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Abstract: Traditionally, the search for memory circuits has been centered on examinations of amnesic and AD patients, cerebral lesions and, neuroimaging. A complementary alternative might be the use of autoradiography with radioligands. Indeed, ex vivo autoradiographic studies offer the advantage to detect functionally active receptors altered by pharmacological tools and memory formation. Hence, herein the 5-HT6 receptor antagonist SB-399885 and the amnesic drugs scopolamine or dizocilpine were used to manipulate memory consolidation and 5-HT6 receptors expression was determined by using [3H]-SB-258585. Thus, memory consolidation was impaired in scopolamine and dizocilpine treated groups relative to control vehicle but improved it in SB-399885-treated animals. SB-399885 improved memory consolidation seems to be associated with decreased 5-HT6 receptors expression in 15 out 17 brain areas. Scopolamine or dizocilpine decreased 5-HT6 receptors expression in nine different brain areas and increased it in CA3 hippocampus or other eight areas, respectively. In brain areas thought to be in charge of procedural memory such basal ganglia (i.e., nucleus accumbens, caudate putamen, and fundus striate) data showed that relative to control animals amnesic groups showed diminished (scopolamine) or augmented (dizocilpine) 5-HT6 receptor expression. SB-399885 showing improved memory displayed an intermediate expression in these same brain regions. A similar intermediate expression occurs with regard to amygdala, septum, and some cortical areas in charge of explicit memory storage. However, relative to control group amnesic and SB-399885 rats in the hippocampus, region where explicit memory is formed, showed a complex 5-HT6 receptors expression. In conclusion, these results indicate neural circuits underlying the effects of 5-HT6 receptor antagonists in autoshaping task and offer some general clues about cognitive processes in general. [Copyright &y& Elsevier]

Rationale: It has been reported that 5-HT1A receptors modulate learning and memory and diverse pharmacological and genetic evidence supports this notion. Nevertheless, there are few works about expression of these receptors during memory formation. Objective: We aimed to determine 5-HT1A receptor expression in brain areas of untrained, passive, and autoshaping trained groups of rats. Methods: Ex vivo receptor autoradiography using the ligand agonist [³H]8-hydroxy-2-[di-n-propylamino]tetralin] (8-OH-DPAT) was used. Results: The trained group relative to untrained animals showed increases of 5-HT1A receptor expression in 14 brain areas, decrements in 7, and no changes in 12. Thus, in contrast to untrained rats, 5-HT1A receptor expression of autoshaping trained rats was augmented in the tubercule olfactory, septal nucleus, nucleus accumbens, caudate putamen, globus pallidus, striate, and parietal (1 and 2), temporal cortex (1 and 3), granular retrosplenial cortex (1), amygdala, and median and dorsal raphe nuclei. In contrast, in the latter group, receptors were decreased in the CA1 area, hypothalamus dorsal, frontal cortex (1 and 3), occipital cortex, cingulate cortex (1 and 2), and cuneiform nucleus. There were significant differences between passive vs trained groups, but not regarding untrained rats, in the lateral olfactory tract, dentate gyrus, CA3 area, ventromedial hypothalamic, lateral hypothalamus, preoptic medial, frontal cortex (2), granular retrosplenial cortex (2), entorhinal cortex (1 and 2), piriform cortex, and substantia nigra. Conclusions: These data suggest that upregulated, downregulated, and "silence" of 5-HT1A receptors in brain areas form part of neural circuits engaged in memory formation by demonstrating a high degree of specificity and memory mapping. [ABSTRACT FROM AUTHOR]

Abstract: Pharmacological evidence indicates a specific role of 5-HT4 receptors on memory function. These receptors are members of G-protein-coupled 7-transmembrane domain receptor superfamily, are positively coupled to adenylyl cyclase, and are heterogeneously located in some structures important for memory, such as the hippocampus and cortical regions. To further clarify 5-HT4 receptors'' role in memory, the expression of these receptors in passive (P3) untrained and autoshaping (A3) trained (3 sessions) adult (3 months) and old (P9 or A9; 9 months) male rats was determined by autoradiography. Adult trained (A3) rats showed a better memory respect to old trained (A9). Using [3H] GR113808 as ligand (0.2 nM specific activity 81 Ci/mmol) for 5-HT4 receptor expression, 29 brain areas were analyzed, 16 areas of A3 and 17 of A9 animals displayed significant changes. The medial mammillary nucleus of A3 group showed diminished 5-HT4 receptor expression, and in other 15 brain areas of A3 or 10 of A9 animals, 5-HT4 receptors were increased. Thus, for A3 rats, 5-HT4 receptors were augmented in olfactory lobule, caudate putamen, fundus striatum, CA2, retrosplenial, frontal, temporal, occipital, and cingulate cortex. Also, 5-HT4 receptors were increased in olfactory tubercule, hippocampal CA1, parietal, piriform, and cingulate cortex of A9. However, hippocampal CA2 and CA3 areas, and frontal, parietal, and temporal cortex of A9 rats, expressed less 5-HT4 receptors. These findings suggest that serotonergic activity, via 5-HT4 receptors in hippocampal, striatum, and cortical areas, mediates memory function and provides further evidence for a complex and regionally specific regulation over 5-HT receptor expression during memory formation. [Copyright &y& Elsevier]

Background: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9)., Objective: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers., Methods: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA)., Results: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1., Conclusions: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To assess thrombotic risk with PAI-1 levels in patients with COVID-19, to evaluate PAI-1 differences between hyperglycemic and/or Type 2 Diabetes Mellitus (T2DM) versus non-hyperglycemic patients, and to analyze the association of plasminogen activator inhibitor-1 (PAI-1) with hyperglycemia and T2DM., Methods: A cross-sectional study carried out in 181 patients hospitalized for COVID-19. Two groups were formed: the patients with hyperglycemia at admission and/or previously diagnosed T2DM group and the non-hyperglycemic group. Fibrinolysis was assessed by measuring PAI-1 levels by ELISA., Results: The mean age was 59.4±16.1 years; 55.8% were male 54.1% of patients presented obesity, 38.1% had pre-existing T2DM and 50.8% had admission hyperglycemia and/or pre-existing T2DM. The patients with admission hyperglycemia and/or preexisting T2DM had higher PAI-1 compared with non-hyperglycemic patients [197.5 (128.8-315.9) vs 158.1 (113.4-201.4) ng/mL; p=0.031]. The glucose levels showed a positive correlation with PAI-1 levels (r=0.284, p=0.041). A multivariate logistic regression analysis showed association of PAI-1 level and hyperglycemia and pre-existing T2DM with severity of COVID-19., Conclusion: Patients hospitalized for COVID-19 infection with preexisting T2DM or hyperglycemia detected during their hospitalization presented a greater increase in PAI-1 levels, which suggests that hyperglycemia contributes directly to the hypercoagulable state and probably a worse outcome from the patients., (Copyright © 2024 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Risk stratification for cognitive impairment in communities originated from autopsies in cognitively healthy individuals. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) incorporates subjective and objective cognitive function (CF) measures to explore neurocognitive disorders (NCD). It can be applied in communities to explore the factors that may influence positively or negatively., Objective: To obtain the relationship between groups of CF classified using the DSM-5 categories, and sociodemographic factors, habits, comorbidities and motor function in older people living in the community., Material and Methods: Cross-sectional study with a probabilistic sample (n = 347). The variables were sociodemographic, habits, comorbidities, and cognitive motor function. The participants were grouped considering subjective and objective CF, plus age, sex, and educational level, and defined according to NCD., Results: 28.5% did not present cognitive disorder, 43.9% had mild disorder < 70 years (mildNCD < 70y), 19% with 70 years or more (mildNCD ≥ 70y), and with major disorder 8.6%. The associated factors for mildNCD < 70y were marital status (MS), physical activity (PA), diabetes mellitus, and frailty; for mildNCD > 70y: MS, occupation, living alone, and heart disease; for majorNCD: PA and grip strength. In the multivariate analysis it was observed greater likelihood in the mildNCD groups than in the non-NCD and majorNCD groups., Conclusions: 4 important groups were identified in a community. The mildNCD was mainly explained by sociodemographic factors, lifestyle, clinical conditions, and motor functionality., (Licencia CC 4.0 (BY-NC-ND) © 2024 Revista Médica del Instituto Mexicano del Seguro Social.)

Introduction: Background: hypovitaminosis D is frequent in kidney transplant recipient (KTR) patients and is associated with deleterious effects both at the bone and extraosseous levels. Treatment with cholecalciferol is effective for the normalization of 25(OH)D, demonstrating a beneficial effect on the calcium-tropic axis in other populations; however, its effect on the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis in RTR has not been reported. The aim of this study was to evaluate the effect of normalization of serum 25(OH)D concentrations on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in KTR treated with cholecalciferol, as well as the association between the components of this axis. Methods: a prospective study in 23 KTR with hypovitaminosis D, with evolution from 1 to 12 months post-transplantation, an estimated glomerular filtration rate > 60 mL/min/1.73 m2 and a history of primary nephropathy treated with cholecalciferol, in whom the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis was evaluated during the state of hypovitaminosis D and at normalization of 25(OH)D. Results: at the normalization of 25(OH)D, a reduction in PTH [103 (58.5-123.9) vs 45.6 (30.1-65.1) pg/mL; p = 0.002] and an increase in serum phosphorus [3.1 (2.3-3.5) vs 3.3 (3-3.6) mg/dL; p = 0.01] were evident, with no differences in calcium, klotho and FGF23 concentrations. The time to achieve normalization of 25(OH)D was 12 weeks (RIC, 4-12), with a dose of 5000 IU/day (RIC, 4000-6000). A positive association between klotho and PTH was corroborated (r = 0.54; p = 0.008; linear regression, β = 0.421; B = 0.004; 95 % CI, 0.003-0.007; p = 0.045). Conclusions: treatment with cholecalciferol is effective for the normalization of 25(OH)D, with a beneficial effect on calcium-phosphotropic metabolism characterized by a reduction in PTH concentration, without significant changes in calcemia or calciuria, as well as an increase in phosphatemia, without modifications in FGF23 or klotho concentrations.

Inflammation and oxidative stress are critical events involved in neurodegeneration. In animal models, it has been shown that chronic consumption of a hypercaloric diet, which leads to inflammatory processes, affects the hippocampus, a brain region fundamental for learning and memory processes. In addition, advanced age and menopause are risk factors for neurodegeneration. Hormone replacement therapy (HRT) ameliorates menopause symptoms. Tibolone (TB), a synthetic hormone, exerts estrogenic, progestogenic and androgenic effects on different tissues. We aimed to determine the effect of short-term TB administration on oxidative stress and inflammation markers in the hippocampus of ovariectomized rats fed a high-fat-and-fructose diet (HFFD). Adult female rats were ovariectomized (OVX) and fed standard diet or HFFD-consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water-and administered vehicle or TB (1 mg/kg for seven days). Finally, we administered hormone receptor antagonists (MPP, RU486 or FLU) to each of the OVX + HFFD + TB groups. Bodyweight, triglycerides and cholesterol, oxidative stress and inflammation markers, and the activity and expression of antioxidant enzymes were quantified in the hippocampus of each experimental group. We observed that short-term TB administration significantly reduced body weight, AGEs, MDA levels, increased SOD and GPx activity, improved GSH/GSSG ratio, and reduced IL-6 and TNF-α. Our findings suggest that short-term administration of TB decreases oxidative stress and reduces inflammation caused by HFFD and early estrogenic decline. These effects occurred via estrogen receptor alpha.

Objective: To determine if the leptin, adiponectin, and leptin/adiponectin ratio (LAR) can predict weight gain at the end of GnRH analogs (GnRHa) treatment in girls with central precocious puberty (CPP)., Material and Methods: Study design: prospective cohort. Serum levels of leptin and adiponectin were determined at diagnosis of CPP. Anthropometry was performed at diagnosis of CPP and every six-months, until treatment with GnRHa was discontinued and they presented menarche. Patients were divided according to BMI<94 and BMI>95 percentile at diagnosis of CPP. The outcome was the increased in weight gain (e.g., from normal weight to overweight) at the end of follow-up. Statistical analysis: repeated measures ANOVA test and Student's t-test were used to compare groups. Logistic regression analysis was used to evaluate the association of leptin and adiponectin levels, as well as LAR values with increased weight gain., Results: Fifty-six CPP patients were studied, 18 had BMI >95 percentile and 38 BMI <94 percentile. Of the 18 patients who initially had BMI >95 th , two patients went from obesity to overweight, while among the 38 patients who started with BMI <94 th , 21 (55.2%) increased their weight gain at the end of follow-up. This last group had higher leptin levels (8.99 ± 0.6 vs 6.14 ± 0.8, p=0.005) and higher LAR values compared to those who remained in the same weight (1.3 ± 0.5 vs 0.96 ± 0.56, p=0.01). In the logistic regression analysis, it was found that higher leptin levels and higher LAR values were associated with increased weight gain (RR 1.31, 95%CI 1.03-1.66, RR 4.86, 95%CI 1.10-21.51, respectively), regardless of birth weight, pubertal stage, age, and bone/chronological age ratio., Conclusions: In patients with CPP, leptin levels and higher LAR values appear to be associated with significantly greater weight gain during GhRHa treatment, particularly in girls starting with BMI < 94 percentile., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zurita-Cruz, Villasís-Keever, Manuel-Apolinar, Damasio-Santana, Garrido-Magaña and Rivera-Hernández.)

Introduction: Background: leptin and adiponectin are associated with cardiovascular disease in chronic kidney disease (CKD) patients and could be useful prognostic factors. Objectives. to explore the usefulness of the leptin/adiponectin ratio (LAR) to predict the presence or worsening of dyslipidemia during 1 year of follow-up in children receiving kidney replacement therapy (KRT). Material and methods: a prospective cohort study was performed. Pediatric KRT patients aged between 8 and 17 years who were undergoing hemodialysis or peritoneal dialysis were included. At enrollment, the lipid profile, adiponectin and leptin levels, and somatometric measurements, including body fat percentage, were determined. At the one-year follow-up, the lipid profile was reassessed. Results: of the 70 patients included, the median age was 13 years, and there was no sex predominance (52.8 % males). At the end of follow-up, the patients were divided into three groups: those without dyslipidemia (WOD), those who developed or experienced worsening of their dyslipidemia (DWD) and those with persistent dyslipidemia (PD). A LAR > 0.85 (OR, 16.7) and body fat percentage (OR, 1.46) were associated with an increased risk of PD and DWD at 12 months, independently of urea level, BMI Z-score, benzafibrate treatment, CKD progression time, and replacement treatment. Conclusions: a LAR > 0.85 and fat body percentage at the beginning of follow-up were strongly associated with the presence, persistence or worsening of dyslipidemia at the 12-month follow-up in children with KRT.

Background: The estimation of left ventricular ejection fraction (LVEF) by 2D echocardiography (2D-ECHO) is the most used tool to assess LV systolic function (LVSF). Global longitudinal strain (GLS) has recently been suggested as a superior method for several evaluations. This study explored the association and prevalence of LV systolic dysfunction (LVSD) by using these methods in patients with end-stage renal disease (ESRD) and severe hyperparathyroidism (SHPTH); both associated with cardiovascular events (CEs)., Aim: To evaluate the myocardial function in patients with ESRD and SHPTH by using the GLS and LVEF measured through conventional 2D-ECHO., Methods: In 62 patients with ESRD and SHPTH, asymptomatic, and without a history of CEs, LVSF was evaluated by 2D-ECHO, obtaining the EF, by the Simpson biplane method, and GLS by speckle tracking., Results: The total patients with ESRD had a preserved LVEF (> 50%) but abnormal GLS (< 13.55%). Additionally, multivariate analysis showed an independent association of GLS and serum parathyroid hormone (PTH), LV mass index, and hemoglobin. Also, PTH was independently associated with lateral e' wave and tricuspid regurgitation velocity., Conclusion: In patients with SHPTH linked to ESRD, the use of GLS by 2D-ECHO is a more sensitive tool than LVEF for detecting LVSD., Competing Interests: Conflict-of-interest statement: The authors here declare no conflicts of interests or relationships regarding the industry at the date of this submission., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identification of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted., (© 2022 Revista Medica del Instituto Mexicano del Seguro Social.)

Background: Knowledge of chronic kidney disease (CKD) with pubertal disorders (PD) in adolescent boys is limited as few studies have explored this disorder. This study aimed to identify the usefulness of assessing hormonal parameters in male adolescents with CKD and their correlation with PD in a 12-month follow-up period., Methods: A prospective cohort study was conducted among male adolescents with CKD (stages IV and V). Data regarding the age at puberty onset were collected from the patients' clinical records and through interview. The patients were followed up for 12 months during their pubertal development. At the beginning, routine hormonal profile tests were performed to examine the patients' thyroid profile, prolactin levels, luteinizing hormone, follicle-stimulating hormone, testosterone, leptin, and receptor leptin. The hormonal profiles of patients with and without PD were compared. Comparisons between the groups were performed using the Student t-test and Fisher's exact tests. Logistic regression analysis was also performed., Results: Data of 64 patients (26/64 with PD) were analyzed. The median age was 15 years and the median time for CKD evolution was 11 months. No differences between groups were noted in the general or biochemical characteristics of the patients. The hormonal parameters, prolactin levels were higher and the free leptin and free thyroxine levels were lower in patients with PD. Leptin receptor levels of >0.90 ng/mL (risk ratio [RR], 8.6; P = 0.004) and hyperprolactinemia (RR, 21.3; P = 0.049) were the risk factors for PD., Conclusions: Leptin receptor levels of >0.90 ng/mL and hyperprolactinemia are associated with the development of PD in male adolescents with CKD., (© 2022 Japan Pediatric Society.)

Objective: To compare cardiometabolic factors and adipokines between patients with recently diagnosed CPP and controls without CPP, paired by BMI Z scores (BMIz) and classified into girls with adequate nutritional status and girls who are overweight or obese., Methods: This cross-sectional study was performed from January 2012 to May 2015 at two tertiary care pediatric centers in Mexico City. We included female patients with idiopathic CPP without other chronic pathology and healthy controls. Patients were divided into groups, BMI < 85th and BMI ≥ 85th percentile, according to 2000 CDC Growth Charts. Anthropometric data and fasting plasma concentrations of lipids, glucose, insulin, and leptin were assessed., Results: There were 73 patients with CPP and 82 without CPP. Sixty-six patients were matched between the groups; no significant difference was noted between the groups according to zBMI. However, differences in the bone/chronological age relationship, birth weight and proportions in different Tanner stages were observed. Among girls with normal BMI, the percentage of body fat (24.6% vs 18.9%, p < 0.001), serum triglycerides (102.9 vs 54.3 mg/dl, p < 0.001), leptin (7.46 vs 5.4 ng/ml, p = 0.010) and free leptin (0.44 vs 0.29 ng/ml, p = 0.044) were higher in those with CPP; additionally, girls with CPP presented a higher proportion of hypertriglyceridemia. In the overweight/obese group, adiponectin levels were lower in girls with CPP (6.23 vs 7.28 pg/ml, p = 0.011)., Conclusions: Girls with CPP and normal BMI at diagnosis had a worse cardiometabolic profile, as reflected by higher levels of free leptin, and higher proportion of hypertriglyceridemia than girls without CPP., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Variations in levels of some adipokines, myokines, osteokines, hepatokines and inflammatory cytokines contribute to abnormal glucose and lipid metabolism. The aim of this study was to determine the pattern of adiponectin, osteocalcin (OCN), irisin, FGF-21, and MCP-1 according to the body size phenotype of middle-aged women, and their associations with BMI, visceral adipose tissue (VAT), and HOMA-IR. A cross-sectional study in 265 women aged from 40 to 65 years was performed. The biochemical characteristics were evaluated in metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy obese, and metabolically unhealthy obese women. There was an association of OCN with BMI (r = -0.107; p = 0.047); adiponectin with BMI (r = -0.217; p = 0.001), insulin (r = -0.415; p = 0.0001), HOMA-IR (r = -0.429; p = 0.0001), and VAT (r = -0.134; p = 0.025); irisin with BMI (r = 0.604; p = 0.001), insulin (r = 0.446; p = 0.0001), HOMA-IR (r = 0.452; p = 0.0001), and VAT (r = 0.645; p = 0.0001); FGF-21 with insulin (r = -0.337; p = 0.030) and HOMA-IR (r = -0.341; p = 0.03); and MCP-1 with BMI (r = 0.481; p = 0.0001), VAT (r = 0.497; p = 0.001), insulin (r = 0.298; p = 0.001), and HOMA-IR (r = 0.255; p = 0.004). A multivariate analysis showed that an elevation of OCN (OR 1.4 ( 95% CI 1.06-1.81)) and a reduction of adiponectin (OR 0.9 (0.84-0.96)) were associated factors for a metabolic unhealthy phenotype in normal weight participants. Likewise, higher irisin (OR 1.007 (1.003-1.011)) and MCP-1 (1.044 (1.008-1.083)) were risk factors for a metabolic unhealthy phenotype in woman with obesity. OCN, adiponectin, irisin, FGF-21, and MCP-1 are associated with some metabolic parameters such as BMI, HOMA-IR, and VAT, and could be possible biomarkers of an unhealthy metabolic phenotype in middle-aged women.

Tryptophan hydroxylase type 2 (Tph2) is the rate-limiting enzyme for serotonin (5-HT) biosynthesis in the brain. Dysfunctional Tph2 alters 5-HT biosynthesis, leading to a deficiency of 5-HT, which could have repercussions on human behavior. In the last decade, several studies have associated polymorphisms of the TPH2 gene with suicidal behavior. Additionally, a 5-HT deficiency has been implicated in various psychiatric pathologies, including alcoholism, impulsive behavior, anxiety, and depression. Therefore, the TPH2 gene could be an ideal target for analyzing the effects of a 5-HT deficiency on brain function. The aim of this study was to use the construct pIRES-hrGFP-1a-Tph2-FLAG to treat CD1-male mice and to transfect HEK-293-cells and then to evaluate whether this treatment increases 5-HT production. 5-HT levels were enhanced 48 h post-transfection, in HEK-293 cells. Three days after the ocular administration of pIRES-hrGFP-1a-Tph2-FLAG to mice, putative 5-HT production was significantly higher than in the control in both hypothalamus and amygdala, but not in the brainstem. Further research will be needed on the possible application of this treatment for psychiatric diseases involving a Tph2 dysfunction or serotonin deficiency., (© 2021. The Author(s).)

Introduction: Cognitive and physical declines are frequent causes of disability among older adults (OAs) in Mexico that imposes significant burden on the health system and OAs' families. Programmes to prevent or delay OAs' cognitive and physical decline are scarce., Methods and Analysis: A double-blind randomised clinical trial will be conducted. The study will aim to evaluate two 24-week double-task (aerobic and cognitive) square-stepping exercise programmes for OAs at risk of cognitive decline-one programme with and another without caregiver participation-and to compare these with an aerobic-balance-stretching exercise programme (control group). 300 OAs (100 per group) affiliated with the Mexican Institute of Social Security (IMSS) between 60 and 65 years of age with self-reported cognitive concerns will participate. They will be stratified by education level and randomly allocated to the groups. The intervention will last 24 weeks, and the effect of each programme will be evaluated 12, 24 and 52 weeks after the intervention. Participants' demographic and clinical characteristics will be collected at baseline. The outcomes will include: (1) general cognitive function; (2) specific cognitive functions; (3) dual-task gait; (4) blood pressure; (5) carotid intima-media thickness; (6) OAs' health-related quality of life; and (7) caregiver burden. The effects of the interventions on each outcome variable will be examined using a repeated-measures analysis of variance (ANOVA), with study groups as the between-subjects variable and time as the within-subject variable., Ethics and Dissemination: The study was approved by the IMSS Ethics and Research Committees (registration number: 2018-785-095). All participants will sign a consent form prior to their participation. The study results will be disseminated to the IMSS authorities, healthcare providers and the research community., Trial Registration Number: ClinicalTrials.gov (NCT04068376)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A history of pre-maturity may be a risk factor for complications in patients under 24 months of age hospitalized for viral respiratory infections (VRIs). Objective: To identify the impact of a history of pre-maturity on in-hospital complications and mortality in patients under 24 months of age who were hospitalized for VRIs over a period of 5 years. Material and Methods: This was a propensity score-matched study. The database was compiled by physicians, electronically validated by engineers, and analyzed by statisticians. Patients diagnosed with VRIs (based on International Classification of Diseases [ICD-10]) codes B974, J12, J120-J129X, J168, J17, J171, J178, J20, J203-J209, J21, J210, J211, J218, J219, J22X, and J189) from 2013 to 2017 were enrolled in the study. The subjects were classified into two groups according to the absence or presence of a history of pre-maturity (P070, P072, P073). Patients with congenital heart disease (CHD) (Q20-Q26) were excluded. Length of hospital stay, in-hospital complications, surgical procedures, and mortality were analyzed. Statistical Analysis: Patients were matched according to age. For comparisons between groups, Student's t -tests and chi 2 tests were applied. A logistic regression model was constructed to identify factors related to in-hospital complications and mortality. Results: In total, 5,880 patients were eligible for inclusion in the analysis. The average patient age was 14.25 weeks. The presence of pre-maturity (coefficient = 1.16), male sex, bronchopulmonary dysplasia (BPD), in-hospital infectious complications (coefficient = 11.31), and invasive medical procedures (coefficient = 18.4) increased the number of days of hospitalization. Invasive medical procedures (OR = 6.13), a history of pre-maturity (OR = 2.54), and male sex (OR = 1.78) increased the risk for in-hospital complications. In-hospital infectious complications (OR = 84.2) and invasive medical procedures (OR = 58.4) were risk factors for mortality. Conclusions: A history of pre-maturity increased the length of hospital stay and the rate of in-hospital complications but did not increase mortality in patients under 24 months of age hospitalized for VRIs., (Copyright © 2020 Zurita-Cruz, Gutierrez-Gonzalez, Manuel-Apolinar, Fernández-Gárate, Arellano-Flores, Correa Gonzalez, Vázquez-Rosales, Pérez Vieyra, Sanchez-Armas and Cisneros-González.)

Background: Modern imaging plays a central role in the care of obese patients, and there is an integral focus on its use and accessibility in individuals who have alterations of various in various organs. The objective in this study was to perform an echographic analysis of musculoskeletal system disorders, endothelial dysfunction and the left ventricle (LV) in obese rats., Methods: Sprague Dawley rats (250 ± 5 g) were obtained and divided into two groups: the control (C) group was fed with a standard diet, and the obese (Ob) group was fed hyper caloric diet with a high fructose-fat content for 4 months. Body weight, cholesterol, triglycerides, glucose, inflammatory cytokines and adhesion molecules (ICAM-1, VCAM-1) were measured. Additionally, two-dimensional echocardiography, abdominal ultrasound and musculoskeletal system studies were performed in the lower extremities., Results: The body weight in the Ob group was increased compared to that in the control group, (p < 0.001); in addition, increased glucose, cholesterol and triglyceride concentrations (p < 0.05) as well as increased levels of the adhesion molecules ICAM-1 and, VCAM-1 (p < 0.01) were found in the Ob group vs the C group. On ultrasound, 75% of the Ob group presented fatty liver and distal joint abnormalities., Conclusion: Obese rats exhibit endothelial dysfunction and musculoskeletal changes, also, fatty liver and articular cysts in the posterior region of the distal lower- extremity joints.

Obesity represents a global health and economic burden, affecting millions of individuals worldwide. This pathology is associated with a chronic low‑grade inflammatory state that is partially responsible for the development of other cardiometabolic complications. Clinical studies have reported an association between high circulating levels of lipocalin‑2 (Lcn2) and increased body weight. Additionally, there is scientific evidence demonstrating the impact of maternal obesity on fetal programming. The latter and the fact that the authors previously found that Lcn2 and its receptor (24p3R) are expressed in the gonads of wild‑type rats, led to the analysis of their mRNA profile and cellular localization in gonads collected from the offspring of obese rats at 21 days postconception (dpc), and 0, 2, 4, 6, 12, 20 and 30 days postnatal (dpn) in the present study. Semi‑quantitative PCR revealed a statistically significant downregulation of Lcn2 and 24p3R mRNA at 21 dpc in the ovaries (P<0.01) and testicles (P<0.001) of the offspring of obese mothers. At 30 dpn, the relative expression of Lcn2 mRNA decreased significantly in the ovaries of the experimental group (P<0.05), while Lcn2 mRNA expression was not detectable in testicles. Regarding 24p3R, its mRNA was only significantly decreased at 21 dpc in ovaries of pups of obese mothers. At 30 dpn, the change in females was not significant. Conversely, in testicles, 24p3R mRNA levels increased slightly in the experimental group at 30 dpn. The Lcn2 protein signal was less intense in gonadal tissue sections from 30 dpn offspring of obese rats (P<0.001), whereas the 24p3R signal was downregulated in ovaries (P<0.001) and slightly upregulated in testicles. It was concluded that maternal obesity changes the expression of Lcn2 and 24p3R in the gonads of the offspring of obese rats, possibly through fetal programming. The consequences of this dysregulation for the offspring's gonadal function remains to be determined.

Background: Viral respiratory infections (VRIs) are a frequent cause of hospitalization in children under 24 months of age. A history of prematurity or heart disease may be a risk factor for complications in patients hospitalized for VRI. The objective was to describe epidemiological data for children hospitalized for IRV and aged 1 to 24 months and to identify risk factors for the presence of in-hospital complications and mortality over a period of 5 years., Methods: This was a cross-sectional study. Patients registered with VRI codes B974, J12, J120-J129X, J168, J17, J171, J178, J20, J203-J209, J21, J210, J211, J218, J219 (based on International Classification of Diseases [ICD-10]) from 2013 to 2017 were included. Three subanalyses were performed to compare [1] patients with pathological history (prematurity, bronchopulmonary dysplasia [BPD] and congenital heart disease [CHD]), [2] diagnoses (pneumonia, acute bronchitis, and acute bronchiolitis), and [3] admission to the pediatric intensive care unit. Days of hospital stay, in-hospital complications, invasive medical procedure and mortality were analyzed., Statistical Analysis: VRI hospitalization prevalence was described. For comparison between groups, Student's t-test, ANOVA and the Chi2 test were applied. To identify factors related to days of hospital stay, in-hospital complications and mortality, a linear and logistic regression model was performed., Results: A total of 66,304 hospitalizations were reported. The average age was 14.7 weeks; hospitalization events were higher in winter (39%), followed by autumn (27.3%). A total of 371 (0.56%) patients died. A total of 7068 (10.6%) hospitalized patients with pathological histories were identified. The presence of BPD (coefficient = 1.6), CHD (coefficient = 1.2), diagnosis of pneumonia (coefficient = 1.2), in-hospital complications (coefficient = 2.1) and invasive medical procedures (coefficient = 15.7) were the most common factors that increased the length of hospital stay. Risk factors for in-hospital complications and mortality were invasive medical procedure (OR = 3.3 & 11.7), BPD (OR = 1.8 & 1.6), CHD (OR = 4.6 & 3.4) and diagnosis of pneumonia (OR = 1.8 & 4.2)., Conclusions: Risk factors for morbidity and mortality in patients hospitalized for VRIs are BPD and CHD, diagnosis of pneumonia and invasive medical procedure.

Background: In adolescents with chronic kidney disease (CKD), menstrual disorders (MD) are common, which can make the management of CKD difficult and can sometimes delay renal transplantation. This study aimed to identify the usefulness of hormonal measurements in adolescents with CKD and their relationships with MD during a 1-year follow-up., Methods: A prospective cohort study was designed. Adolescents with CKD stages IV and V were included. Through clinical files and via interview, the ages at puberty onset, menarche and the date of last menstruation were identified. A 1-year follow-up was conducted over a menstrual cycle calendar. At the beginning of follow-up, routine hormonal profiles (thyroid profiles, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol) were assessed. We compared the hormonal profiles of the patients with and without MD (wMD vs. woMD). Comparisons between groups were made by Wilcoxon and Fisher's tests. Logistic regression analysis was used., Results: Fifty-seven patients, including 30 patients classified as wMD, were analyzed. The median age was 15 years, and the median time of CKD evolution was 18 months. There were no differences in general and biochemical characteristics between patients wMD and woMD. In terms of hormonal measurements, the levels of thyroid-stimulating hormone (TSH) and prolactin were higher in the wMD patients. A prolactin level ≥ 36.8 ng/ml was a risk factor for presenting with MD (RR 34.4, p = 0.002)., Conclusions: Hyperprolactinemia is correlated with MD in adolescents with CKD.

Objective: To evaluate the resistin/uric acid index as a prognostic factor associated with body mass index (BMI) z-score change after 1 year of lifestyle interventions for obesity., Study Design: In this prospective cohort study, we included 102 adolescents with overweight or obesity (BMI ≥85th percentile). Weight and height were measured at the start of the lifestyle change intervention and 12 months later. Serum levels of resistin and uric acid were quantified at the beginning of the intervention. The intervention consisted of nutrition education, exercise, and physical activity promotion., Results: The sample included 54 girls and 48 boys; the median age was 11 years (range 10-16 years). The BMI z-score decreased during follow-up (median BMI z-score at baseline was 1.81 vs 1.70 after 1 year, P < .001). The resistin/uric acid index was positively correlated with BMI z-score change (r = 0.27, P < .01). In the linear regression analysis, the resistin/uric acid index was significantly associated with BMI z-score modification at the 12-month follow-up (β = 0.17; 95% CI 0.08-0.26; P < .01)., Conclusions: The resistin/uric acid index can be considered a prognostic factor for identifying adolescents with overweight or obesity with a greater probability of improving their BMI. This index could help establish different interventions for adolescents with overweight and obesity; however, additional studies are needed to confirm the usefulness of this index., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tryptophan hydroxylase-type 2 (Tph2) is the first rate-limiting step in the biosynthesis of serotonin (5-HT) in the brain. The ophthalmic administration (Op-Ad) is a non-invasive method that allows delivering genetic vehicles through the eye and reaches the brain. Here, the murine Tph2 gene was cloned in a non-viral vector (pIRES-hrGFP-1a), generating pIRES-hrGFP-1a-Tph2, plus the FLAG-tag. Recombinant Tph2-FLAG was detected and tested in vitro and in vivo, where 25 μg of pIRES-hrGFP-1a-Tph2-FLAG was Op-Ad to mice. The construct was capable of expressing and producing the recombinant Tph2-FLAG in vitro and in vivo. The in vivo assays showed that the construct efficiently crossed the Hemato-Ocular Barrier and the Blood-Brain Barrier, reached brain cells, passed the optical nerves, and transcribed mRNA-Tph2-FLAG in different brain areas. The recombinant Tph2-FLAG was observed in amygdala and brainstem, mainly in raphe dorsal and medial. Relative Tph2 expression of threefold over basal level was recorded three days after Op-Ad. These results demonstrated that pIRES-hrGFP-Tph2-FLAG, administrated through the eyes was capable of reaching the brain, transcribing, and translating Tph2. In conclusion, this study showed the feasibility of delivering therapeutic genes, such as the Tph2, the first enzyme, rate-limiting step in the 5-HT biosynthesis.

Background: Hepatic encephalopathy (HE) in patients with chronic liver disease (CLD) is one of the main causes of reentry to the emergency department. Oxidative stress (OxS) regulated by ammonia leads to cerebral edema and astrocytes senescence in animal models, but seems to be different in humans., Objective: To analyze if OxS and ammonia in plasma are related to each other in the different grades of HE-CLD and to compare them with healthy volunteers (HV)., Methods: In a cross-sectional study, we included 60 subjects in 2 groups: (a) 30 HV and (b) 30 HE patients. Plasma levels of oxidation lipids/proteins, ammonia, and West-Haven score were evaluated. Student t test, Spearman's correlation, and ANOVA with Dunn's post hoc test were performed., Results: Ammonia in HV and HE patients was 39-49 vs. 95-345 μmol/L, respectively (p < 0.0001). Malondialdehyde (MDA) in HV was 6.58 ± 3.11 compared to 16.69 ± 6.19 μmol/L in HE (p < 0.0001). Protein oxidation by osazone (carbonyls), formazan, and dityrosines was higher in HE than in HV (p < 0.0001). Ammonia level was directly associated to HE severity, but without correlation with lipid MDA or protein OxS formazan, carbonyls, and dityrosines. Lipid peroxidation showed higher levels at degree 2 and protein oxidation at degree 3 of HE., Conclusions: We confirm that OxS accompanies hyperammonemia in HE; however they contribute in different proportions to their natural progression. Early reduction of OxS in HE could contribute to minimize the neurotoxicity into CLD., (© 2019 S. Karger AG, Basel.)

Background: Atherosclerosis is a primary risk factor for cardiovascular disease (CVD). Proinflammatory biochemical factors can influence vascular health; monocyte chemoattractant protein-1 (MCP-1) is elevated in patients with CVD while fibroblast growth factor-21 (FGF-21) acts directly on cardiac tissue to reduce infarction damage. However, the relationship between plasma concentrations of MCP-1, FGF-21 and subclinical CVD indices remains equivocal., Aim: To determine the association between MCP-1, FGF-21 and subclinical atherosclerosis [i.e., carotid intima-media thickness (cIMT)] in women without clinical evidence of CVD., Methods: A cross-sectional analysis of 140 women without history of CVD was performed. Anthropometrics were collected, serum concentrations of MCP-1 and FGF-21 were determined by enzyme-linked immunosorbent assay, and cIMT was quantified (B-mode ultrasonography). The correlations between MCP-1, FGF-21 and the presence of clinical and laboratory of subclinical atherosclerosis (i.e., cIMT ≥0.70 mm), comparison intergroup and odd ratio with multiple logistic regression were analyzed., Results: MCP-1, but not FGF-21 correlated with some obesity indicators. In median comparison among groups, subclinical atherosclerosis showed higher serum concentrations of MCP-1and lower serum concentrations of FGF-21. In postmenopausal women, there were significant differences MCP-1 (p = 0.001), and FGF-21 (p = 0.010). Multiple logistic regression analysis in postmenopausal women with subclinical atherosclerosis, between MCP-1 (p = 0.001) and FGF-21 (p = 0.037) showed association with cIMT, along with age., Conclusions: MCP-1 and FGF-21 levels are associated with subclinical atherosclerosis disease severity (i.e., cIMT) in postmenopausal women without CVD. Further efforts focused on characterizing the relationship between novel blood-borne markers of early CVD pathology are warranted and should be pursued., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In addition to oxidative stress due to the increase of free radicals, estrogen deficiency is associated with changes in enzymatic activity, glutathione redox ratio (GSH/GSSG), and the content of oxidative markers such as malondialdehyde. Tibolone, a synthetic steroid, has been used as an elective treatment for the relief of menopausal symptoms. However, the acute effects of hormonal therapy with tibolone on metabolic parameters and oxidative stress markers associated with the first stages of estrogen deficiency are still unknown. The study aimed to evaluate if the acute administration of tibolone reduces oxidative stress in ovariectomized rats fed high-fat-and-fructose diet. Rats were fed a standard diet or a diet consisting of 10% lard-supplemented chow and 20% high-fructose syrup in the drinking water plus tibolone or vehicle for seven days. Weight, cholesterol, triglycerides, and glucose levels, as well as antioxidant enzymes and oxidative stress markers were quantified in the serum of each experimental group. It was observed that seven days of diet and tibolone treatment in the ovariectomized group reduced weight, triglycerides, cholesterol, glucose levels and advanced glycation end products but did not change GSH/GSSG ratio nor the enzymatic activity of superoxide dismutase. Also, both glutathione peroxidase and glutathione reductase activity decreased, as well as malondialdehyde levels. These results suggest that the acute treatment with tibolone prevented the changes in the metabolic parameters analyzed as well as the increase in the levels of malondialdehyde and AGEs induced by ovariectomy and high-fat diet., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Endothelial dysfunction and subsequent inflammation contribute to the development of vascular cognitive impairment (VCI). Soluble intercellular adhesion molecule-1 (sICAM-1) is upregulated in endothelial dysfunction and promotes an inflammatory response; however, the relationship between sICAM-1 and VCI remains equivocal., Objective: To determine whether sICAM-1 contributes to the prediction of VCI., Methods: Community-dwelling older adults (n = 172) from the "Cohort of Obesity, Sarcopenia and Frailty of Older Mexican Adults" (COSFOMA) study were identified as VCI or controls using standard neuropsychological evaluations and neuroimaging. sICAM-1 was quantified using ELISA, and multivariate logistic regression determined the association between sICAM-1 and VCI., Results: A total of 31 VCI cases were identified. sICAM-1 was higher in VCI (VCI: 450.7 [241.6] ng/mL vs. controls: 296.9 [140.9] ng/mL). sICAM-1 concentrations above the 90th percentile (464.1 ng/mL) were associated with VCI group membership in all models (OR: 6.9, 95% CI: 1.1-42.2). The final saturated model explained 64% of the variance in VCI group membership., Conclusion: High concentrations of sICAM-1 are independently associated with VCI group membership. Efforts to further characterize the relationship between indices of endothelial dysfunction and pathological changes to the aging brain should be further pursued., (© 2019 S. Karger AG, Basel.)

Objective: To compare serum resistin concentrations between prepubertal girls with a BMI > 85th percentile and girls with precocious puberty (CPP) who have and have not undergone GnRH analog treatment., Patients and Methods: This is a cross-sectional study in girls with a BMI > 85th percentile and a median age of 8 years. We included 31 girls with CPP who did not receive treatment (CPPoT), 23 girls with CPP who were treated with leuprolide (CPPT), 22 prepubertal girls and 24 pubertal girls. Anthropometric data and the fasting plasma concentrations of lipids, glucose, insulin, and resistin were measured., Results: The z-BMI scores were similar among the groups (p = 0.344), and body fat percentage (BF%) was similar among CPPT, CPPoT and prepubertal girls (p = 0.151). Resistin and insulin levels were lower in girls with CPP (CPPT and CPPoT) than in prepubertal and pubertal girls (median resistin level: CPPT 11.8 pg/ml vs CPPoT 11 pg/ml vs prepubertal 16 pg/ml vs pubertal 16 pg/ml, p = 0.001; median insulin level: CPPT 10.7 μUI/mL vs CPPoT 10.2 μUI/mL vs prepubertal 14.4 μUI/mL vs pubertal 32 μUI/mL p = 0.02). ANCOVA analysis, after adjustments for pubertal stage, BF% and z-BMI, showed that CPP modifies resistin levels (F = 31.4; p = 0.0001) independently of these parameters (p < 0.05)., Conclusions: In the group of girls with overweight or obesity, the resistin level was lower in girls with CPP than in prepubertal and pubertal girls. More studies are needed to understand the role of resistin in CPP patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Numerous clinical studies have reported the association between high circulating levels of lipocalin-2 (LCN2) and metabolic diseases. However, only few studies have addressed sexually dimorphic, either in its circulating concentration or in its expression in other organs. To the best of our knowledge, LCN2 and the 24p3 receptor (24p3R), have not been identified in gonads; therefore, the present study analyzed their mRNA expression profile and cellular localization in gonads collected from fetal rats at 21 days post coitum, as well as from neonatal rats at 0, 2, 4, 6, 12, 20 and 30 postnatal days. Semiquantitative polymerase chain reaction and immunohistochemical assays revealed that the LCN2 mRNA during perinatal and pre-pubertal stages presented a sex-specific expression pattern, being higher in ovaries than in testes collected at these stages. Furthermore, the mRNA levels of the long and short isoforms of the 24p3R (507 and 350 bp, respectively), were lower in female gonads from postnatal day 0 onwards in comparison with the levels observed in males, but before birth, the short isoform of the 24p3R was higher in ovaries than in testes. In addition, in females, the abundance of mRNA of this isoform was drastically diminished at 24 h after birth. Furthermore, this specific expression profile of LCN2 and 24p3R at perinatal and prepubertal stages coincides with events of cellular proliferation and apoptosis within both gonads. Immunohistochemical assays revealed that in ovaries, LCN2 and 24p3R are present in germinal and somatic cells of follicles, while in testes, this adipokine and its receptor are only located in germinal cells. These findings suggest that in murine gonads, LCN2/24p3R signaling may be involved either in cell proliferation or cell death driven by gonadotropin-independent or -dependent mechanisms.

Background: Type 2 diabetes mellitus (DM2) is a chronic disease, and for treatment to succeed, it is necessary to harmonize the mental health of the patient with the environment, which impacts quality of life and adherence to medical regimens. The objetive of this study is describe the quality of life of patients with DM2 and the factors relates to its modification., Methods: This investigation was a cross-sectional study. Patients over 18 years of age with DM2 were selected. The following variables related to quality of life were studied: age, sex, occupation, marital status, years of DM2 evolution, comorbidities and presence of depression (Beck Depression Inventory). Perceived quality of life was measured with a health-related quality of life (HRQoL) scale, the 36-Item Short-Form Survey (SF-36). Patients were classified according to SF-36 HRQoL score (< 50, 51-75 and > 76 points)., Results: Among the 1394 patients included, the median age was 62 years. Global HRQoL had a median of 50.1 points. Bivariate analysis showed that age, marital status, sex, occupation, comorbidities, duration of DM2 and comorbidities had impacts on HRQoL. The logistic regression model identified age (odds ratio [OR] 1.04) and depression (OR 4.4) as independent factors that influenced overall quality of life., Conclusions: Patients with DM2 have poor HRQoL, which is associated with a high frequency of depression. Older age and the presence of depression impair patient HRQoL., Trial Registration: R-2013-781-052. Registered 20 December 2014.