Dostarlimab for the treatment of endometrium cancer and other solid tumors.

The use of monoclonal antibodies directed against programmed cell death protein 1 (PD-1) and its ligand, programmed cell death 1 ligand 1 (PD-L1), widely extends to a large number of tumors such as melanoma, non-small cell lung, renal or lymphomas, among others. Some of them are already approved as first- or second-line treatment, as pembrolizumab, nivolumab or cemiplimab. Dostarlimab is an investigational humanized anti-PD-1 that is being developed both in monotherapy and as combination therapy, for gynecological tumors but also for lung cancer or melanoma. The preliminary results, particularly in endometrial cancer, show a high affinity against PD-1 with encouraging clinical activity. Here we summarize the development of this compound as well as the current preclinical and clinical data and potential future development.

Prevalence, risk factors and complications of oropharyngeal dysphagia in stroke patients: A cohort study.

BACKGROUND: Oropharyngeal dysphagia (OD) is a prevalent poststroke condition with severe complications and increased mortality. Poststroke OD prevalence varies among studies and there is little evidence of its related risk factors and associated complications. OBJECTIVE: to evaluate the prevalence of OD after stroke and the risk factors and associated complications. METHODS: We performed a prospective longitudinal study of stroke patients consecutively admitted to a general hospital. OD was diagnosed with the volume-viscosity swallow test (V-VST). Demographic, functional status and topographical and clinical variables of stroke were collected to assess risk factors for OD. We evaluated functional status, mortality, respiratory infections, and readmissions 3 and 12 months after stroke. A multivariate regression analysis determined associated risk factors for OD and for each outcome variable. KEY RESULTS: We included 395 stroke patients with a 45.06% prevalence of OD on admission. OD was independently associated with age (OR = 1.05; CI = 1.02-1.08), previous stroke (OR = 2.40; CI = 1.00-5.79), severity using the National Institute of Health Stroke Scale (OR = 3.52; CI = 1.57-7.87) and volume of the lesion (OR = 1.02; CI = 1.01-1.03). OD after stroke was an independent risk factor for prolonged hospital stay (P = .049; ß = 0.938) and institutionalization after discharge (OR = 0.47; CI = 0.24-0.92); OD was an independent risk factor for poorer functional capacity (OR = 3.00; CI = 1.58-5.68) and increased mortality (HR = 6.90; CI = 1.57-30.34) 3 months after stroke. CONCLUSIONS & INFERENCES: Poststroke OD is prevalent and associated with poor short and long term prognosis. Stroke severity and patient status before stroke were more relevant to OD than lesion location. Systematic screening programs and early OD management could significantly improve poststroke patient outcome.

Azul de metileno en el síndrome de escape capilar refractario / Methylene blue for refractory capillary leak syndrome

No disponible

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain.

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [(11)C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy.

BACKGROUND: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. METHODS: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. RESULTS: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05). CONCLUSIONS: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.

Real-time G-protein-coupled receptor imaging to understand and quantify receptor dynamics.

Understanding the trafficking of G-protein-coupled receptors (GPCRs) and their regulation by agonists and antagonists is fundamental to develop more effective drugs. Optical methods using fluorescent-tagged receptors and spinning disk confocal microscopy are useful tools to investigate membrane receptor dynamics in living cells. The aim of this study was to develop a method to characterize receptor dynamics using this system which offers the advantage of very fast image acquisition with minimal cell perturbation. However, in short-term assays photobleaching was still a problem. Thus, we developed a procedure to perform a photobleaching-corrected image analysis. A study of short-term dynamics of the long isoform of the dopamine type 2 receptor revealed an agonist-induced increase in the mobile fraction of receptors with a rate of movement of 0.08 µm/s For long-term assays, the ratio between the relative fluorescence intensity at the cell surface versus that in the intracellular compartment indicated that receptor internalization only occurred in cells co-expressing G protein-coupled receptor kinase 2. These results indicate that the lateral movement of receptors and receptor internalization are not directly coupled. Thus, we believe that live imaging of GPCRs using spinning disk confocal image analysis constitutes a powerful tool to study of receptor dynamics.

Atención al paciente neurológico en los Servicios de Urgencias. Revisión de la situación actual en España / Neurological patient care in Emergency Departments. A review of the current situation in Spain

Introducción: Asistimos a múltiples cambios en la asistencia neurológica urgente, en el contexto del progresivo desarrollo de la especialidad y del aumento de la población y de la demanda sanitaria.Fuentes: Empleamos Medline y documentación de la Sociedad Española de neurología (SEN) como principales fuentes de datos para revisar trabajos publicados al respecto en nuestro país. Encontramos artículos que describen la atención neurológica en urgencias de diferentes hospitales españoles, artículos de revisión, y otros con planteamientos de organización asistencial neurológica.Desarrollo: Ictus, cefalea y epilepsia son las patologías más frecuentes en urgencias. Hasta el 10-15% de las urgencias médicas son neurológicas. Su frecuencia aumenta con la edad y se ve incrementada a lo largo de la última década. La figura del neurólogo de guardia conlleva una reducción significativa de ingresos hospitalarios y de la estancia media, entre otros parámetros de calidad asistencial. El ictus ha motivado múltiples trabajos específicos, que relacionan la presencia del neurólogo 24 horas con mejoras en el pronóstico, la calidad asistencial y el coste global del ictus. La SEN ha expresado reiteradamente su preocupación por la atención urgente al paciente neurológico y aboga por una mayor generalización de las guardias de neurología en nuestro país.Conclusiones: La patología neurológica urgente es frecuente, compleja y en muchos casos potencialmente grave. El papel del neurólogo en urgencias es relevante para un manejo óptimo de la misma. La figura del neurólogo de guardia, ausente aún en muchos hospitales españoles, puede mejorar tanto la calidad asistencial como la eficiencia (AU)

Introduction: We are currently seeing many changes in urgent neurological care, in the contextof the progressive development of the speciality and of the increasing population and care demand.Sources: Medline and ocumentation obtained from the Spanish Society of Neurology (SEN) were employed as main data sources to review papers on the matter published in our country. We found articles describing neurological care in Emergency Departments (ED) of different Spanish hospitals, review articles, and others with neurological care organisational approaches. Development: Stroke, headache and epilepsy were the most common disorders seen in ED.Up to 10-15% of medical emergencies were neurological. Their frequency increased with ageand has been increasing over the last decade. The presence of a neurologist 24 hours a day,everyday, led to a significant reduction in hospital admissions and in length of stay, as well asother parameters of quality of care. Stroke has motivated many specific works that associate the presence of a neurologist in ED with an improvement in prognosis, quality of care and the overall cost of stroke. SEN has repeatedly expressed its concern about urgent neurological care provided to patients, and it promotes a greater generalization of on-call neurologists in hospitals in our country. Conclusions: Urgent neurological disease is common, complex, and in many cases, potentially serious. The role of the neurologist in the ED is important for its optimum management. On-call neurologists, still absent in many Spanish hospitals, can improve both the quality of care andits efficiency (AU)

Multiple sclerosis and cognitive decline: is ApoE-4 a surrogate marker?

BACKGROUND - The role of the apolipoprotein E (ApoE) polymorphism has been well demonstrated in neurodegenerative disorders such as Alzheimer. However, its role in multiple sclerosis (MS) remains unclear. AIMS - The aims of our study were as follows: (i) to assess whether ApoE-4 might be a surrogate marker of cognitive decline in MS; (ii) to confirm the presence of cognitive impairment in mildly disabled patients treated with interferon-beta; and (iii) to analyse the correlation between cognitive disturbances and clinical variables. MATERIAL AND METHODS - Fifty relapsing-remitting MS patients underwent a battery of neuropsychological tests and were genotyped for ApoE. Their scores were compared with those of 35 controls. RESULTS - No association was found between ApoE-4 and cognitive impairment. Significant differences in most domains were observed between MS and the control group. Cognitive decline was not related to disability progression. CONCLUSION - No association between cognitive impairment and ApoE-4 or clinical markers was detected in our MS patients.

Neurological patient care in emergency departments. A review of the current situation in Spain.

INTRODUCTION: We are currently seeing many changes in urgent neurological care, in the context of the progressive development of the specialty and of the increasing population and care demand. SOURCES: Medline and documentation obtained from the Spanish Society of Neurology (SEN) were employed as main data sources to review papers on the matter published in our country. We found articles describing neurological care in Emergency Departments (ED) of different Spanish hospitals, review articles, and others with neurological care organisational approaches. DEVELOPMENT: Stroke, headache and epilepsy were the most common disorders seen in ED. Up to 10-15% of medical emergencies were neurological. Their frequency increased with age and has been increasing over the last decade. The presence of a neurologist 24 hours a day, everyday, led to a significant reduction in hospital admissions and in length of stay, as well as other parameters of quality of care. Stroke has motivated many specific works that associate the presence of a neurologist in ED with an improvement in prognosis, quality of care and the overall cost of stroke. SEN has repeatedly expressed its concern about urgent neurological care provided to patients, and it promotes a greater generalization of on-call neurologists in hospitals in our country. CONCLUSIONS: Urgent neurological disease is common, complex, and in many cases, potentially serious. The role of the neurologist in the ED is important for its optimum management. On-call neurologists, still absent in many Spanish hospitals, can improve both the quality of care and its efficiency.

Parálisis diafragmática en el postoperatorio de cirugía cardiaca infantil / Diaphragmatic paralysis after pediatric cardiac surgery

Objetivo: Describir la frecuencia, morbimortalidad y tratamiento de la disfunción diafragmática (DD) en el postoperatorio de la cirugía cardiaca infantil. Pacientes y métodos: Serie de casos de DD identificados entre la población de niños intervenidos de cirugía cardiaca en el hospital «12 de Octubre» de Madrid, entre 1997 y 2006. Se obtuvieron retrospectivamente datos demográficos, de la cirugía y del postoperatorio, así como de la estancia hospitalaria yde la morbimortalidad. Resultados: Cirugía cardiaca en 1.063 niños, diagnosticándose 23 casos de DD. Se excluyó un caso secundario a neuropatía generalizada. La frecuencia global fue del 2,1%. La mediana de edad fue de 14 días (1 día-16 meses), siendo 20 de los casos menores de 1 año. Se realizó plicatura en 13 pacientes (62%). Las indicaciones de plicatura fueron: fracaso de extubación (n= 11) y dificultad respiratoria persistente (n= 2).Fue preciso realizar plicatura quirúrgica en 9 de los 13 neonatos. El tiempo de ventilación mecánica invasiva, estancia en unidad de cuidados intensivos pediátricos (UCIP) y estancia hospitalaria en los casos con paresia fue de 8, 12 y 20 días(mediana), respectivamente. Las parálisis precisaron mayor tiempo de ventilación invasiva y de ingreso (19, 34 y 47,5 días). Conclusiones: A todo neonato intervenido de una cardiopatía compleja debería realizársele una ecografía diafragmática en respiración espontánea previa a su extubación, para así establecer el diagnóstico de manera precoz, con el objetivo de reducir el tiempo de ventilación mecánica y la morbilidad asociada (AU)

The objective of this study is to describe the frequency, morbimortality and treatment of diaphragmatic dysfunction (DD) after pediatric cardiac surgery. Patients and methods: Series of DD cases identified among the population of children who underwent cardiac surgery at the hospital 12 de Octubre of Madrid from the years 1997-2006. Demographic, surgical and postsurgical data have been obtained retrospectively, as well as data on hospital stay and the morbimortality. Results: A total of 1,063 children underwent cardiac surgery, diagnosing 23 DD cases. A secondary case was excluded due to generalized neuropathy. The global frequency was of 2.1%,the mean age was 14 days (1 d-16 m), being 20 of the cases under 1 year of age. Reefing was performed in 13 patients (62%). The indications for reefing were due to extubation failure (n= 11) and persistent respiratory difficulties (n= 2).Surgical reefing had to be performed in 9 from the 13 newborns. In the cases of paresis the length of the invasive mechanical ventilation, stay at the PICU and hospital stay was 8,12 and 20 days (mean) respectively. The paralysis required alonger time of invasive ventilation and hospitalization (19, 34 and 47,5 days).Conclusions: A diaphragm echography in spontaneous breathing should be performed on any newborn that underwent a complex cardiopathy surgery previous to the extubation in order to determine an early diagnosis and to reduce the length of mechanical ventilation and associated morbidity (AU)

Prevalencia de enfermedad por reflujo gastroesofágico en la población adulta Venezolana

La enfermedad por reflujo gastroesofágico (ERGE) es una enfermedad crónica recurrente, que constituye uno de los trastornos gastrointestinales que afecta con mayor frecuencia a población mundial. Objetivo: Determinar la prevalencia de enfermedad por reflujo gastroesofágico en la población adulta venezolana. Pacientes y Métodos: Se realiza un estudio descriptivo, de corte transversal, multicéntrico durante los meses de abril y mayo de 2008. Se entrevistaron a individuos en edades comprendidas entre 15 - 65 años de diferentes estados del país (Aragua, Anzoátegui, Barinas, Carabobo, Delta Amacuro, Distrito Capital, Mérida, Miranda, Sucre, Zulia) escogidos a través del azar simple, realizándose un muestreo por conglomerados, de donde, en cada estado se seleccionó un Municipio y de éste, lugares como iglesias, centro comerciales, cines y paradas de autobuses. Se tomó en consideración la población de cada municipio según el Censo Nacional 2001. Resultados: Un total de 1318 individuos fueron encuestados en los estados incluidos, 814 mujeres (61,76%) y 504 Hombres (38,24%). En cuanto a la distribución por categoría de edad, el grupo de 25-35 años constituyó el de mayor predominio. Se obtuvo una Prevalencia Nacional de 11,54%, donde los síntomas cardinales pirosis y regurgitación ácida representaron 16,62% y 12,75% respectivamente. Conclusión: La prevalencia nacional de enfermedad por reflujo gastroesofágico en la población venezolana es del 11,54%.

The gastroesophageal reflux disease (GERD) is a chronic recurrent illness that represents one of the most common gastrointestinal disorders that affects worldwide population. Aim: To determine the prevalence of gastroesophageal reflux disease in the Venezuelan adult population. Patients and Methods: A Descriptive, cross section, multicentric study was made. A survey was done to people in ages between 15 - 65 years of different states of the country (Aragua, Anzoátegui, Barinas, Carabobo, Delta Amacuro, Distrito Capital, Mérida, Miranda, Sucre, Zulia) chosen randomly. Cluster sampling was performed, where in each State was selected a municipality and, of which one places like churches, malls, cinemas and bus stops. To calculate de amount of people The National Census 2001 was taken in account in each municipality. Results: A total of 1318 individuals were surveyed in the mentioned States including, 814 women (61.76%) and 504 men (38.24%). The predominant distribution by age was the group of 25-35 years old. A National Prevalence of 11.54% was obtained, where the cardinal symptoms were heartburn and acid regurgitation represented 16.62% and 12.75% respectively. Conclusion: The national prevalence of gastroesophageal reflux disease in the Venezuelan adult population is 11.54%.

Interferón-beta y hepatitis autoinmune en la esclerosis múltiple: ¿causa-efecto o asociación? / No disponible

No disponible

G-protein-coupled receptor heteromers: function and ligand pharmacology.

Almost all existing models for G-protein-coupled receptors (GPCRs) are based on the occurrence of monomers. Recent studies show that many GPCRs are dimers. Therefore for some receptors dimers and not monomers are the main species interacting with hormones/neurotransmitters/drugs. There are reasons for equivocal interpretations of the data fitting to receptor dimers assuming they are monomers. Fitting data using a dimer-based model gives not only the equilibrium dissociation constants for high and low affinity binding to receptor dimers but also a 'cooperativity index' that reflects the molecular communication between monomers within the dimer. The dimer cooperativity index (D(C)) is a valuable tool that enables to interpret and quantify, for instance, the effect of allosteric regulators. For different receptors heteromerization confers a specific functional property for the receptor heteromer that can be considered as a 'dimer fingerprint'. The occurrence of heteromers with different pharmacological and signalling properties opens a complete new field to search for novel drug targets useful to combat a variety of diseases and potentially with fewer side effects. Antagonists, which are quite common marketed drugs targeting GPCRs, display variable affinities when a given receptor is expressed with different heteromeric partners. This fact should be taken into account in the development of new drugs.

An approach to estimating the intangible costs of multiple sclerosis according to disability in Catalonia, Spain.

Multiple sclerosis (MS) is a chronic demyelinating disease, which represents a great economic burden to society. Cost-of-illness studies of MS tend to underestimate the intangible costs related to pain, anxiety and helplessness. The purpose of this study was to estimate the intangible costs of MS, and determine whether these costs increase as disability progresses. We studied 211 consecutive patients with MS who attended our MS unit. Patients mean age was 41.6 (SD: 10.7) years, 69% were female, and their mean Expanded Disability Status Scale (EDSS) score was 2.47 (SD: 2.05). Quality-of-life was measured with the EuroQoL visual analogue scale. Quality-adjusted life year (QALY) was calculated for each patient. Patients were grouped into five disability stages according to their EDSS, and QALY was compared between patients and a group of healthy controls matched by age and sex. A benchmark value was ascribed to each QALY lost, and the intangible costs per patient-year were calculated as Euros 0 (EDSS =0), Euros 1100 (EDSS =1-3), Euros 8250 (EDSS =3.5-5.5), Euros 9900 (EDSS =6-7) and Euros 11,000 (EDSS >7.5). Sensitivity analysis showed a similar progression of costs. We conclude that intangible costs are relevant in MS, especially when disability increases. Although the method to calculate the costs remains controversial, we consider that they should be included in cost analysis of MS.

Specificity of frontal dysfunctions in relapsing-remitting multiple sclerosis.

Various studies have reported deficits in frontal cognitive functions in patients with multiple sclerosis (MS). However, the frontal deficit is not uniform and is often very subtle. The aim of this study was to assess frontal functions in a broad sample of patients with relapsing-remitting multiple sclerosis at the mild-to-moderate stage. The sample included a series of 165 patients. We used a test battery covering the frontal functions that have been described as being altered in MS. Significant differences were found between the patient group and healthy controls on the WAIS Arithmetic subtest, the PASAT, category word recall and the number of trials required to reach the first category of the WCST. In conclusion, we observed significant differences with respect to the control group in terms of information processing speed and working memory. These functions involve connections between the frontal lobe and other brain regions.

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy followed by adjuvant doxorubicin and cyclophosphamide therapy in stage II and III breast cancer patients: results of a phase II study.

INTRODUCTION: The purpose of this phase II study was to evaluate the efficacy and safety of neoadjuvant docetaxel/gemcitabine treatment in a biweekly regimen. MATERIALS AND METHODS: Patients with stage II/III breast cancer were treated with docetaxel (65 mg/m(2)) followed by gemcitabine (2500 mg/m(2)) every 2 weeks for 6 cycles. Patients with a clinical response or stable disease underwent mastectomy or breast-conserving surgery plus axillary dissection. After surgery, patients received 4 cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. RESULTS: Thirty-five patients were included in the trial. The overall response rate was 71.4% (95% CI: 53.7-85.4), with 8 complete and 17 partial responses. Breast conservation was possible in 59% of the patients. Toxicity was manageable. CONCLUSIONS: We consider biweekly docetaxel and gemcitabine could be an active and tolerable regimen option in the neoadjuvant setting sequentially with standard adjuvant doxorubicin-cyclophosphamide in patients with stage II or III breast cancer.

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy followed by adjuvant doxorubicin and cyclophosphamide therapy in stage II and III breast cancer patients: results of a phase II study

INTRODUCTION: The purpose of this phase II study was to evaluate the efficacy and safety of neoadjuvant docetaxel/gemcitabine treatment in a biweekly regimen. MATERIALS AND METHODS: Patients with stage II/III breast cancer were treated with docetaxel (65 mg/m(2)) followed by gemcitabine (2500 mg/m(2)) every 2 weeks for 6 cycles. Patients with a clinical response or stable disease underwent mastectomy or breast-conserving surgery plus axillary dissection. After surgery, patients received 4 cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. RESULTS: Thirty-five patients were included in the trial. The overall response rate was 71.4% (95% CI: 53.7-85.4), with 8 complete and 17 partial responses. Breast conservation was possible in 59% of the patients. Toxicity was manageable. CONCLUSIONS: We consider biweekly docetaxel and gemcitabine could be an active and tolerable regimen option in the neoadjuvant setting sequentially with standard adjuvant doxorubicin-cyclophosphamide in patients with stage II or III breast cancer (AU)

Abnormal sudomotor skin responses to temperature and pain stimuli in syringomyelia.

Thermoalgesic sensory deficits in patients with syringomyelia may escape objective documentation with conventional electrophysiological techniques. We examined six patients with radiologically proven centrospinal cavities and patchy thermoalgesic sensory deficits by recording the evoked potentials and the sympathetic sudomotor skin responses (SSR) to laser stimuli. While electrical stimuli to the affected areas induced evoked potentials and SSRs of normal latency and amplitude, CO2 laser stimulation induced absent or abnormally reduced evoked potentials. Also, warmth and heat pain stimulation with a Peltier thermode induced absent or abnormal SSRs when applied over the affected areas but well defined SSRs when applied to the corresponding contralateral areas. Our results reveal the utility of recording the SSR to pain and temperature stimuli over specific body sites to demonstrate impairment of pain and temperature pathways in patients with syringomyelia. Comparison of electrical versus laser and temperature induced SSRs is an objective means to evaluate the selective thermoalgesic sensory deficit in these patients.

Receptor-receptor interactions involving adenosine A1 or dopamine D1 receptors and accessory proteins.

The molecular basis for the known intramembrane receptor-receptor interactions among heptahelical receptors (G protein coupled receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for learning and memory. Heteromerization of D(2) dopamine and A(2A) adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D(1) dopamine and A(1) adenosine receptors is reviewed. Heteromers formed by dopamine D(1) and D(2) receptors and by adenosine A(1) and A(2A) receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting with receptor-receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed. Overall, the knowledge of the reason why such complex networks of receptor-receptor and receptor-protein interactions occur in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases.