of CYP2C and CYP4A inhibitors sulfaphenazole and HET0016, respectively, were examined on the endothelium-dependent relaxations and O2- and H2O2 levels of preglomerular arteries. Non-nitric oxide (NO) non-prostanoid endothelium-derived hyperpolarization (EDH)-type responses were preserved but resistant to the CYP epoxygenase blocker sulfaphenazole in OZR in contrast to those in LZR. Sulfaphenazole did not further inhibit reduced arterial H2O2 levels, and CYP2C11/CYP2C23 enzymes were downregulated in intrarenal arteries from OZR. Renal EDH-mediated relaxations were preserved in obese rats by the enhanced activity and expression of endothelial calcium-activated potassium channels (KCa). CYP4A blockade restored impaired NO-mediated dilatation and inhibited augmented O2- production in kidney arteries from OZR. The current data demonstrate that both decreased endothelial CYP2C11/ CYP2C23-derived vasodilator H2O2 and augmented CYP4A-derived 20-HETE contribute to endothelial dysfunction and vascular oxidative stress in obesity. CYP4A inhibitors ameliorate arterial oxidative stress and restore endothelial function which suggests its therapeutic potential for the vascular complications of obesity-associated kidney injury.

Altered production of reproductive neuropeptides in rats subjected to chronic intermittent hypoxia.

Hypobaric hypoxia is a stressful condition known to decrease fertility both in humans and animals. However, the mechanism by which the hypothalamus-pituitary-gonad axis is altered remains unknown. The aim of the present study was to analyze the effects of chronic intermittent and continuous exposure to hypoxia on hypothalamic-pituitary-gonadal axis regulation in male rats. Thirty adult male Wistar rats were assigned to one of the following three groups: control group; chronic intermittent hypoxia: subjected to 600 mbar for 18 h/d five days a week; and chronic continuous hypoxia: subjected to 600 mbar for 23.5 hours/day seven days a week, for 30 days. Plasma luteinizing hormone and testosterone concentration, hypothalamic GnRh, Kiss1 and Rfrp3 mRNA levels and PGE2 content were determined. Levels of Rfrp3, a negative regulator of GnRH and LH release, were higher in intermittently exposed animals than in controls. Levels of Kiss1, a neuropeptide that stimulates the release of GnRH only increased in animals exposed to continuous hypoxia. Plasma luteinizing hormone and testosterone concentrations and body weight were lower in rats subjected to intermittent hypoxia as compared to the remaining groups. GnRh mRNA levels as well as PGE2 content remained unchanged in all groups. Taken together, results suggest that besides the well documented direct effects of hypoxia on the testes, infertility observed in male rats exposed to hypoxia may also be due to overexpression of negative regulators of GnRH and luteinizing hormone release. Intermittent, rather than continuous, to hypoxia exposure would seem to be more detrimental to fertility.

The Profile of the Obstetric Patients with SARS-CoV-2 Infection According to Country of Origin of the Publication: A Systematic Review of the Literature.

SARS-CoV-2 is the novel member of coronavirus responsible for the worldwide pandemic COVID-19, affecting all types of people. In this context, established research identified pregnant women as a susceptible group of SARS-CoV-2 infection, although there is still limited data regarding the real impact of COVID-19 in this group. With that purpose, we conducted a systematic review describing the maternal-fetal results of pregnant women infected by SARS-CoV-2, in aim to analyze the profile of the obstetric patients according to the country of origin of the publication. A total of 38 articles were included in this systematic review with 2670 patients from 7 countries, with 20 works published from China (52.6%). We reported significative differences according to the median maternal age, with Spain as the country with the highest age (34.6 years); The percentage of tabaquism; proportion of symptomatic patients in the triage; type of radiological exam (China and France conduct CT scans on all their patients in comparison to the use of chest X-Ray in the rest of the countries studied); percentages of C-sections (83.9% in China; 35.9% Spain, p < 0.001); maternal mortality rate, proportion of patients who need treatments, the use of antivirals, antibiotics, and anticoagulants as well as measurements of the newborns. Perinatal results are favorable in the majority of countries, with very low rates of vertical transmission in the majority of works. The studies collected in this review showed moderate to high index of quality. The different works describe the affectation during the first wave of the pandemic, where the pregnant woman with SARS-CoV-2 infection is generally symptomatic during the third trimester of gestation along with other factors associated with worse prognosis of the disease, such as higher age, body mass index, and further comorbidities developed during pregnancy. In the obstetric patient, proportion of C-sections are elevated together with prematurity, increasing maternal perinatal morbimortality. Differences found between countries could be based on the proper profile of the patient in each region, the period of the pandemic directly affecting how it was managed, and the variations regarding in situ medical attention.

Mandibular biomechanical behavior of rats submitted to chronic intermittent or continuous hypoxia and periodontitis.

BACKGROUND: The aim of this study was to investigate the effects of exposure to continuous (CH) and intermittent (IH) hypoxia on biomechanical properties of the mandible and periodontal tissue of animals submitted to experimental periodontitis (EP) when applying loads in a hypoxic environment. METHODS: Adult female Wistar rats were exposed during 90 days to IH or CH (simulated high altitude of 4200 m above sea level). Fourteen days prior to the euthanasia, EP was induced to half of the animals of each group. RESULTS: Only in the rats with EP, IH decreased the maximum capacity of the mandible to withstand load and the limit of elastic load. Indicators of intrinsic properties of the bone material were significantly reduced by both types of hypoxia in rats with EP. Hypoxia enhanced the alveolar bone loss induced by EP in the buccal side of the mandible, without showing additional effects in lingual or interradicular bone. Hypoxia increased prostaglandin E2 content in gingival tissue of healthy animals and further elevated the E2 levels increased by EP. CONCLUSIONS: When periodontitis is present, hypoxic stress induces a decrease in mineral properties that ultimately affects the ability of the mandible to resist load, mainly during intermittent exposure to hypoxia. These effects on bone may be related to the higher levels of prostaglandin E2 reached in the surrounding gingival tissue. The findings of this study may stimulate strategies to prevent unwanted effects of hypoxia on periodontal tissues.

Treatment of Frail Older Adults and Elderly Patients With Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia: Results of a Prospective Trial With Minimal Chemotherapy.

BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) in older adults and elderly patients is a challenge, and modern protocols include targeted therapy and immunotherapy in combination with attenuated or minimal chemotherapy. However, frail patients are excluded from these trials, and reports on the outcome of this subgroup of patients are scarce. Our objective was to analyze the outcome of unfit older adults and elderly patients with Philadelphia chromosome-negative ALL included in a prospective trial (ALL-07FRAIL). PATIENTS AND METHODS: Older adults and elderly patients with Charlson Comorbidity Index (CCI) ≥ 4 were included. Induction therapy consisted of vincristine and dexamethasone, and maintenance therapy with mercaptopurine and methotrexate for 2 years. RESULTS: Seventy-two patients with a median age of 67 years (range, 57-89 years) and a median CCI of 5 (range, 4-12) were included. The rates of early withdrawal, early death, resistance, and complete response (CR) were 5%, 10%, 31%, and 54%, respectively. Six patients with CR abandoned the study, 5 died in CR, and 23 relapsed (cumulative relapse incidence 75%). The medians of disease-free and overall survival (OS) were 6.9 months (95% confidence interval [CI], 0.3-13.5 months) and 7.6 months (95% CI, 6.3-8.9 months), respectively. The most frequent toxic events were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases). Eastern Cooperative Oncology Group score but not the CCI had significant impact on OS. CONCLUSION: Complete remission with very attenuated chemotherapy can be attained in one-half of older or elderly infirm patients with ALL. These results suggest that some of these patients could benefit from the concomitant or subsequent use of immunotherapy and/or targeted therapy.

Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity.

Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial H2O2.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O2.-) and H2O2 production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O2.- generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH-dependent O2.- production was augmented while NADPH-dependent H2O2 generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent H2O2 generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O2.- production but reduced H2O2 generation and blunted endothelial Nox2-derived H2O2-mediated in obese rats. Moreover, increased Nox1-derived O2.- contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O2.- in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased H2O2 generation and H2O2-mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.

Sleep quality and clinical and psychological manifestations in women with mild systemic lupus erythematosus activity compared to women with fibromyalgia: A preliminary study.

Objectives: This study analyzed sleep quality in fibromyalgia (FM) and systemic lupus erythematosus (SLE) and explored its relationship with other clinical and psychological manifestations.Methods: Twenty women with FM, 19 women with SLE and 22 healthy women participated in the study. Subjective sleep quality, fatigue, pain, depression and anxiety were evaluated with self-reports, and objective sleep measures were obtained with actigraphy. Comparisons were analyzed with Chi-square, Kruskal-Wallis's H and Mann-Whitney's U tests. Relationships between measurements were analyzed with Spearman's correlation coefficients.Results: Subjective sleep quality was altered in the FM and SLE groups compared to the control group (15.53 ± 3.27, 8.47 ± 3.20, 4.91 ± 2.79, p < .05, respectively). FM and SLE patients reported higher levels of pain (22.65 ± 9.87, 10.21 ± 9.93, 2.30 ± 3.096, p < .05), fatigue (4.67 ± 0.37, 3.59 ± 3.04, 2.33 ± 0.59, p < .05) and depressive symptoms (9.90 ± 3.78, 4.53 ± 3.04, 4.17 ± 3.95, p < .05) than controls, respectively. Worse subjective quality of sleep was associated with higher pain intensity and more depressive symptoms in FM and SLE. Actigraphy measures showed that FM patients spent more time in bed than subjects in the remaining groups.Conclusion: Sleep deterioration is related to more pain and depressive symptoms in FM and SLE. Addressing sleep disturbances may improve not only sleep quality but also depressive symptoms and pain.

Bladder Dysfunction in an Obese Zucker Rat: The Role of TRPA1 Channels, Oxidative Stress, and Hydrogen Sulfide.

PURPOSE: This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (H2S) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR). MATERIALS AND METHODS: Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the H2S synthase cystathionine beta-synthase (CBS) and cysthathionine-γ-lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and H2S production were also performed. RESULTS: Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated H2S production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR. CONCLUSIONS: These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/H2S pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR.

Qualitative and quantitative evaluation of the use of Twitter as a tool of antimicrobial stewardship.

INTRODUCTION: Social media networks have transformed the sources of information, including health information. In particular, the microblogging service Twitter has been used as a learning tool in the field of medicine as well as a tool for disease surveillance and outbreak management. As antimicrobial resistance is one of the biggest concerns of public health, we aimed to review how Twitter is being used as a tool for antimicrobial stewardship (AMS). METHODS: We used the software Kampal Social® to collect, analyze and monitor tweets from the whole Twitter network to assess the activity that takes place about antibiotics. The study was carried out in three phases: data acquisition, during which we collected data over a six-month period (from 21 September 2016 to 8 February 2017) by monitoring selected users, hashtags and keywords that we knew to be related to AMS; data cleansing, which involved identifying users who were not related to the topic, thus creating a new collection process to remove those users and add newly discovered ones; and, finally, data acquisition and analysis (From 1 April 2017 to 7 March 2018), during which we collected data using the new users obtained in the cleansing phase. We qualitatively characterized the most influential users, we analysed the use of hashtags and the flow of information (the most retweeted users and the global network formed by all the users). RESULTS: Using the tool Kampal Social®, and after a cleansing phase to remove irrelevant information, we worked with a dataset of 1,765,388 tweets. Studying the qualitative characterization of the top-ten influencers, we found that most of them are institutional users, but individual users, such as physicians, and an important medical journal also appeared. Regarding hashtags, '#antibiotics' was the one with the most occurrences. Hashtags follow a regular distribution over time, with some defined peaks connected to important dates and reports about antibiotics. As for the flow of information, we obtained a rather dense network of interconnections formed by all the users who had sent a message, which means that a strong relation exists between the different organizations, professionals and users in general. CONCLUSIONS: Institutions, medical journals, physicians and pharmacists are key opinion leaders in the topic of antibiotics, so they must incorporate social media into their communication strategy to spread the AMS message. More evidence is needed regarding the optimal method of communication to spread information throughout the general population. The development of tools capable of collecting and querying large amounts of Twitter data helped us to assess the impact of antibiotic awareness campaigns and to gain an idea of how Twitter is being used to spread the message about AMS.

Hydrogen peroxide derived from NADPH oxidase 4- and 2 contributes to the endothelium-dependent vasodilatation of intrarenal arteries.

The role of NADPH oxidase (Nox)-derived reactive oxygen species in kidney vascular function has extensively been investigated in the harmful context of oxidative stress in diabetes and obesity-associated kidney disease. Since hydrogen peroxide (H2O2) has recently been involved in the non-nitric oxide (NO) non-prostanoid relaxations of intrarenal arteries, the present study was sought to investigate whether NADPH oxidases may be functional sources of vasodilator H2O2 in the kidney and to assess their role in the endothelium-dependent relaxations of human and rat intrarenal arteries. Renal interlobar arteries isolated from the kidney of renal tumor patients who underwent nephrectomy, and from the kidney of Wistar rats, were mounted in microvascular myographs to assess function. Superoxide (O2.-) and H2O2 production was measured by chemiluminescence and Amplex Red fluorescence, and Nox2 and Nox4 enzymes were detected by Western blotting and by double inmunolabeling along with eNOS. Nox2 and Nox4 proteins were expressed in the endothelium of renal arterioles and glomeruli co-localized with eNOS, levels of expression of both enzymes being higher in the cortex than in isolated arteries. Pharmacological inhibition of Nox with apocynin and of CYP 2C epoxygenases with sulfaphenazol, but not of the NO synthase (NOS), reduced renal NADPH-stimulated O2.- and H2O2 production. Under conditions of cyclooxygenase and NOS blockade, acetylcholine induced endothelium-dependent relaxations that were blunted by the non-selective Nox inhibitor apocynin and by the Nox2 or the Nox1/4 inhibitors gp91ds-tat and GKT136901, respectively. Acetylcholine stimulated H2O2 production that was reduced by gp91ds-tat and by GKT136901. These results suggest the specific involvement of Nox4 and Nox2 subunits as physiologically relevant endothelial sources of H2O2 generation that contribute to the endothelium-dependent vasodilatation of renal arteries and therefore have a protective role in kidney vasculature.

Comparison of intensive, pediatric-inspired therapy with non-intensive therapy in older adults aged 55-65 years with Philadelphia chromosome-negative acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVE: The standardization of treatment of older adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) is challenging, especially in the age range of 55-65 years. This study aimed to compare intensive, pediatric-inspired therapy with non-intensive therapy in this population of patients. PATIENTS AND METHODS: The outcomes of 67 patients prospectively included in two consecutive pediatric-inspired intensive protocols (ALL-HR03 and ALL-HR11) from the Spanish PETHEMA Group were compared with those from 44 patients included in a contemporary semi-intensive protocol (ALL-OLD07). RESULTS: Baseline patient and ALL characteristics were similar in both groups, except for a younger median age in the intensive group (medians: 58 vs. 62 years). Patients treated intensively had a higher complete remission rate (85% vs. 64%, p = 0.005), a lower cumulative incidence of relapse (39% [95%CI, 25% to 52%] vs. 60% [95%CI, 38% to 77%], p = .003), a similar cumulative incidence of treatment-related mortality (28% [95% CI, 18%, 40%] vs. 21% [95% CI, 10%, 34%]) and superior event-free survival at 2 years (37% [95%CI, 25%-49%) vs. 21% [8%-34%], p = 0.002). On multivariable analysis the type of protocol was the only variable with independent significance for event-free survival (HR [95% CI]: 2 [1.3, 3], p = .002). CONCLUSIONS: Compared with less intensive chemotherapy, pediatric-inspired intensive chemotherapy significantly improves the outcome of older adults with Ph-negative ALL in the age range of 55-65 years.

Phosphodiesterase type 4 inhibition enhances nitric oxide- and hydrogen sulfide-mediated bladder neck inhibitory neurotransmission.

Nitric oxide (NO) and hydrogen sulfide (H2S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples. Endogenous H2S production measurement and electrical field stimulation (EFS) were also performed. A rich PDE4 and PDE4A expression was observed mainly limited to nerve fibers of the smooth muscle layer of both species. Moreover, roflumilast produced a much more potent smooth muscle relaxation than that induced by tadalafil. In porcine samples, H2S generation was diminished by H2S and NO synthase inhibition and augmented by roflumilast. Relaxations elicited by EFS were potentiated by roflumilast. These results suggest that PDE4, mainly PDE4A, is mostly located within nerve fibers of the pig and human bladder neck, where roflumilast produces a powerful smooth muscle relaxation. In pig, the fact that roflumilast increases endogenous H2S production and EFS-induced relaxations suggests a modulation of PDE4 on NO- and H2S-mediated inhibitory neurotransmission.

The Process of Acclimation to Chronic Hypoxia Leads to Submandibular Gland and Periodontal Alterations: An Insight on the Role of Inflammatory Mediators.

The exposition to hypoxia is a stressful stimulus, and the organism develops acclimation mechanisms to ensure homeostasis, but if this fails, it leads to the development of pathological processes. Considering the large number of people under hypoxic conditions, it is of utmost importance to study the mechanisms implicated in hypoxic acclimation in oral tissues and the possible alteration of some important inflammatory markers that regulate salivary and periodontal function. It is the aim of the present study to analyze submandibular (SMG) and periodontal status of animals chronically exposed to continuous (CCH) or intermittent (CIH) hypoxia in order to elucidate the underlying molecular mechanisms that may lead to hypoxic acclimation. Adult Wistar rats were exposed to CCH or CIH simulating 4200 meters of altitude during 90 days. Salivary secretion was decreased in animals exposed to hypoxia, being lower in CIH, together with increased prostaglandin E2 (PGE2) content, TBARS concentration, and the presence of apoptotic nuclei and irregular secretion granules in SMG. AQP-5 mRNA levels decreased in both hypoxic groups. Only the CCH group showed higher HIF-1α staining, while CIH alone exhibited interradicular bone loss and increased concentration of the bone resorption marker CTX-I. In summary, animals exposed to CIH show a worse salivary secretion rate, which related with higher levels of PGE2, suggesting a negative role of this inflammatory mediator during hypoxia acclimation. We link the weak immunorreactivity of HIF-1α in CIH with improper hypoxia acclimation, which is necessary to sustaining SMG physiology under this environmental condition. The alveolar bone loss observed in CIH rats could be due mainly to a direct effect of PGE2, as suggested by its higher content in gingival tissue, but also to the indirect effect of hyposalivation. This study may eventually contribute to finding therapeutics to treat the decreased salivary flow, improving in that way oral health.

Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+).

Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA.

Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.

CYP epoxygenase-derived H2O2 is involved in the endothelium-derived hyperpolarization (EDH) and relaxation of intrarenal arteries.

Reactive oxygen species (ROS) like hydrogen peroxide (H2O2) are involved in the in endothelium-derived hyperpolarization (EDH)-type relaxant responses of coronary and mesenteric arterioles. The role of ROS in kidney vascular function has mainly been investigated in the context of harmful ROS generation associated to kidney disease. The present study was sought to investigate whether H2O2 is involved in the endothelium-dependent relaxations of intrarenal arteries as well the possible endothelial sources of ROS generation involved in these responses. Under conditions of cyclooxygenase (COX) and nitric oxide (NO) synthase inhibition, acetylcholine (ACh) induced relaxations and stimulated H2O2 release that were reduced by catalase and by the glutathione peroxidase (GPx) mimetic ebselen in rat renal interlobar arteries, suggesting the involvement of H2O2 in the endothelium-dependent responses. ACh relaxations were also blunted by the CYP2C inhibitor sulfaphenazole and by the NADPH oxidase inhibitor apocynin. Acetylcholine stimulated both superoxide (O2•-) and H2O2 production that were reduced by sulfaphenazole and apocynin. Expression of the antioxidant enzyme CuZnSOD and of the H2O2 reducing enzymes catalase and GPx-1 was found in both intrarenal arteries and renal cortex. On the other hand, exogenous H2O2 relaxed renal arteries by decreasing vascular smooth muscle (VSM) intracellular calcium concentration [Ca2+]i and markedly enhanced endothelial KCa currents in freshly isolated renal endothelial cells. CYP2C11 and CYP2C23 epoxygenases were highly expressed in interlobar renal arteries and renal cortex, respectively, and were co-localized with eNOS in renal endothelial cells. These results demonstrate that H2O2 is involved in the EDH-type relaxant responses of renal arteries and that CYP 2C epoxygenases are physiologically relevant endothelial sources of vasodilator H2O2 in the kidney.

Effects of chronic lead exposure on bone mineral properties in femurs of growing rats.

Lead exposure has been associated with several defective skeletal growth processes and bone mineral alterations. The aim of the present study is to make a more detailed description of the toxic effects of lead intoxication on bone intrinsic material properties as mineral composition, morphology and microstructural characteristics. For this purpose, Wistar rats were exposed (n=12) to 1000ppm lead acetate in drinking water for 90days while control group (n=8) were treated with sodium acetate. Femurs were examined using inductively coupled plasma optical emission spectrometry (ICP-OES), Attenuated Total Reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD), and micro-Computed Tomography (µCT). Results showed that femur from the lead-exposed rats had higher carbonate content in bone mineral and (Ca2++Mg2++ Na+)/P ratio values, although no variations were observed in crystal maturity and crystallite size. From morphological analyses, lead exposure rats showed a decreased in trabecular bone surface and distribution while trabecular thickness and cortical area increased. These overall effects indicate a similar mechanism of bone maturation normally associated to age-related processes. These responses are correlated with the adverse actions induced by lead on the processes regulating bone turnover mechanism. This information may explain the osteoporosis diseases associated to lead intoxication as well as the risk of fracture observed in populations exposed to this toxicant.