Prevalence of Advanced Parkinson's Disease in Patients Treated in the Hospitals of the Spanish National Healthcare System: The PARADISE Study.

BACKGROUND: Advanced Parkinson's disease (APD) has been recently defined as a stage in which certain symptoms and complications are present, with a detrimental influence on the overall patient's health conditions and with a poor response to conventional treatments. However, historically, the term APD has been controversial, thus consequently, APD prevalence has not been previously studied. OBJECTIVES: The main objective was to determine the prevalence of APD in patients diagnosed with idiopathic PD in hospitals of the Spanish National Healthcare System. Secondary objectives were the prevalence and incidence of PD and the clinical and sociodemographic characteristics and quality of life of patients with APD or non-APD. METHODS: This was a non-interventional, cross-sectional, multicenter, national study in the hospital setting. RESULTS: The study population included 929 patients with PD (mean age 71.8 ± 10.1 years; 53.8% male) and a mean time since diagnosis of 6.6 ± 5.4 years. At the time of diagnosis, 613 patients (66.06%) reported having had premotor symptoms. The Hoehn and Yahr stage was 1 in 15.7% of the patients, 2 in 42.8%, 3 in 30.1%, 4 in 9.9%, and 5 in 1.4%; 46.9% of the patients had comorbidities (mean age-adjusted Charlson comorbidity index 3.5 ± 1.7; median 10-year survival 77%) and the mean 8-item Parkinson's Disease Quality of Life Questionnaire was 27.8 ± 20.5. We found an APD prevalence of 38.21% (95%CI: 35.08-41.42%), a PD prevalence of 118.4 (95%CI: 117.3-119.6), and a PD incidence of 9.4 (95%CI: 5.42-13.4) all per 100,000 population. Among the APD population, a 15.2% were receiving some form of therapy for advanced stages of the disease (deep brain stimulation, levodopa/carbidopa intestinal gel, or apomorphine subcutaneous infusion). CONCLUSIONS: The percentage of patients with APD in the hospitals of the Spanish National Healthcare System was 38.2%.

Patient and caregiver outcomes with levodopa-carbidopa intestinal gel in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson's Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, -12.8 ± 14.6; P < 0.0001), motor symptoms (UPDRS-III in "On," -6.5 ± 11.8; P = 0.0002), NMS (NMSS, -35.7 ± 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, -6.6 ± 21.1; P = 0.0297), fatigue (PFS-16, -0.6 ± 1.0; P = 0.0003), depression (BDI-II, -5.1 ± 9.4; P = 0.0002), anxiety (BAI, -6.2 ± 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 ± 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BAI, BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, -1.1 ± 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LCIG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients' QoL does not correspond with improvements in caregivers' QoL or burden.

Design of a Culturally-Informed Virtual Human for Educating Hispanic Women about Cervical Cancer.

Significant health disparities exist between Hispanics and the general US population, complicated in part by communication, literacy, and linguistic factors. There are few available Spanish-language interactive, technology-driven health education programs that engage patients who have a range of health literacy levels. We describe the development of an interactive virtual patient educator for educating and counseling Hispanic women about cervical cancer and human papillomavirus. Specifically, we describe the iterative design methodology and rationale, usability evaluation, and pilot testing of the system with Hispanic women in a rural community in Florida. The pilot study findings provide preliminary evidence of the feasibility of the proposed patient education approach. The proposed application and the lessons learned will prove beneficial for future work targeted towards different cultural populations.

Acceptability of a Virtual Patient Educator for Hispanic Women.

There are few Spanish language interactive, technology-driven health education programs. Objectives of this feasibility study were to (a) learn more about computer and technology usage among Hispanic women living in a rural community and (b) evaluate acceptability of the concept of using an embodied conversational agent (ECA) computer application among this population. A survey about computer usage history and interest in computers was administered to a convenience sample of 26 women. A sample video prototype of a hospital discharge ECA was administered followed by questions to gauge opinion about the ECA. Data indicate women exhibited both a high level of computer experience and enthusiasm for the ECA. Feedback from community is essential to ensure equity in state of the art dissemination of health information.

Creating a patient navigation model to address cervical cancer disparities in a rural Hispanic farmworker community.

This report describes the implementation of a pilot patient navigation (PN) program created to address cervical cancer disparities in a predominantly Hispanic agricultural community. Since November 2009, a patient navigator has provided services to patients of Catholic Mobile Medical Services (CMMS). The PN program has resulted in the need for additional clinic sessions to accommodate the demand for preventive care at CMMS.

Amperometric study of the kinetics of exocytosis in mouse adrenal slice chromaffin cells: physiological and methodological insights.

This study was designed to examine the kinetics of neurotransmitter release using the carbon fiber amperometric technique on cells in slices of mouse adrenal glands superfused with bicarbonate phosphate buffer-based solutions. The exocytotic amperometric response evoked by electrical stimulation was significantly faster than that produced after exogenous application of ACh or K+. Splanchnic nerve-evoked neurotransmitter release was blocked by hexamethonium, indicating the involvement of ACh nicotinic receptors. We discuss the implications of our data for understanding the mechanisms underlying the vesicle fusion process.

A choline-evoked [Ca2+]c signal causes catecholamine release and hyperpolarization of chromaffin cells.

In bovine chromaffin cells fast-superfused with Krebs-HEPES solution containing 1-2 mM Ca2+, 5 s pulses of choline (1-10 mM), elicited catecholamine secretory responses that were only approximately 10% of those evoked by ACh (0.01-0.1 mM). However, in high-Ca2+ solutions (10-20 mM) the size of the choline secretory responses approached those of ACh. The choline responses (10 mM choline in 20 mM Ca2+, 10Cho/20Ca2+) tended to decline upon repetitive pulsing, whereas those of ACh were well maintained. The confocal [Ca2+]c increases evoked by 10Cho/20Ca2+ were similar to those of ACh. Whereas 10Cho/20Ca2+ caused mostly hyperpolarization of chromaffin cells, 0.1ACh/20 Ca2+ caused first depolarization and then hyperpolarization; in regular solutions (2 mM Ca2+), the hyperpolarizing responses did not show up. In Xenopus oocytes injected with mRNA for bovine alpha7 nicotinic receptors (nAChRs), 10Cho/20 Ca2+ fully activated an inward current; in oocytes expressing alpha3beta4, however, the inward current elicited by choline amounted to only 4% of the size of alpha7 current. Our results suggest that choline activates the entry of Ca2+ through alpha7 nAChRs; this leads to a cytosolic concentration of calcium ([Ca2+]c) rise that causes the activation of nearby Ca2+-dependent K+ channels and the hyperpolarization of the chromaffin cell. This response, which could be unmasked provided that cells were stimulated with high-Ca2+ solutions, may be the underlying mechanism through which choline exerts a modulatory effect on the electrical activity of the chromaffin cell and on neurotransmitter release at cholinergic synapses.

SNX482 selectively blocks P/Q Ca2+ channels and delays the inactivation of Na+ channels of chromaffin cells.

The effects of the toxin SXN482 on Ca2+ channel currents (ICa), Na+ currents (INa), and K+ currents (IK) have been studied in bovine adrenal medullary chromaffin cells voltage-clamped at -80 mV. Currents were elicited by depolarising pulses to 0-10 mV (ICa and INa) or to +60 mV (IK). SNX482 blocked ICa in a concentration-dependent manner. The inhibition curve exhibited two phases. The first high-affinity phase comprised 28% of the whole-cell current and exhibited an IC50 of 30.2 nM. The second low-affinity phase comprised over 70% of ICa and had an IC50 of 758.6 nM. Blockade was rapid and fully reversible upon washout of the toxin. Occlusion experiments showed additivity of blockade exerted by nifedipine plus SNX482 (0.3 microM) and by omega-conotoxin GVIA plus SNX482. In contrast, blockade exerted by combined omega-agatoxin IVA plus SNX482 (about 50% of the whole cell) did not show additivity. At 0.3 microM and higher concentrations, SNX482 delayed the inactivation of INa. The time constant (tau) for inactivation of INa in control conditions doubled in the presence of 0.5 microM SNX482. At 0.3 microM, SNX482 did not affect IK. Our data demonstrate that: (i) SNX482 selectively blocks P/Q Ca2+ channels at submicromolar concentrations; (ii) the toxin partially blocks Na+ channels; (iii) SNX482 delays the inactivation of Na+ channels. These results reveal novel properties of SNX482 and cast doubts on the claimed selectivity and specificity of the toxin to block the R-type Ca2+ channel.

Calcium entry, calcium redistribution, and exocytosis.

At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca(2+) concentration, [Ca(2+)](c), depend on at least three efficient regulatory mechanisms: (1) the plasmalemmal Ca(2+) channels; (2) the endoplasmic reticulum (ER); and (3) the mitochondria. High-voltage activated Ca(2+) channels of the L, N, P/Q, and R subtypes are expressed with different densities in various mammalian species; they are regulated by G proteins coupled to purinergic and opiate receptors, as well as by voltage and the local changes of [Ca(2+)](c). Targeted aequorin and confocal microscopy show that Ca(2+) entry through Ca(2+) channels can refill the ER to near millimolar concentrations and causes the release of ER Ca(2+) (CICR). We have also seen that, depending on its degree of filling, the ER may act as a sink or source of Ca(2+) that modulates the release of catecholamine. Targeted aequorins with different Ca(2+) affinities show that mitochondria undergo surprisingly rapid millimolar Ca(2+) transients ([Ca(2+)](M)) upon stimulation of chromaffin cells with ACh, high K(+), or caffeine. Physiological stimuli generate [Ca(2+)](c) microdomains at these functional complexes in which the local subplasmalemmal [Ca(2+)](c) rises abruptly from 0.1 micro M to about 50 micro M. This triggers CICR, mitochondrial Ca(2+) uptake, and exocytosis in nearby secretory active sites. That this is true is shown by the observation that protonophores abolish mitochondrial Ca(2+) uptake and drastically increase catecholamine release by 3- to 5-fold. This increase is likely due to acceleration of vesicle transport from a reserve pool to a ready-release vesicle pool; such transport might be controlled by Ca(2+) redistribution to the cytoskeleton, through CICR and/or mitochondrial Ca(2+) release.

Acetylcholine and potassium elicit different patterns of exocytosis in chromaffin cells when the intracellular calcium handling is disturbed.

During fast superfusion of bovine chromaffin cells with normal Krebs-HEPES solution containing 2 mM Ca2+, pulses of 100 microM ACh or 100 mM K+ of increasing duration (1-5 s) caused similar exocytosis of about 3-4 microC catecholamine. Depletion of endoplasmic reticulum (ER) Ca2+ by pretreatment with 1 microM thapsigargin, 10 mM caffeine and 10 microM ryanodine more than halved the responses to ACh but did not affect the responses to K+ responses. In these ER Ca2+-depleted cells the protonophore carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) (20 microM given during the 5 s preceding each pulse) augmented the responses to ACh responses fourfold for all pulse durations applied (1-5 s) whereas responses to K+ were potentiated twofold with 1 to 2 s pulses but were not affected with longer pulse durations. ACh pulses applied to fura-2-loaded cells evoked increases of bulk cytosolic [Ca2+] ([Ca2+](c)) that were substantially smaller than those elicited by K+ pulses. Confocal microscopy of fluo-3-loaded cells showed that ACh pulses elicited discrete and more localized [Ca2+](c) elevations, whereas K+ pulses produced higher [Ca2+](c) transients that spread out quickly throughout the cytosol. These results suggest that mitochondria sense the increase of local [Ca2+](c) elicited by ACh (that evokes firing of action potentials) much better than that induced by K+ (that produces sustained cell depolarisation). This implies that mitochondria are more sensitive to the local [Ca2+](c) changes resulting from the physiological triggering of action potentials by ACh.