Association between socioeconomic status and hospitalisation requirement in older patients attended at the emergency department: A retrospective cohort study.

INTRODUCTION AND OBJECTIVE: A low socioeconomic status (SES) has been associated with poor health results. The present study aimed to investigate if SES of older patients attending the emergency department is associated with the use of healthcare resources and outcomes. PATIENTS AND METHODS: Observational, retrospective study including consecutive patients 65 years or older admitted to the emergency department. Variables at baseline, index episode, and follow-up were recorded. SES was measured using an indirect theoretical index and patients were categorised into two groups according to whether they lived in a neighbourhood with a low or high SES. Primary outcomes included hospitalisation after the emergency department visit and prolonged hospitalisation (>7 days) at index episode. Secondary outcomes included emergency department re-consultant and hospital admission in the following 3 months after the index episode, and all-cause mortality after long-term follow-up. Logistic regression and cumulative hazards regression models were used to investigate associations between SES and outcomes. RESULTS: The cohort included 553 patients (80 years [73-85], 50.5% female, 55.9% with low SES). After the emergency department visit, 234 patients (42.3%) required hospital admission. A low SES was inversely associated with hospitalisation with an adjusted odds ratio=0.654 (95% CI 0.441-0.970). Among hospitalised patients, a low SES was associated with prolonged hospitalisation (adjusted odds ratio=2.739; 95% CI 1.470-5.104). Follow-up outcomes, including all-cause mortality, were not associated with SES. CONCLUSIONS: Older patients living in more deprived urban areas were hospitalised less often after emergency department care, but hospital stays were longer. Understanding the effect of social determinants in healthcare use is mandatory to tailor resources to patient needs.

Multidisciplinary intervention and cognitive remediation therapy for adults with obesity: A study protocol for a randomized controlled clinical trial.

Background: Cognitive Remediation Therapy (CRT) is a psychological treatment which aims to improve the neurocognitive processes that interfere with the daily functioning of individuals and has proven to be useful in the treatment of obesity. This therapy has been implemented in some countries as a co-adjuvant treatment for people with obesity, but it has not been tested in Mexico, where obesity is one of the main public health problems, so it is essential to implement more studies of this type to obtain effective treatments to control weight. Objective: To describe the research procedure of a multidisciplinary intervention protocol for adults with obesity in a randomized controlled clinical trial. Method: Participants will be adults from 19 to 60 years of age with obesity, who will be randomly assigned to experimental and control groups. The control group will receive intervention only after the experimental group has completed the intervention program. Measurements of body composition, nutritional state, psycho-physiological and physical activities of the participants will be obtained before and after the intervention, with a three-month follow-up after the intervention has concluded. Conclusion: Results of this study will provide useful evidence for the implementation and follow-up of a multidisciplinary intervention with CRT to promote a better efficacy in the treatment and control of obesity.

A variant in GRN of Spanish origin presenting with heterogeneous phenotypes.

INTRODUCTION: The variant c.1414-1G>T in the GRN gene has previously been reported as probably pathogenic in subjects of Hispanic origin in the American continent. METHODS: We report 5 families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings. RESULTS: Phenotypes were strikingly different, including cases presenting with behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, rapidly progressive motor neuron disease (pathologically documented), and tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G>T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11. CONCLUSIONS: We conclude that variant c.1414-1G>T of the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect.

The silent variants of pituitary tumors: demographic, radiological and molecular characteristics.

INTRODUCTION: Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known. AIM: To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression. METHODS: This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR. RESULTS: We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations. CONCLUSIONS: This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

Is Somatostatin Receptor and Dopamine Receptor profiling useful in the management of silent somatotroph tumors?

Silent somatotroph tumors (sSTs) are pituitary neuroendocrine tumors (PitNETs) which do not give rise to the clinical syndrome of acromegaly. Differently to their functioning counterparts, the adjuvant medical treatment with somatostatin analogues (SSAs) or dopamine receptors agonists (DAs) has been scarcely addressed in these tumors. As preliminary results of an ongoing research on silencing mechanisms involved in the pathogenesis of sSTs, we have characterized by qRT-PCR the expression of SSTRs and DRDs in a large series of 18 silent and 68 functioning STs. Although the expression of SSTR2 and SSTR5 was lower in sSTs than in functioning ones, we found a negative correlation between SSTR2 and the tumor size of the sSTs. Additionally, levels of expression of DRD2 were similar between the two subtypes suggesting a possible basis for the treatment of these tumors with SSAs and DAs.

Why don't corticotroph tumors always produce Cushing's disease?

OBJECTIVE: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. DESIGN: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. METHODS: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. RESULTS: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. CONCLUSIONS: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. METHODS: A study was made of (i) the quarterly JCV DNA levels in peripheral blood mononuclear cells (PBMCs), serum and urine samples in 100 multiple sclerosis patients during their natalizumab treatment (3-39 months), (ii) the association between human leukocyte antigen (HLA) class II and the previous viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. RESULTS: (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natalizumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P(corrected) = 0.108). (iii) The variants in PBMCs and serum of the non-PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neurotropic variants in the three previous compartments were found by the PML diagnosis. CONCLUSIONS: The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly.

[Adequacy of clinical interventions in patients with advanced and complex disease. Proposal of a decision making algorithm]. / Adecuación de las intervenciones clínicas en pacientes con enfermedad avanzada y compleja. Propuesta de algoritmo para la toma de decisiones.

Decision making in the patient with chronic advanced disease is especially complex. Health professionals are obliged to prevent avoidable suffering and not to add any more damage to that of the disease itself. The adequacy of the clinical interventions consists of only offering those diagnostic and therapeutic procedures appropriate to the clinical situation of the patient and to perform only those allowed by the patient or representative. In this article, the use of an algorithm is proposed that should serve to help health professionals in this decision making process.

Glutamate supply positively affects serum cholesterol concentrations without increases in total protein and urea around the onset of puberty in goats.

Different neurotransmitter and neuromodulatory systems regulate synthesis and secretion of GnRH. Whereas the endocrine and neural systems are activated in response to the metabolic status and the circulating levels of specific blood metabolites, glutamate receptors have been reported at hepatic level. This study evaluated the possible effect of glutamate supplementation upon changes in serum concentrations across time for total protein (TP), urea (UR) and cholesterol (CL) around the onset of puberty in goats. Prepuberal female goats (n=18) were randomly assigned to: (1) excitatory amino acids group, GLUT, n=10; 16.52±1.04kg live weight (LW), 3.4±0.12 body condition score (BCS) receiving an i.v. infusion of 7mgkg(-1) LW of l-glutamate, and (2) Control group, CONT, n=8; 16.1±1.04kg LW, 3.1±0.12 BCS. General averages for LW (23.2±0.72kg), BCS (3.37±0.10 units), serum TP (65.28±2.46mgdL(-1)), UR (23.42±0.95mgdL(-1)), CL (77.89±1.10mgdL(-1)) as well as the serum levels for TP and UR across time did not differ (P>0.05) between treatments. However, while GLUT positively affected (P<0.05) both the onset (207±9 vs. 225±12 d) and the percentage (70 vs. 25%) of females showing puberty, a treatment×time interaction effect (P<0.05) was observed in the GLUT group, with increases in serum cholesterol, coincident with the onset of puberty. Therefore, in peripuberal glutamate supplemented goats, serum cholesterol profile could act as a metabolic modulator for the establishment of puberty, denoting also a potential role of glutamate as modulator of lipid metabolism.

Toll-like receptor-9 in Spanish multiple sclerosis patients: an association with the gender.

BACKGROUND AND PURPOSE: Toll-like receptor-9 (TLR9) is a potent inducer of innate immune system triggered by infection with viruses, some of them previously related to multiple sclerosis (MS). The aim of this study was to analyze the possible association of two TLR9 single nucleotide polymorphisms (SNPs; rs352162 and rs187084) with susceptibility to MS. METHODS: Two independent cohorts of MS patients and controls were included: 574 clinically definite relapsing-remitting MS patients (367 females) and 807 healthy controls (418 females) for the first cohort; and 366 relapsing-remitting MS patients (238 females) and 224 healthy controls (160 females) for the second cohort. Genotyping was performed by TaqMan assays. RESULTS: The AT haplotype was found to be significantly higher in women than in men (P = 0.013 and P = 0.044). CONCLUSIONS: Here two possible genetic markers are proposed that could be also associated with the differences observed in the clinical course of MS in both genders. Further studies with larger cohorts should be performed to confirm these results.

Central administration of aminoprocalcitonin inhibits food intake and stimulates the hypothalamic-pituitary-adrenal axis in rats via the corticotrophin-releasing factor system.

Aminoprocalcitonin (N-PCT), a neuroendocrine peptide derived from procalcitonin, reduces food intake and body weight when administered centrally in rats. We have recently shown that N-PCT is expressed in brain areas known to be involved in energy homeostasis, including the paraventricular nucleus (PVN) of the hypothalamus, which contains a prominent population of corticotrophin-releasing factor (CRF)-synthesising neurones. CRF plays a pivotal role in the regulation of the hypothalamic-pituitary adrenal (HPA) axis and food intake. However, little is known about functional interactions of N-PCT and CRF. In the present study, we found endogenous N-PCT protein in the rat PVN. We also showed N-PCT immunoreactivity in PVN co-localised with NeuN, a neuronal marker, or glial fibrillary acidic protein, an astrocyte marker. Double staining immunohistochemistry revealed that N-PCT co-localised with CRF in parvocellular neurones of the PVN. Intracerebroventricular N-PCT administration increased CRF mRNA and content in the hypothalamus, suggesting that N-PCT stimulates the HPA axis and suppresses food intake and body weight via CRF-dependent pathways. In keeping with this, i.c.v. co-injection of D-Phe-CRF(12-41), a CRF receptor antagonist, significantly attenuated N-PCT-induced reduction in food intake and body weight in a dose-dependent manner. Furthermore, i.c.v. administration of N-PCT increased plasma adrenocorticotrophic hormone and corticosterone concentrations and induced the expression of Fos protein, a marker of neuronal activity, in parvocellular CRF neurones. These data collectively support the hypothesis that N-PCT inhibits food intake and body weight and stimulates the HPA axis via CRF-mediated pathways.

[Development of Lennox-Gastaut syndrome in adulthood]. / Evolucion del sindrome de Lennox-Gastaut en la edad adulta.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that starts in childhood and has an unknown pathophysiological mechanism. Studies on the progress of LGS reveal a poor prognosis. PATIENTS AND METHODS: A retrospective study of 1629 patients with epilepsy was conducted. Patients included in the study were those with an age of onset during childhood, tonic seizures and atypical absences (who might also suffer from other types of seizures); electroencephalogram (EEG) showing generalised slow spike-wave and generalised fast activity; mental retardation and a follow-up time of at least 10 years. RESULTS: The sample consisted of 12 patients, 9 of whom were males. Follow-up time: 20 years. Onset of seizures: 3 years. Cryptogenic LGS: 67%; symptomatic: 33%. Frequency of the seizures at onset: daily (83.3%) or weekly (16.7%). Types of seizures: tonic and atypical absences (100%); drop-attacks (83%); generalised tonic-clonic (75%); myoclonias (41.7%); partial (8.3%) and pseudo-epileptic (8.3%). EEG with slow background activity, generalised slow spike-wave and generalised fast activity: 100%. Fifty percent of the patients had at least one epileptic status. They used an average of 7.5 different antiepileptic drugs. At the end of the follow-up 33% were suffering from seizures on a daily basis; 17% were weekly and 42% monthly. A total of 8.3% were free from seizures. All of them were following combination therapy: 17% in bitherapy and 83% with an average of 3.8 drugs (range: 3-5). A total of 92% suffered from severe or very severe mental retardation. Fifty percent required neuroleptic drugs due to behavioural disorders. CONCLUSIONS: Despite the fact that the diagnosis of LGS is serious, we observed a decrease in the number of seizures after several years of development, although the antiepileptic combination therapy remains constant. The mental retardation and behavioural disorders lead to a poor functional prognosis.

Neutralizing antibodies, MxA expression and MMP-9/TIMP-1 ratio as markers of bioavailability of interferon-beta treatment in multiple sclerosis patients: a two-year follow-up study.

BACKGROUND: The objective of this study was to correlate the detection of neutralizing antibodies (NAbs) by the cytopathic effect (CPE) assay, with the expression of myxovirus resistance protein A (MxA), and the ratio between matrix metalloproteinase 9 (MMP-9) and its tissular inhibitor (TIMP-1), in order to evaluate their usefulness as markers of interferon beta (IFN-beta) bioavailability. METHODS: Pairs of blood and serum samples were collected from 50 patients with multiple sclerosis (MS) during 2 years of IFN-beta treatment. Expression of MxA, MMP-9 and TIMP-1 were analysed by quantitative PCR, and NAbs were measured by CPE assay. RESULTS: During the study, 60% of patients presented NAbs. The number of serum samples that were NAbs+ was significantly increased amongst patients with relapses (41/92 vs. 33/108, P = 0.04). With one serum sample and with a NAb titre >100 tenfold reduction unit (TRU), 66.7% of patients with MS suffered from relapses, 41.7% suffered from progression, and 75% was not an optimal clinical responder. We did not find any significant difference in MxA. We found that 62.5% of patients with MS patients whose ratio was increased twofold after 2 years suffered from relapses, 37.5% suffered from progression, and 68.7% was not an optimal clinical responder. CONCLUSION: The early detection of NAbs by CPE assay and the finding of only one serum sample with a NAb titre >100 TRU seem to be markers of low bioavailability of IFN-beta, whilst a twofold decrease in the MMP-9/TIMP-1 ratio by quantitative PCR assay seems to be a marker of high bioavailability of IFN-beta.

Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events.

OBJECTIVE: Approximately 15-20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications. METHODS: Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ET(A)R and ET(B)R) messenger RNA were measured by real-time quantitative reverse transcriptase-PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot. RESULTS: ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ET(A)R and ET(B)R/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1beta, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032). CONCLUSIONS: The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

Protection against free radicals (UVB irradiation) of a water-soluble enzymatic extract from rice bran. Study using human keratinocyte monolayer and reconstructed human epidermis.

The antioxidant capacity of a water-soluble enzymatic extract from rice bran (EERB) has been tested in two cell models: keratinocyte monolayers and human reconstructed epidermis. Cells were incubated in culture medium in presence of different amounts of EERB and were UVB irradiated. Cell population assessment (MTT assay) and MDA (malonaldehyde) production were evaluated. The EERB did not induce cytotoxic effect for concentrations inferior or equal to 100 microg/mL. Human keratinocyte monolayers were protected of irradiation preventing 33% the lipid peroxidation process at concentration of 10 microg/ml of EEBR. In reconstructed human epidermis, 100 microg/mL decreased lipid peroxidation process by 44% (p<0.01) with regards to irradiated negative control. This effect was comparable to that of vitamin E at 600 microg/mL. Our data indicate that EERB is potentially able to efficiently counteract UVB-induced response. The EERB, diluted at 10% with water has very good skin compatibility. This product showed a sun protection factor of 4.8+/-0.3. Thus we can propose EERB as a useful natural standardized extract in skin photoprotection with promising applications in the field of dermatology.

Trajectories of evolution and drivers of change in European mountain cattle farming systems.

In the last few decades, significant changes in livestock farming systems and land use were observed in European mountain areas with large implications for the sustainability of grazing agro-ecosystems. System dynamic studies become essential to understand these changes, identify the drivers involved and trying to anticipate what might happen in the future. The objectives of this study were as follows: (i) to analyse the main recent changes that occurred in mountain cattle farming in the Spanish Pyrenees; (ii) to typify diverse trajectories of evolution of these systems; and (iii) to establish drivers of change that might help understand the evolution of mountain agriculture. A constant sample of mountain cattle farms was analysed for the period 1990 to 2004. In total, 30% of farms have disappeared during this time interval. For the remaining farms, the most important general changes observed were as follows: increment of size; change of productive orientation from mixed beef-dairy to pure beef production; extensification of grazing management; reduction of family labour and increase of pluriactivity; reduction of unitary variable costs; and increase of labour productivity. After the elimination of common temporal effects between dates, multivariate techniques allowed for the identification of three patterns and six specific trajectories of evolution that are profiled in the text. Relationships between the patterns of evolution and other variables referring the farm, the household and the socio-economic environment were identified as drivers of change: (i) the specific location of the farm in relation to the capital village of the municipality and the evolution other sectors of the economy, in particular tourism; (ii) the size of the family labour, presence of successors and degree of dynamism of the farmer; and (iii) the initial orientation of production.