A novel kinetic model for a cocoa waste fermentation to ethanol reaction and its experimental validation.

A non-segregated kinetic model is proposed to describe a fermentation process of agro-industrial residues derived via cocoa (mucilage juice) by Pichia kudriavzevii. The novel proposed hybrid model is based on a multiple coupling reaction mechanisms (structured) to describe the kinetics of substrate consumption, biomass, carbon dioxide, and ethanol, coupled to an unstructured model for the activity enzyme. The parameters of the kinetic model are estimated by non-linear least-squares curve fitting using the Marquardt-Levenberg algorithm. In addition, numerical simulations were compared with the experimental data via residual graphs. The effectiveness of the model was statistically evaluated using dimensionless efficiency coefficients under different initial conditions. A global sensitivity analysis was applied (Fisher's information matrix). The experimental results of the batch reactor showed a maximum ethanol concentration of 29 g/L, with a yield of 0.48 g-ethanol/g-glucose and a productivity of 0.30 g/L h. The method determined that the cell formation coefficient and the specific substrate consumption rate (θ1 and θ2) directly influence most of the states of our system. The proposed scheme is particularly suitable to assist in the rational design of cell factory properties or fermentation processes because it can represent the complex biochemistry in more detail and under different initial experimental conditions; the above reveals that the generated model is robust and can be considered for control and optimization purposes.

Mutational Profile and Retinal Phenotypes of PCARE-Related Cone-Rod Dystrophies in a Mexican Cohort.

Purpose: The aim of the study is to describe the genotype and phenotype of a Mexican cohort with PCARE-related retinal disease. Methods: The study included 14 patients from 11 unrelated pedigrees with retinal dystrophies who were demonstrated to carry biallelic pathogenic variants in PCARE. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field test, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed either by gene panel sequencing or by exome sequencing. Results: According to the results of multimodal imaging and functional tests, all 14 patients were diagnosed with cone-rod dystrophy. Six different PCARE pathogenic alleles were identified in our cohort, including three novel mutations: c.3048_3049del (p.Tyr1016∗), c.3314_3315del (p.Ser1105∗), and c.551A > G (p.His184Arg). Notably, alleles p.His184Arg, p.Arg613∗, and p.Arg984∗ were present in 18 of the 22 (82%) PCARE alleles from probands in our cohort. Conclusion: Our work expands the PCARE mutational profile by identifying three novel pathogenic variants causing retinal dystrophy. While phenotypic variations occurred among patients, a cone-rod dystrophy pattern was observed in all affected individuals.

The therapeutic landscape of tauopathies: challenges and prospects.

Tauopathies are a group of neurodegenerative disorders characterized by the aggregation of the microtubule-associated protein tau. Aggregates of misfolded tau protein are believed to be implicated in neuronal death, which leads to a range of symptoms including cognitive decline, behavioral change, dementia, and motor deficits. Currently, there are no effective treatments for tauopathies. There are four clinical candidates in phase III trials and 16 in phase II trials. While no effective treatments are currently approved, there is increasing evidence to suggest that various therapeutic approaches may slow the progression of tauopathies or improve symptoms. This review outlines the landscape of therapeutic drugs (indexed through February 28, 2023) that target tau pathology and describes drug candidates in clinical development as well as those in the discovery and preclinical phases. The review also contains information on notable therapeutic programs that are inactive or that have been discontinued from development.

Persistence of SARS-CoV-2 total immunoglobulins in a series of convalescent plasma and blood donors.

BACKGROUND: The vast majority of COVID-19 cases both symptomatic and asymptomatic develop immunity after COVID-19 contagion. Whether lasting differences exist between infection and vaccination boosted immunity is yet to be known. The aim of this study was to determine how long total anti-SARS-CoV2 antibodies due to past infection persist in peripheral blood and whether sex, age or haematological features can influence their lasting. MATERIAL AND METHODS: A series of 2421 donations either of SARS-CoV-2 convalescent plasma or whole blood from 1107 repeat donors from January 2020 to March 2021 was analysed. An automated chemiluminescence immunoassay for total antibodies recognizing the nucleocapsid protein of SARS-CoV-2 in human serum and plasma was performed. Sex, age, blood group, blood cell counts and percentages and immunoglobulin concentrations were extracted from electronic recordings. Blood donation is allowed after a minimum of one-month post symptom's relapse. Donors were 69.7% males and their average age was 46. The 250 donors who had later donations after a positive one underwent further analysis. Both qualitative (positivity) and quantitative (rise or decline of optical density regarding consecutive donations) outcomes were evaluated. RESULTS AND DISCUSSION: In 97.6% of donors with follow-up, anti-SARS-CoV-2 protein N total antibodies remained positive at the end of a follow-up period of 12.4 weeks median time (1-46, SD = 9.65) after the first positive determination. The blood group was not related to antibody waning. Lower lymphocyte counts and higher neutrophils would help predict future waning or decay of antibodies. Most recovered donors maintain their total anti-SARS-CoV-2 N protein antibodies for at least 16 weeks (at least one month must have been awaited from infection resolution to blood donation). The 10 individuals that could be followed up longer than 40 weeks (approximately 44 weeks after symptom's relapse) were all still positive.

TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to γ-secretase modulation and amyloid-ß42 lowering by GSM-10h.

BACKGROUND: Cleavage of the amyloid precursor protein (APP) by ß-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-ß (Aß) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aß42 peptide while avoiding deleterious activity on Notch processing. OBJECTIVE: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aß peptides to induce neurotoxicity in rat primary cortical neurons. METHODS: The effect of GSM-10h on Aß levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. RESULTS: In cells, GSM-10h decreased levels of Aß42 while concomitantly increasing levels of Aß38 in the absence of effects on Aß40 levels. In TASTPM mice, GSM-10h effectively lowered brain Aß42 and increased brain Aß38, with no effect on Notch signalling. Unlike Aß42, which causes neuronal cell death, neither Aß37 nor Aß38 were neurotoxic. CONCLUSIONS: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.

Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity.

The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido]propionamide], a nonpeptide bombesin (BB) BB1/BB2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction (3.75 and 7.5 mg/kg, i.p.), dose-dependently attenuated the number of vocalizations emitted by guinea pig pups separated from their mother (1-30 mg/kg, i.p.), reduced latency to approach a palatable snack in an anxiogenic (unfamiliar) environment, and reduced the fear-potentiated startle response (5 and 10 mg/kg, i.p., and 100-200 ng per rat, i.c.v.). When administered directly to the dorsal raphé nucleus (DRN), PD 176252 (20-500 ng) increased social interaction under aversive conditions, as did the 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (50 ng). Furthermore, intra-DRN microinfusion of the peptide antagonist (PD 176252) suppressed, whereas its agonist [neuromedin B (NMB)-30] promoted, the in vivo release of 5-HT in the ventral hippocampus. In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist. Together, these findings suggest that endogenous BB-like peptides at the DRN evoke the release of 5-HT from the limbic nerve terminals originating from the raphé, specifically at the ventral hippocampus, resulting in anxiogenesis. The finding that this action was attenuated by BB receptor (BB1 and/or BB2) antagonists suggests that these compounds may represent a novel class of anxiolytic agents.

Differential evaluation of the baroreceptor cardiac reflex effectiveness as a function of sequence length.

Recently a new index of baroreceptor cardiac function has been proposed, the baroreflex effectiveness index (BEI). BEI was defined as the ratio between the number of systolic blood pressure (SBP) ramps (progressive beat-to-beat increases ("up") or decreases ("down")) followed by reflex changes in heart period and the total number of SBP ramps. In this study we tested BEI as a function of the length of cardiac sequences in which the reflex operates (3, 4, 5, and 6 beats) in human subjects in the laboratory. Results show an overall BEI of .65, with greater values for the "up" (.69) than for the "down" sequences (.62). These values are much higher than previously reported. When analyzed as a function of sequence length, BEI increases as sequence length decreases. This difference is more progressively observed in the "up" than in the "down" sequences. Both slope and overall blood pressure change of the SBP ramps increase as sequence length increases. Overall blood pressure change of the SBP ramps can predict BEI for the 4- (r2 approximately .057) and 3-beat sequences (r2 approximately .20). These results suggest the need to examine the effects of the setting/experimental manipulation on the average length of cardiac sequences, given that an observed change in BEI could be genuine or simply associated with a modification in the pattern of sequence length.

Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes.

Several transgenic mouse models of Alzheimer's disease (AD) have been developed that exhibit beta-amyloid (Abeta) neuropathology and behavioural deficits. However, not all studies have investigated the relationship between the development of cognitive impairment and neuropathology. Therefore, temporal changes in cognition were investigated in male and female double-mutant APPswexPS1.M146V (TASTPM) transgenic mice using an object recognition test and correlated with the development of cerebral Abeta neuropathology. Both male and female TASTPM mice exhibited similar significant cognitive impairment at 6, 8 and 10 months of age in the object recognition test, compared to wild-type littermates. There was no such cognitive impairment at 3 or 4 months of age. Quantitative immunohistochemistry using a battery of Abeta antibodies demonstrated that cerebral Abeta deposition was first apparent in 3-month-old mice, and it increased with age. The early appearance of cerebral Abeta deposits in the double-transgenic TASTPM mice supports the evidence that mutations in the PS1 gene accelerate Abeta deposition. The cerebral Abeta load was greater in female than in male TASTPM mice at all ages investigated. In the electron microscope, mature Abeta plaques comprising a fibrillar core surrounded by degenerating neurites and reactive glia were first observed in the cortex of TASTPM mice at 6 months of age, the same age at which cognitive impairment became apparent. These results suggest that the cognitive impairment in TASTPM mice is related to the disruption of neural connectivity and not simply Abeta deposition, which first occurs 3 months earlier.

Proyecto "KAIRÓS": monitorización ambulatoria de la presión arterial en farmacia comunitaria. Control y seguimiento de la presión arterial en pacientes hipertensos ancianos tratados / 'KAIRÓS' project: ambulatory monitoring of blood pressure in community pharmacies. Monitoring and follow-up of blood pressure in hypertensive elderly patients under treatment

Objetivos: Conocer, mediante la monitorización ambulatoria de la presión arterial (MAPA) en farmacia comunitaria (FC), el grado de control de la presión arterial (PA) del paciente hipertenso anciano. Identificación del perfil circadiano. Identificación de hipertensión clínica aislada (HCA) e hipertensión enmascarada no controlada (HENC). Métodos: Muestreo consecutivo de los pacientes hipertensos ancianos con tratamiento farmacológico antihipertensivo atendidos en dos FC. Se realizó medida aislada de presión arterial en farmacia comunitaria (MAFC) y MAPA durante un mínimo de 29h a cada paciente. Se envió informe al médico para su valoración. Resultados: 219 pacientes (47,9% mujeres, edad media 71,5±5,4 años). El grado de control con medida con MAFC (74 pacientes) es del 34% y con MAPA (99 pacientes) es del 45%. La prevalencia de patrón circadiano dipper fue del 29,7%. 21 pacientes hipertensos controlados con MAFC (<140/90) (9,6%) tuvieron cifras de PA≥130/80 en MAPA 24h y/o ≥135/85 en MAPA actividad y/o ≥120/70 MAPA nocturna, considerándose pacientes con hipertensión enmascarada no controlada (HENC). 46 pacientes hipertensos no controlados en MAFC (≥140/90) (21%) tuvieron cifras de PA<130/80 en MAPA 24h y <135/85 en MAPA actividad y <120/70 MAPA nocturna, considerándose pacientes con hipertensión clínica aislada (HCA). Conclusiones: El grado de control de la PA de pacientes hipertensos ancianos es mayor cuando se analiza mediante MAPA. Su perfil circadiano es mayoritariamente non dipper. La realización de MAPA en FC permite identificar la HCA y la HENC. La medida islada de PA es insuficiente para optimizar el control de la HTA en estos pacientes

Objectives: Learning, through ambulatory blood pressure monitoring (AMBP) in community pharmacies (CP), the level of blood pressure (BP) monitoring in hypertensive elderly patients. Identification of circadian profile. Identification of isolated clinical hypertension (ICH) and hidden uncontrolled hypertension (HUH). Methods: Consecutive sampling of hypertensive elderly patients with antihypertensive drug treatment attended to at two CPs. Isolated measuring of blood pressure in a community pharmacy (IMCP) and AMBP were conducted over at least 29 hours in each patient. The report was sent to the doctor for evaluation. Results: 219 patients (47.9% females, aged 71.5±5.4 years on average). The level of control with IMCP measurement (74 patients) is 34% and with AMBP (99 patients) is 45%. The prevalence of the dipper circadian rhythm was 29.7%. 21 hypertensive patients controlled with IMCP (<140/90) (9.6%) had BP values of≥130/80 in AMBP 24h, and/or ≥135/85 in AMBP activity and/or ≥120/70 night time AMBP, considering patients with hidden uncontrolled hypertension (HUH). 46 hypertensive uncontrolled patients in IMCP (≥140/90) (21%) had BP values of<130/80 in AMBP 24h and <135/85 in AMBP activity and <120/70 night time AMBP, considering patients with isolated clinical hypertension (ICH). Conclusions: The level of BP control of hypertensive elderly patients is higher when measured with AMBP. Its circadian profile is mostly non dipper. AMBP measurement in CPs allows identification of ICH and HUH. Isolated BP measurements are not sufficient to optimize HBP control in these patients

Comparison of baroreceptor cardiac reflex sensitivity estimates from inter-systolic and ECG R-R intervals.

Baroreceptor reflex sensitivity (BRS) is frequently evaluated using the spontaneous sequence method. Many of these studies use the inter-systolic interval (ISI) derived from a blood pressure monitor (e.g., Finapres) as interbeat interval measure instead of the traditionally recommended R-R series derived from the ECG. In this study, we examine possible differences between estimates of BRS from ISI and ECG R-R intervals. BRS was evaluated in 35 participants under three conditions: rest, mental arithmetic, and recovery periods. Although correlations between the two estimates are very high (all rs>.9), small but significant differences were found: the measures from ISI systematically yield higher BRS values and result in the detection of a greater number of reflex sequences. The higher BRS values from measures of ISI are due to the effects of pulse transit time fluctuations associated with the sequences of change in blood pressure.

[Patient satisfaction with the patient-doctor relationship measured using the questionnaire (PDRQ-9)]. / Satisfacción del paciente con la relación con su médico de familia: un estudio con el Patient-Doctor Relationship Questionnaire.

OBJECTIVE: To describe patient satisfaction of their relationship with the family physician, using the PDRQ-9 questionnaire and assess its psychometric properties. DESIGN: Cross-sectional study. SETTING: Six Primary Care Health centres in the Community of Madrid, Spain. PARTICIPANTS: Four hundred and fifty one patients randomly selected from those who had just visited their family physician. INTERVENTIONS: Interviews were carried out to collect demographic characteristics, health needs, the accessibility to the service, and the socioeconomic situation of the subjects. MEASUREMENTS: The PDRQ-9 responses were collected and a synthetic satisfaction index was constructed. A multivariable model was designed to explain differences in satisfaction. RESULTS: The mean satisfaction index was 4.41 (95% CI: 4.33-4.48) on a scale of 1 (the worst) to 5 (the best satisfaction possible), with a median of 4.78 (interquartile range 4.00-5.00). Four of every 10 subjects expressed the maximum possible satisfaction ("ceiling effect"). A single factor explained 75.3% of the variance, with a Cronbach alpha value of 0.952. Age (OR 1.03, 95% CI: 1.02-1.05) and living in rural areas (OR 1.44, 95% CI: 0.94-2.20) were associated with above average satisfaction. CONCLUSIONS: Primary care users feel their relationship with their family physicians are very satisfactory, particularly in those who are older and who live in rural areas. The PDRQ-9 questionnaire shows a high internal consistency, but it is not good enough to discriminate in the upper part of the scale.

Tonic blood pressure modulates the relationship between baroreceptor cardiac reflex sensitivity and cognitive performance.

This study explored the effects of tonic blood pressure on the association between baroreceptor cardiac reflex sensitivity and cognitive performance. Sixty female participants completed a mental arithmetic task. Baroreceptor reflex sensitivity was assessed using sequence analysis. An interaction was found, indicating that the relationship between baroreceptor reflex sensitivity and cognitive performance is modulated by blood pressure levels. Reflex sensitivity was inversely associated to performance indices in the subgroup of participants with systolic blood pressure above the mean, whereas the association was positive in participants with systolic values below the mean. These results are in accordance with the findings in the field of pain perception and suggest that tonic blood pressure modulates the inhibitory effects of baroreceptor stimulation on high central nervous functions.

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.

Short-term effects of a brief respiratory training on baroreceptor cardiac reflex function in normotensive and mild hypertensive subjects.

Baroreceptor cardiac reflex sensitivity is reduced in hypertension and is considered a powerful prognostic factor in cardiovascular health. This study analyzes the acute effects of a brief respiratory training on baroreceptor sensitivity and on two new proposed baroreflex parameters: baroreceptor power (i.e., the percentage of cardiac beats regulated by the baroreflex) and effectiveness (i.e., the frequency in which the baroreflex responds to transient alterations in blood pressure). Twenty-two participants, 10 primary mild hypertensives and 12 normotensives, learned and practiced a respiratory pattern characterized by breathing at 6 bpm, with time of expiration being twice time of inspiration, predominantly abdominal, and with pursed lips. Baroreceptor parameters are differentiated in terms of increases ("up" sequences) or decreases ("down" sequences) in blood pressure. Irrespective of the groups, the breathing manipulation increased baroreceptor sensitivity (only in the "up" sequences), power, and effectiveness (only in the "down" sequences). These results suggest that this type of respiratory training could be used as a promising intervention to increase baroreceptor cardiac function in primary hypertension.

La calidad de vida relacionada con la salud como factor explicativo de la utilización de la consulta de medicina de familia: un estudio bajo el modelo conductual / Quality of life related to health as a factor explaining the use of family medical consultation: a study on the behavioral model

Fundamento: La utilización de servicios sanitarios se ha estudiado desde varios modelos conceptuales. El objetivo de este trabajo es valorar la influencia de la calidad de vida relacionada con la salud (CVRS) en la variabilidad de la utilización de la consulta de atención primaria bajo el «modelo conductual». Métodos: Estudio transversal analítico. Se entrevistó a 451 sujetos de 6 centros de salud en la Comunidad de Madrid. Se recogieron características relacionadas con factores ambientales e individuales (predisponentes, facilitadores y de necesidad) y la CVRS (Euroqol-5D). La utilización se recogió de la historia clínica informatizada. Resultados: Hubo una mediana de 13 visitas/año (rango intercuartil 7-20). La CVRS explicaba un 5,2% de la variabilidad en la utilización, vivir en barrios de rentas altas un 2,4%, la edad un 7,4%, la renta individual un 1,0% y los factores relacionados con «necesidad» (enfermedades crónicas e ingresos hospitalarios) explicaban un 4,1% de variabilidad adicional. Cada cambio de tercil de la CVRS se asoció con una disminución del 13,8% en las consultas/año. La residencia en zonas de renta alta y cada aumento de 1000 de renta individual disminuían la utilización un 17,5% y un 9,5% respectivamente. La edad se asociaba con un aumento de un 8,0% de visitas/año por década. El sufrir enfermedades crónicas o ingresos hospitalarios suponía aumentar un 51,9% y un 26,5% las visitas anuales. Conclusiones: La CVRS se asocia de manera independiente con la variabilidad en la utilización de la consulta del médico de familia, una vez ajustado el efecto de la necesidad, como propone el «modelo conductual»(AU)

Background: Health services utilization has been studied under several conceptual models. This study is aimed to assess the influence of Health Related Quality of Life (HRQL) on the variability of the primary care consultation utilization under the «behavioral model» Methods: A cross-sectional study. Interviews were conducted with 451 subjects at six health centers in the Community of Madrid. Environmental and individual characteristics (predisposing, enabling and need factors) and HRQL (EuroQol-5D) were collected. Annual visits were retrieved from the computerized clinical history. Results: Median utilization was 13 visits/year (interquartile range 7- 20). HRQL explained 5,2% of utilization variability, living in high-income areas an additional 2.4%, age a 7.4%, incomes a 1.0% and «need factors» (chronic illnesses or a hospital admission in the last year) explained an additional 4.1% of the variability. Each increase of the tercile in the perception of HRQL was associated with a decrease of 13,8% of the number of visits/year. Living in high-income areas, and each increase of 1000 in the incomes decreased the percentage of annual visits 17.5 % and 9.5% respectively. Age is associated with an increase of 8.0% of annual visits per decade. Suffering from chronic illnesses or a hospital admission in the last year increased the average number of visits/year to 51.9 and 26.5%. Conclusions: HRQL is independently associated with the variability of the demand for the family physician after adjusting by « health need» factors as the «behavioral model» proposes(AU)

Modification of baroreceptor cardiac reflex function by biofeedback.

Baroreceptor sensitivity (BRS) is considered a powerful prognostic factor in cardiovascular health. This study investigated the possibility of modifying the baroreflex cardiac function through biofeedback. Thirty-two psychology students underwent 3 biofeedback sessions, with four 5-min trials each, in which they had to increase and decrease baroreflex function. BRS was assessed by a system that analyzed baroreflex cardiac function on-line using a noninvasive spontaneous sequence method in the time domain. Baroreceptor parameters were differentiated in terms of blood pressure increases ("up" sequences) or blood pressure decreases ("down" sequences). BRS in the "up" sequences increased during the Increase Condition and decreased during the Decrease Condition. BRS in the "down" sequences decreased during the Decrease Condition but was unchanged during the Increase Condition. The increase in BRS during the Increase Condition was associated with a significant reduction in blood pressure and increase in heart period. The opposite cardiovascular changes were observed during the Decrease Condition. Suggestions for future research were discussed.

Differential analysis in the time domain of the baroreceptor cardiac reflex sensitivity as a function of sequence length.

Analysis of baroreceptor sensitivity (BRS) in the time domain through the spontaneous sequence method used a measure of BRS based on the average of all sequences detected, without making any distinction in cardiac cycle length. In this article, we study differentially the functioning of the baroreflex as a function of the length of the cardiac sequences (3, 4, 5, or 6 cardiac cycles). One hundred and four students performed three mental stress tasks: mental arithmetic, memory, and visual attention. The results show that (1) as sequence length decreases, the relationships between BRS and indexes of vagal cardiac control increase, (2) the BRS associated with the more short sequences (3 and 4 beats) is the most vulnerable to mental stress, particularly the mental arithmetic task, and (3) BRS increases progressively as sequence length decreases. These results suggest that the nature and functioning of the baroreflex differ as a function of the length of the cardiac sequences.

Gabapentin and the neurokinin(1) receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain.

The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.

BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes.

BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.

Satisfacción del paciente con la relación con su médico de familia: un estudio con el Patient-Doctor Relationship Questionnaire / Patient satisfaction with the Patient-Doctor Relationship measured using the Questionnaire (PDRQ-9)

Objetivo: Describir la satisfacción del paciente con la relación con su médico de familia mediante la utilización del Patient-Doctor Relationship Questionnaire versión de 9 preguntas (PDRQ-9) y reevaluar las propiedades psicométricas de éste.DiseñoEstudio transversal.EmplazamientoSeis centros de Atención Primaria (AP) en la Comunidad de Madrid, España.ParticipantesCuatrocientos cincuenta y un pacientes aleatorizadamente seleccionados que acababan de acudir a una consulta de Medicina de Familia. Mediciones: Entrevista en la que se recogen características sociodemográficas del sujeto, su necesidad en salud, la accesibilidad al servicio y la situación socioeconómica. Se recogen las contestaciones a los 9 ítems del PDRQ-9 y se construye un índice sintético de satisfacción; se explican las diferencias en la satisfacción con un modelo multivariante. Resultados: La media de la satisfacción fue de 4,41 (intervalo de confianza [IC] del 95%: 4,33–4,48) en una escala de uno (menor satisfacción) a 5 (mayor satisfacción) con una mediana de 4,78 (rango intercuartil: 4,00–5,00). Cuatro de cada 10 sujetos expresaban la máxima satisfacción posible (efecto techo). Un único factor explicaba el 75,3% de la variancia, con un valor alfa de Cronbach de 0,952. La edad (OR: 1,03, IC del 95%: 1,02–1,05) y el vivir en zonas rurales (OR: 1,44, IC del 95%: 0,94–2,20) se asociaban con una satisfacción mayor. Conclusiones: Los usuarios de AP están bastante satisfechos con la relación con su médico, especialmente los de más edad y los que viven en ámbitos rurales. El PDRQ-9 tiene una elevada consistencia interna, pero presenta problemas de discriminación en la parte alta de la escala (AU)

Objective: To describe patient satisfaction of their relationship with the family physician, using the PDRQ-9 questionnaire and assess its psychometric properties. Design: Cross-sectional study. Setting: Six Primary Care Health centres in the Community of Madrid, Spain. Participants: Four hundred and fifty one patients randomly selected from those who had just visited their family physician. Interventions: Interviews were carried out to collect demographic characteristics, health needs, the accessibility to the service, and the socioeconomic situation of the subjects. Measurements: The PDRQ-9 responses were collected and a synthetic satisfaction index was constructed. A multivariable model was designed to explain differences in satisfaction.ResultsThe mean satisfaction index was 4.41 (95% CI: 4.33–4.48) on a scale of 1 (the worst) to 5 (the best satisfaction possible), with a median of 4.78 (interquartile range 4.00–5.00). Four of every 10 subjects expressed the maximum possible satisfaction ("ceiling effect"). A single factor explained 75.3% of the variance, with a Cronbach á value of 0.952. Age (OR 1.03, 95% CI: 1.02–1.05) and living in rural areas (OR 1.44, 95% CI: 0.94–2.20) were associated with above average satisfaction. Conclusions: Primary care users feel their relationship with their family physicians are very satisfactory, particularly in those who are older and who live in rural areas. The PDRQ-9 questionnaire shows a high internal consistency, but it is not good enough to discriminate in the upper part of the scale (AU)