Socio-economic inequality and healthcare costs over the life course - A dynamic microsimulation approach.

OBJECTIVES: Although there is well-established evidence for the existence of socio-economic inequalities in virtually all dimensions of health, little is known about the implications of these socio-economic disparities for healthcare costs from a cumulative life course perspective. Accounting for differentials in healthcare use patterns and mortality, we assess how lifetime costs differ between socio-economic groups. STUDY DESIGN: This study used dynamic microsimulation modelling. METHODS: Combining price weights for healthcare services with information on healthcare consumption from the 2014 Austrian Health Interview Survey (n = 15,771), we calculated average cost profiles by gender, age and education consistent with aggregate System of Health Accounts. A dynamic microsimulation model was used to project cumulative healthcare costs over the entire lifecycle for the 2019 birth cohort in four different scenarios to illustrate the influence of the different cost determinants on lifetime costs. RESULTS: Before considering social inequalities in mortality, men with compulsory education have close to 66% higher lifetime costs than men with tertiary education; for women, the difference is close to 20%. Accounting for longevity differentials reduces this gap to approximately 40% for men and 10% for women. Closing the gap in healthcare use and in longevity between socio-economic groups would reduce lifetime healthcare expenditure by 4.1% in the 2019 birth cohort and by 19% in the whole population. CONCLUSIONS: Accounting for mortality differentials between socio-economic groups has a large impact on estimated lifetime healthcare costs. Reducing social inequalities in health can contribute to containing healthcare expenditures against the backdrop of rising life expectancy.

ATP-Evoked Intracellular Ca²âº Signaling of Different Supporting Cells in the Hearing Mouse Hemicochlea.

Hearing and its protection is regulated by ATP-evoked Ca(2+) signaling in the supporting cells of the organ of Corti, however, the unique anatomy of the cochlea hampers observing these mechanisms. For the first time, we have performed functional ratiometric Ca(2+) imaging (fura-2) in three different supporting cell types in the hemicochlea preparation of hearing mice to measure purinergic receptor-mediated Ca(2+) signaling in pillar, Deiters' and Hensen's cells. Their resting [Ca(2+)]i was determined and compared in the same type of preparation. ATP evoked reversible, repeatable and dose-dependent Ca(2+) transients in all three cell types, showing desensitization. Inhibiting the Ca(2+) signaling of the ionotropic P2X (omission of extracellular Ca(2+)) and metabotropic P2Y purinergic receptors (depletion of intracellular Ca(2+) stores) revealed the involvement of both receptor types. Detection of P2X2,3,4,6,7 and P2Y1,2,6,12,14 receptor mRNAs by RT-PCR supported this finding and antagonism by PPADS suggested different functional purinergic receptor population in pillar versus Deiters' and Hensen's cells. The sum of the extra- and intracellular Ca(2+)-dependent components of the response was about equal with the control ATP response (linear additivity) in pillar cells, and showed supralinearity in Deiters' and Hensen's cells. Calcium-induced calcium release might explain this synergistic interaction. The more pronounced Ca(2+) leak from the endoplasmic reticulum in Deiters' and Hensen's cells, unmasked by cyclopiazonic acid, may also suggests the higher activity of the internal stores in Ca(2+) signaling in these cells. Differences in Ca(2+) homeostasis and ATP-induced Ca(2+) signaling might reflect the distinct roles these cells play in cochlear function and pathophysiology.

Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism.

The brain receives and integrates environmental and metabolic information, transforms these signals into adequate neuronal circuit activities, and generates physiological behaviors to promote energy homeostasis. The responsible neuronal circuitries show lifetime plasticity and guaranty metabolic health and survival. However, this highly evolved organization has become challenged nowadays by chronic overload with nutrients and reduced physical activity, which results in an ever-increasing number of obese individuals worldwide. Research within the last two decades has aimed to decipher the responsible molecular and cellular mechanisms for regulation of the hypothalamic melanocortin neurons, which have a key role in the control of food intake and energy metabolism. This review maps the central connections of the melanocortin system and highlights its global position and divergent character in physiological and pathological metabolic events. Moreover, recently uncovered molecular and cellular processes in hypothalamic neurons and glial cells that drive plastic morphological and physiological changes in these cells, and account for regulation of food intake and energy metabolism, are brought into focus. Finally, potential functional interactions between metabolic disorders and psychiatric diseases are discussed.

Helping our patients take HIV pre-exposure prophylaxis (PrEP): a systematic review of adherence interventions.

OBJECTIVES: Adherence is critical for maximizing the effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection. Strategies for promoting adherence to HIV treatment, and their potential application to PrEP adherence, have received considerable attention. However, adherence promotion strategies for prevention medications have not been well characterized and may be more applicable to PrEP. We aimed to identify adherence support interventions that have been effective in other prevention fields and could be applied in the HIV prevention context to support pill taking among PrEP users. METHODS: To identify adherence support interventions that could be evaluated and applied in the PrEP context, we conducted a systematic review across the following prevention fields: hypertension, latent tuberculosis infection, hyperlipidaemia, oral contraceptives, osteoporosis, malaria prophylaxis, and post-exposure prophylaxis for HIV infection. We included randomized controlled trials that evaluated the efficacy of interventions to improve adherence to daily oral medications prescribed for primary prevention in healthy individuals or for secondary prevention in asymptomatic individuals. RESULTS: Our searches identified 585 studies, of which 48 studies met the eligibility criteria and were included in the review; nine evaluated multiple strategies, yielding 64 separately tested interventions. Interventions with the strongest evidence for improving adherence included complex, resource-intensive interventions, which combined multiple adherence support approaches, and low-cost, low-intensity interventions that provided education or telephone calls for adherence support. CONCLUSIONS: Our review identified adherence interventions with strong evidence of efficacy across prevention fields and provides recommendations for evaluating these interventions in upcoming PrEP studies.

Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

BACKGROUND: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. PURPOSE: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Therapy of Castleman's disease with siltuximab - case report and review of literature.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is characterized by constitutional symptoms, enlarged lymph nodes and laboratory test abnormalities, which are primarily related to the overproduction of interleukin-6 (IL-6). This form (iMCD) was treated earlier with cytostatics used for lymphoma, later with bio-logic therapy as rituximab, immunodulatory drugs and proteasome inhibitors, and in the last years with an anti-IL-6 antibody, siltuximab. Siltuximab is a human-mouse chimeric immunoglobulin G1k monoclonal antibody against human IL-6 approved in the European Union for the treatment of iMCD. In view of the limited treatment options for iMCD, this case report aimed to evaluate the efficacy and safety of siltuximab in the management of this condition. CASE: We describe a young woman with iMCD diagnosed at the age of 25 years. For first line treatment, rituximab and dexamethasone were used without any cytostatic because the patient wished to give birth to a healthy child in the future. However, the response after this first line therapy was short. In addition, after 3 years from the start of rituximab + dexamethasone therapy, it was necessary to administer treatment for the relapse of iMCD. We decided for siltuximab in this young woman, still aged < 30 years, and started administration of siltuximab in 3-week intervals. RESULTS: After administration of first two infusions of siltuximab, all inflammatory markers returned to normal value. Moreover, serum hemoglobin and albumin levels as well as C-reactive protein normalized after the first two administrations of siltuximab. The clinical response continue, siltuximab is still administered in 3-week intervals. PET/CT with fluorodeoxyglucose confirmed a very good anatomic and metabolic response to the treatment. Siltuximab demonstrated a favorable safety profile, and the prolonged treatment was well tolerated. CONCLUSION: This result is encouraging and demonstrates the potential of siltuximab as treatment of CD. As earlier published, this case confirms that significantly elevated inflammatory markers in a patient with CD predict a good response to siltuximab.

Effects of chronic weight perturbation on energy homeostasis and brain structure in mice.

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.

Effects of genetic vs. environmental factors on cardiovascular autonomic function: a twin study.

AIMS: Cardiovascular autonomic function is often assessed in patients with diabetes by measuring heart rate variability and baroreflex sensitivity, the heritability of which is not fully understood. The present study was aimed to determine the effects of genetic and environmental factors on heart rate variability and baroreflex sensitivity in monozygotic and dizygotic adult healthy twin pairs. METHODS: A total of 101 (63 monozygotic, 38 dizygotic) adult twin pairs (n = 202; mean age 44.3 years) were investigated. Anthropometric variables and serum metabolic markers were measured, while environmental characteristics were evaluated by questionnaires. Linear and spectral indices of heart rate variability and baroreflex sensitivity were determined by non-invasive methods. All measurements were adjusted for age and gender (model 1) and for all significantly relevant covariates (model 2). Heritability A-C-E structural equation models were used for characterizing the proportion of additive genetic, shared and unshared environmental influences. RESULTS: Genetic influence of different cardiovascular autonomic indices was estimated between 10.3 and 39.4%, common environmental influence was found between 0.0 and 33.2%, while unshared environmental influence was observed between 60.6 and 81.4% in model 1 analysis. In multivariable-adjusted heritability estimates (model 2), the magnitude of the genetic effects decreased to 0.0%, common environmental influence was nearly unchanged (values between 4.4 and 14.5%), while unshared environmental influence slightly increased (values between 85.5 and 96.5%). CONCLUSIONS: Unshared environmental but not genetic factors have substantial influence on cardiovascular autonomic function, suggesting that appropriate treatment of all modifiable environmental factors is of importance in order to prevent or ameliorate cardiovascular autonomic neuropathy.

[The expected worldwide burden of oesophagus, stomach and colorectal cancers]. / Ocekávaná zátez nádory jícnu, zaludku a kolorekta ve svete.

According database of Globocan 2008 of total 482 thousand worldwide new esophagel cancers are reported 16.9% cases in more developed and 83.1% in less developed regions, 6.9% in EU, 2.7% in the Eastern Europe; of total 989 thousand new stomach cancers are reported 27.8% in more developed and 72.2% in less developed regions, 8.4% in EU, 7.4% in the Eastern Europe; of total 1.235 milion new colorectal cancers are reported 59% cases in more developed and 41% in less developed regions, 27% in EU, 10.5% in the Eastern Europe. Of total 59,052 all neoplasms (without skin cancers) were reported 10,439 new cases of these three diagnoses in recent Czech Cancer Registry survey, higher by 595 cases than numbers based in Globocan 2008. However, according to these data the Czech males reached the 3rd order and females the 14th order by their cumulative risk of colorectal cancer in the world. The alarming worldwide numbers of new 4.771 milion of these three diagnoses and 3,137 thousands deaths from them, expected in 2030 with a higher risk in population of less developed regions require greater international cooperation and personal responsibility for improving the life-style, which would be failed the expected statistics.

[Pneumosurgery in the management of colorectal carcinomas]. / Pneumochirurgie v resení karcinomu kolorekta.

OBJECTIVE: Surgically solved lung involvement in patients after surgery of colorectal cancer. MATERIALS AND METHODS: Altogether 15 patients, 9 men (median age in the time of lung diagnosis 67 years) and 6 women (median age 59 years) underwent classical open pulmonary surgery during 2003-2008 years from the follow-up cohort of 836 persons after operation due to colorectal cancer in the time period of 1996-2008 years. The indication for lung surgery: solitary pulmonary lesion. Procedures distribution: pulmonary lobectomy 7, bilobectomy 2, segmentectomy 4, wedge resection 2. The requirement of the European Society of Thoracic Surgeons (ESTS) guidelines of complete pulmonary resection has been met by 10 operations (66.7%) with lobe specific lymphadenectomy. Histopathology investigation: Formalin fixed, paraffin embedded samples were investigated after hematoxylin-and-eosin staining, supplemented in case of need by immunohistochemistry of CK7, CK20 and TTF1. RESULTS: Eleven pulmonary metastases were found, in two cases with interlobar lymfatics involvement. Two metachronous primary adenocarcinomas of the lung (ADL) were diagnosed, one of them with metastases into hilar lymphatics. In remaining two patients pulmonary chondrohamartoma was discovered. CONCLUSION: Solitary pulmonary opacity in patient after colorectal surgery might not represent simple metastasis explicitly. Complete resection is needed.

[Complications in patients undergoing pulmonary oncological surgery]. / Komplikace u pacientu po operaci pro plicní malignitu.

AIM: A survey evaluating incidence and risk factors of complications in persons underwent complete open lung resection because of primary or secondary lung malignancy. MATERIAL AND METHODS: Retrospective study of 189 open surgery procedures in 128 males and 61 females, mean age males 61 years (range 21-78), females 64 years (range 33-80) during a five-years period (2003-2007). Data processing and analysis were performed with the statistical software system Statistica and compared by parametres odds ratio a chi2 test. RESULTS: Complications were divided into five groups. First group was defined as complications in perioperative period and was composed of three events 1.5%: endotracheal tube dysfunction (i.e. 0.5%), heavy cardiac arrhytmia 0.5% and serious haemorrhage, that occurred immediately after operation 0.5%. Second group includes complications within period of 7 days after surgery: prolonged air leak (PAL > 7 days) 7.4%, bronchopneumonia 6.9%, cardiac arrhythmia 6.9%, postoperative delirium 4.2%, atelectasis 2.6%, wound infection 1.1%, bleeding 1.1% and chylothorax 0.5%. Third group contains events between 8th and 30th postoperative days: thoracic empyema 2.1%, dysphonia 2.1%, painfull shoulder 1.1%, alimentary tract infection 0.5% and bronchial closure insufficiency 0.5%. Fourth group contains patients with severe complications, that led to death during 30 days after operation: ischemic stroke 0.5% and pulmonary embolism 0.5%. Patients without any complication formed the fifth group of 60.5%. CONCLUSION: Main risk factors for complications in postoperative period after lung resection due to primary or secondary lung malignancy in our group of patients are COPD, corticotherapy, time of operation over 3 hours, BMI over 25, left side tumor localization and bronchoplastic procedure. For cardiac arrhytmia seems to be risk factor pneumonectomy and previous neoadjuvant radiochemotherapy.

SAS CARE 2 - a randomized study of CPAP in patients with obstructive sleep disordered breathing following ischemic stroke or transient ischemic attack.

OBJECTIVE/BACKGROUND: The benefit of Continuous Positive Airway Pressure (CPAP) treatment following ischemic stroke in patients with obstructive sleep-disordered breathing (SDB) is unclear. We set out to investigate this open question in a randomized controlled trial as part of the SAS-CARE study. PATIENTS/METHODS: Non-sleepy patients (ESS < 10) with ischemic stroke or transient ischemic attack (TIA) and obstructive SDB (AHI ≥ 20) 3 months post-stroke were randomized 1:1 to CPAP treatment (CPAP+) or standard care. Primary outcome was the occurrence of vascular events (TIA/stroke, myocardial infarction/revascularization, hospitalization for heart failure or unstable angina) or death within 24 months post-stroke. Secondary outcomes included Modified Rankin Scale (mRS) and Barthel Index. RESULTS: Among 238 SAS-CARE patients 41 (17%) non-sleepy obstructive SDB patients were randomized to CPAP (n = 19) or standard care (n = 22). Most patients (80%) had stroke and were males (78%), mean age was 64 ± 7 years and mean NIHSS score 0.6 ± 1.0 (range: 0-5). The primary endpoint was met by one patient in the standard care arm (a new stroke). In an intent-to treat analysis disregarding adherence, this corresponds to an absolute risk difference of 4.5% or an NNT = 22. mRS and Barthel Index were stable and similar between arms. CPAP adherence was sufficient in 60% of evaluable patients at month 24. CONCLUSION: No benefit of CPAP started three months post-stroke was found in terms of new cardio- and cerebrovascular events over 2 years. This may be related to the small size of this study, the mild stoke severity, the exclusion of sleepy patients, the delayed start of treatment, and the overall low event rate.

Plasma homovanillic acid concentration and the severity of schizophrenic illness.

Concentrations of plasma homovanillic acid before treatment were highly correlated with global severity of illness in schizophrenic patients, both before and after treatment. In contrast, a fixed dose of haloperidol did not affect those concentrations. Thus, in patients with a diagnosis of schizophrenia, plasma homovanillic acid may reflect the severity of illness, but not be influenced by short-term pharmacological perturbations by neuroleptics.

Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial.

The efficacy and safety of the new drug, BGP-15, were compared with placebo in insulin-resistant patients in a 28-day dose-ranging study. Forty-seven nondiabetic patients with impaired glucose tolerance were randomly assigned to 4 weeks of treatment with 200 or 400 mg of BGP-15 or placebo. Insulin resistance was determined by hyperinsulinemic euglycemic clamp technique and homeostasis model assessment method, and beta-cell function was measured by intravenous glucose tolerance test. Each BGP-15 dose significantly increased whole body insulin sensitivity (M-1, p=0.032), total body glucose utilization (M-2, p=0.035), muscle tissue glucose utilization (M-3, p=0.040), and fat-free body mass glucose utilization (M-4, p=0.038) compared to baseline and placebo. No adverse drug effects were observed during treatment. BGP-15 at 200 or 400 mg significantly improved insulin sensitivity in insulin-resistant, nondiabetic patients during treatment compared to placebo and was safe and well-tolerated. This was the first clinical study demonstrating the insulin-sensitizing effect of a molecule, which is considered as a co-inducer of heat shock proteins.

[Pulmonary segmentectomy for tumour]. / Plicní segmentektomie pro nádor.

BACKGROUND: An analysis of outcome data of pulmonary segmentectomy focused on local efficacy in primary non small cell lung cancer and true or seeming lung metastasis. PATIENTS AND METHODS: Miscellaneous series of twenty patients treated with classical open procedure involving individuals with primary or metachronous non small cell lung cancer, solitary pulmonary metastasis of extrapulmonary cancer and/or benign pulmonary lesions, lung metastasis mimicing. Thirteen patients after segmentectomy because of malignancy are separated into a group of 7 cases with NSCLC up to 20 mm in diameter, and a group of 6 persons with solitary pulmonary opacity up to 38 mm treated previously surgically for extrapulmonary cancer. Both without enlargement of hilar and/or mediastinal lymphatics proven on preoperative CT imaging. Third part of the group collects benign pulmonary lesions: chondrohamartoma, pneumonitis and pulmonary infarct. Persons involved through a ten years period are followed up at 3 (4)-months intervals. RESULTS: No perioperative and thirty day mortality was registered. Six cases of distant recurrence were recorded, three in NSCLC and three in extrapulmonary cancer patients. Five patients died within the follow-up period, three of them through the general progression of the oncological disease. Two deaths were non-cancer related. One R1 disease was discovered in a patient with primary lung adenocarcinoma. No local recurrence was recorded in both cancer series with median age of 63 yrs (range 45-79 yrs) and median duration of follow up 35 months. CONCLUSION: Lung segmentectomy seems to accomplish local control of early stage non small cell lung cancer and pulmonary metastasis of extrapulmonary cancer in selected patients.

Right carinal pneumonectomy for a delayed diagnosis.

The authors present the case of a male patient misdiagnosed with right upper lobe tuberculosis and repeatedly treated for this in the last two years, without response. In our institution, the source of the hemoptysis proved to be a pulmonary carcinoma, which in its evolution involved the carina and the last tracheal ring. Right carenal pneumonectomy with two tracheal ring resection is performed, with reconstruction of the airway by anastomosing the main left bronchus to trachea. The resection involved also the azygos vein and the lateral wall of the superior vena cava (angioplastic resection), the vagus nerve and the pericardium, the last are being reconstructed with synthetic mesh. Histopatologic diagnosis is squamous cell carcinoma moderately differentiated. The right tracheal sleeve pneumonectomy was the therapeutically choice for a middle-aged patient with recurrent hemoptysis and retrostenotic lung destruction.

Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.

Various aspects of the complex spatio-temporal patterning of hypothalamic signaling that leads to the development of synchronized nocturnal feeding in the rat are critically examined. Undoubtedly, as depicted in Fig. 7, a distinct ARN in the hypothalamus is involved in the control of nocturnal appetite. At least four basic elements operate within this ARN. These are: 1) A discrete appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and orexin transduces and releases appetite-stimulating signals. 2) Similarly, anorexigenic signal-producing pathways (e.g., CRH, GLP-1, alpha MSH, and CART) orchestrate neural events for dissipation of appetite and to terminate feeding, possibly by interrupting NPY efflux and action at a postsynaptic level within the hypothalamus. It is possible that some of these may represent the physiologically relevant "off" switches under the influence of GABA alone, or AgrP alone, or in combination with NPY released from the NPY-, GABA-, and AgrP-coproducing neurons. 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals. Since interruption of neurotransmission in the VMN resulted in hyperphagia and development of leptin resistance, it seems likely that the VMN is an effector site for the restraint exercised by leptin. The daily rhythms in leptin synthesis and release are temporally dissociable because the onset of daily rise in leptin gene expression in adipocytes precedes that in leptin secretion. Nevertheless, these rhythms are in phase with daily ingestive behavior because the peak in circulating leptin levels occurs during the middle of the feeding period. These observations, coupled with the fact that circulating levels of leptin are directly related to adiposity, pose a new challenge for elucidating the precise role of leptin in daily patterning of feeding in the rat. 4) A neural timing mechanism also operates upstream from the ARN in the daily management of energy homeostasis. Although the precise anatomical boundaries are not clearly defined, this device is likely to be composed of a group of neurons that integrate incoming internal and external information for the timely onset of the drive to eat. Evidently, this network operates independently in primates, but it is entrained to the circadian time keeper in the SCN of rodents. Apart from its role in the onset of drive to eat, the circadian patterns of gene expression of NPY, GAL, and POMC denote independent control of the timing device on the synthesis and availability for release of orexigenic signals. The VMN-DMN-PVN complex is apparently an integrated constituent of the timing mechanism in this context, because lesions in each of these sites result in loss of regulated feeding. The accumulated evidence points to the PVN and surrounding neural sites within this framework as the primary sites of release and action of various orexigenic and anorexigenic signals. A novel finding is the identification of the interconnected wiring of the DMN-mPVN axis that may mediate leptin restraint on NPY-induced feeding. The chemical phenotypes of leptin and NPY target neurons in this axis remain to be identified. These multiple orexigenic and anorexigenic pathways in the hypothalamic ARN appear to represent redundancy, a characteristic of regulated biological systems to provide a "fail-safe" neural mechanism to meet an organism's constant energy needs for growth and maintenance. Within this formulation, the coexisting orexigenic signals (NPY, NE, GAL, GABA, and AgrP) represent either another level of redundancy or it is possible that these signals operate within the ARN as reinforcing agents to varying degrees under different circumstances. (ABSTRACT TRUNCATED)

The role of N-methyl-D-aspartate receptors and nitric oxide in cochlear dopamine release.

Dopamine (DA) released from lateral olivocochlear (LOC) terminals may have a neuroprotective effect in the cochlea. To explore the role of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) in the modulation of a cochlear DA release, we measured the release of [3H]DA from isolated mouse cochlea in response to the application of NMDA. NMDA at 100 muM significantly increased the electrical-field stimulation-evoked and resting release of DA from the cochlea. The NO donor sodium nitroprusside enhanced the basal outflow of DA but failed to influence the evoked release. The administration of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) alone was ineffective, but it significantly inhibited the initial phase of the NMDA-induced elevation of DA outflow, which suggested the role of NO in the NMDA-induced DA release. The DA uptake inhibitor nomifensine increased the electrically evoked release of DA. Nomifensine failed to change the effect of NMDA on the resting or electrically-evoked DA release, which suggested that the uptake mechanism does not play a role in NMDA-evoked and NO-mediated DA release. In summary, we provide evidence that NO can modulate the release of DA from the cochlea following NMDA receptor activation, but does not affect the uptake of DA.

Uncoupling protein 2/3 immunoreactivity and the ascending dopaminergic and noradrenergic neuronal systems: relevance for volume transmission.

Uncoupling proteins in the inner mitochondrial membrane uncouples oxidative phosphorylation from ATP synthesis. It has been suggested that these proteins are involved in thermogenesis as well as in the regulation of reactive oxygen species production in the mitochondria. The present work was conducted to investigate the localization of the uncoupling protein 2-like immunoreactivity (uncoupling protein 2/3 immunoreactivity) in the main catecholaminergic projection fields in the rat brain as well as in the areas of the dopaminergic and noradrenergic nerve cell groups. In particular, the relationships of tyrosine hydroxylase, dopamine beta-hydroxylase and uncoupling protein 2/3 immunoreactivity were assessed by double immunolabeling and confocal laser microscopy analysis associated with computer-assisted image analysis. Uncoupling protein 2/3 immunoreactivity was observed in discrete dopaminergic terminals in the nucleus accumbens and in the cerebral cortex whereas it was found in scattered noradrenergic terminals in the caudate putamen and Islands of Calleja Magna. One interesting finding was that uncoupling protein 2/3 immunoreactivity together with tyrosine hydroxylase immunoreactivity in the shell of nucleus accumbens was observed surrounding the previously characterized D1 receptor rich nerve cell column system characterized by a relative lack of tyrosine hydroxylase immunoreactivity. Moreover, in animal models of dopaminergic pathway degeneration, plastic changes in uncoupling protein 2/3 terminals have been shown in the cerebral cortex and striatum as seen from the increased size and intensity of uncoupling protein 2/3 immunoreactivity of their varicosities. Taken together, these findings open up the possibility that uncoupling protein 2/3 could play an important role modulating the dopaminergic and noradrenergic neurotransmission within discrete brain regions.