Evidence-based guides in tracheostomy use in critical patients. / Guías basadas en la evidencia para el uso de traqueostomía en el paciente crítico.

OBJECTIVES: Provide evidence based guidelines for tracheostomy in critically ill adult patients and identify areas needing further research. METHODS: A task force composed of representatives of 10 member countries of the Pan-American and Iberic Federation of Societies of Critical and Intensive Therapy Medicine and of the Latin American Critical Care Trial Investigators Network developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: The group identified 23 relevant questions among 87 issues that were initially identified. In the initial search, 333 relevant publications were identified of which 226 publications were chosen. The task force generated a total of 19 recommendations: 10 positive (1B=3, 2C=3, 2D=4) and 9 negative (1B=8, 2C=1). A recommendation was not possible in six questions. CONCLUSION: Percutaneous techniques are associated with a lower risk of infections compared to surgical tracheostomy. Early tracheostomy only seems to reduce the duration of ventilator use but not the incidence of pneumonia, the length of stay, or the long-term mortality rate. The evidence does not support the use of routine bronchoscopy guidance or laryngeal masks during the procedure. Finally, proper prior training is as important or even a more significant factor in reducing complications than the technique used.

Prevalence of faecal incontinence and analysis of its impact on quality of life and mental health.

AIM: Faecal incontinence is a significant healthcare problem, with an estimated prevalence of up to 5% of the general population. Little is known about its prevalence among patients attending primary care. METHOD: A cross-sectional multicentre study was undertaken. Adult patients attending 10 primary health centres were interviewed. Faecal incontinence was defined as involuntary leakage of flatus, liquid or solid stool at least once in the preceding 4 weeks. Health-related and disease-specific quality of life was assessed using the 36-item Short-Form Health Survey and the Fecal Incontinence Quality of Life scale, respectively. Mental health status was assessed using the 28-item General Health Questionnaire. An adjusted multivariate analysis was performed to study the association of faecal incontinence with the presence of altered mental health status. RESULTS: A total of 518 subjects (mean age 60.3 years) were studied. The prevalence of faecal incontinence was 10.8%. Altered mental health status was found in 51.8% of patients with faecal incontinence and in 30.5% of those without (P = 0.001). Faecal incontinence was a significant independent factor for altered mental health status (odds ratio, 2.088; 95% CI 1.138-3.829; P = 0.017). CONCLUSION: The prevalence of faecal incontinence in primary care is high, with a significant impact on quality of life and mental health status.

Faecal incontinence after seton treatment for anal fistulae with and without surgical division of internal anal sphincter: a systematic review.

OBJECTIVE: The challenge of surgery for anal fistula is to eradicate the fistula track while maintaining anal continence. Seton placement is recommended to reduce postoperative faecal incontinence but interestingly a great range of functional impairment after surgery has been published. The aim of this study was to analyse the influence of intra-operative internal anal sphincter division during tight or cutting seton technique for cryptogenic anal fistula, on the results of recurrence and postoperative faecal incontinence. METHOD: A systematic literature review was performed to identify published series from 1966 to May 2007 of patients with anal fistula treated by a tight or cutting seton technique. The published series has been divided in to those where preservation of internal anal sphincter was performed (PIAS group) or where intra-operative surgical division was undertaken in the time of seton placement (SIAS group) .The main endpoints of the review were to study anal fistula recurrence rate and postoperative faecal incontinence. RESULTS: Eighteen studies including 19 series and 448 patients were analysed in detail. Recurrence rate was 5.0% and 3.0% in PIAS and SIAS group respectively. Overall faecal incontinence rate was 5.6% in PIAS group and 25.2% in SIAS group. CONCLUSION: Although based on low-evidence studies, intra-operative preservation of internal anal sphincter at the time of seton insertion for anal fistula seems to reduce the postoperative faecal incontinence without a substantial increase in recurrence rates.

The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells.

Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4-naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.

An alternative management for high-risk patients with rectal prolapse.

INDICATION: The management of rectal prolapse in presence of high-risk comorbidities can be challenging. We report the use of an anal plug as a noninvasive alternative in patients with contraindication of surgery. METHOD: This small device opens up in about 30 s to fit the contour of the lower rectum avoiding faecal leakage or in our case, the rectal prolapse. Although the plug is poorly tolerated in some cases, this device may be used up to 12 h per day and no adverse effects have been reported. COMPARISON WITH OTHER METHODS: Nonsurgical alternatives described in the literature, such as sclerotherpy in children, are not routinely used in the adult population. The main advantage of the anal plug is its simplicity and safety as in the series published for the treatment of faecal incontinence no adverse events were described. CONCLUSION: An anal plug for rectal prolapse is an alternative in high-risk patients or during the time before surgical treatment.

Adaptation and validation of the Bristol scale stool form translated into the Spanish language among health professionals and patients.

BACKGROUND: stool type represents an important semiologic part of medical interviews. The Bristol Scale Stool Form is a clinical tool to evaluate stool consistency and form. The aim of this study was to translate and adapt the Bristol Scale Stool Form into Spanish. Differences in validation results between health professionals and patients surveyed were also evaluated. METHODS: the study population included 79 physicians, 79 nurses, and 78 patients. Subjects were invited to match a randomly selected text defining one of the seven stool types in the scale with one of seven drawings described originally. A random selection of samples was offered for re-test reliability. RESULTS: the overall Kappa index was 0.708. Thirty-two subjects repeated the test for a test-retest assessment in a mean interval of 7.76 days, and the percentage concordance between definition and image was 84.4% with a Kappa index of 0.816. There were no differences in the validation study between physicians, nurses, and patients. CONCLUSIONS: this study has shown that the Spanish version of the Bristol Scale Stool Form is reliable for use as a tool to evaluate stool consistency and form.

French medical practice in type 2 diabetes: the need for better control of cardiovascular risk factors.

AIMS: In type 2 diabetes (T2D), to describe treatments to prevent cardiovascular disease, to compare current practice to French guidelines, and to identify factors associated with recommended treatments. METHODS: In the Echantillon National Témoin Représentatif des Personnes Diabétiques (ENTRED) study, 10,000 adults treated for diabetes (any type) were randomly selected from the French National Health Insurance System database. Deliveries during the last quarter of 2001 of treatments to prevent cardiovascular disease were extracted. Questionnaires were mailed to these people and their care providers. Final populations included 3324 people with T2D and their 1553 care providers. RESULTS: Overall, 18% reported coronary heart disease (CHD) and 44% others were classified as having a high cardiovascular risk; 68% received one or more antihypertensive treatment: ACE inhibitor/angiotensin receptor blocker (ARB), 44%; diuretic, 35%; calcium channel blocker, 25%; beta-blocker, 24%. Among those receiving antihypertensive treatment, 59% had blood pressure greater than 130/80mmHg. Overall, 42% received a hypolipidaemic treatment: statin, 25%; fibrate, 18%. About half the people with a high cardiovascular risk had LDL cholesterol greater than 1g/L, but only 32% were given a statin. Among people with an abnormal albumin/creatinine ratio (11%), 59% received an ACE inhibitor/ARB. Among those with CHD, 35% received the two treatments recommended in 1999 (beta-blockers and antiplatelet agents); in multivariate analyses, this two-treatment delivery was positively associated with male gender, self-reported hypertension and consulting a cardiologist. CONCLUSION: Cardiovascular risk profiles reported by providers in T2D people are high. Despite recent progress, there is a need for major improvement in practices intended to prevent cardiovascular disease in these people, especially in those at greatest CHD risk.

Prevalence of macrovascular complications and cardiovascular risk factors in people treated for diabetes and living in France: the ENTRED study 2001.

AIM: The aim of this study is to estimate the prevalence of macrovascular complications and cardiovascular risk factors among people with diabetes living in France and to compare these prevalences with other national estimates. METHODS: We randomly sampled 10,000 people who received one or more reimbursements for insulin or oral hypoglycaemic treatment from the major national medical insurance system during the period October-December 2001; 3646 of the 10,000 people completed a questionnaire; for a subgroup of 1718 people, their care providers completed a medical questionnaire. RESULTS: The prevalence of diagnosed macrovascular complications was of 17% according to patients (angina or myocardial infarction, 15%; coronary revascularization, 9%) and of 20% overall, according to physicians (angina or myocardial infarction, 16%; coronary revascularization, 6%; stroke, 5%). Macrovascular complications were more frequent in people with type 2 than type 1 diabetes, reflecting an age effect. The prevalences of cardiovascular risk factors in type 1 and type 2 diabetes were: current smoking, 35 and 14%; overweight, 28 and 42%; obesity, 9 and 36%; blood pressure superior to 130/80 mmHg, 29 and 59%; LDL cholesterol superior or equal to 3.4 mmol/l, 18 and 26%, respectively. CONCLUSIONS: Compared with other European countries, elevated blood pressure is more frequent in people with diabetes living in France; compared with US estimates, the prevalence of macrovascular complications is lower, glucose control better and blood pressure control poorer in France. These data, observed in a country with widespread access to care and at low cost to the patient, nevertheless demonstrate an urgent need for improving the cardiovascular risk profile of people with type 1 and type 2 diabetes, both with and without macrovascular complications.

Unusual diagnoses made by convex-probe endobronchial ultrasound-guided transbronchial needle aspiration.

Endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) has proven to be an effective and minimally invasive tool to diagnose and stage lung cancer. However, its use for the diagnosis of rare mediastinal and lung pathologies has been rarely described. Hereby we describe a retrospective chart review of our EBUS-TBNA database for unusual diagnosis made between July 2012 and October 2016. Those conditions considered unusual for EBUS-TBNA diagnosis were identified and their medical records reviewed.

Analgesia in patients with acute abdominal pain.

BACKGROUND: For decades, analgesia for patients with acute abdominal pain was withheld until a definitive diagnosis was established for fear of masking the symptoms, changing physical findings or ultimately delaying diagnosis and treatment of a surgical condition. This non-evidence-based approach has been challenged by recent studies demonstrating that the use of analgesia in the initial evaluation of patients with acute abdominal pain leads to significant pain reduction without affecting diagnostic accuracy. However, early administration of analgesia to such patients can greatly reduce their pain and does not interfere with a diagnosis, which may even be facilitated due to the severity of physical symptoms being reduced. OBJECTIVES: To determine if the currently available evidence supports the use of opioid analgesia in patient management with acute abdominal pain; and to assess changes in a patient comfort while awaiting definitive diagnosis and final treatment decisions. SEARCH STRATEGY: Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 4, 2006), MEDLINE (1966 to 2006) and EMBASE (1980 to 2006). Randomized controlled trial filter for MEDLINE and EMBASE search. Trials will also be identified by "related articles". The searches were not limited by language or publication status. SELECTION CRITERIA: Randomized controlled trials (RCTs) that include adult patients with acute abdominal pain, without gender restriction, comparing any opioid analgesia regime to no analgesia administered prior to any intervention regardless of outcomes. DATA COLLECTION AND ANALYSIS: Two authors looked independently at the titles and abstracts of reports. Potentially relevant studies selected by at least one reviewer were retrieved in full text versions for potential inclusion. Allocation concealment was important to avoid bias and was graded using the Cochrane approach. The data from studies included was reviewed qualitatively and quantitatively using the Cochrane Collaborations methodology and statistical software RevMan Analysis 1.0.5. In the case of homogeneity or non- worrying heterogeneity, a random effects model was used. Sensitivity analysis was performed based on quality assessment. MAIN RESULTS: Six studies fulfilled the inclusion criteria. Improvement with use of opioid analgesia was verified in variables patient comfort, reduction of pain, changes in physical examination. AUTHORS' CONCLUSIONS: The review provide some evidence to support the notion that the use of opioid analgesics in patients with acute abdominal pain is helpful in terms of patient comfort and does not retard decisions to treat.

[Cocaine and trisomy 8 associated with prenatal diagnosis of corpus callosum agenesis]. / Cocaïne et trisomie 8 associées au diagnostic prénatal d'agénésie du corps calleux.

We report the case of a newborn presenting an agenesis of corpus callosum (ACC) discovered in the prenatal period and initially related to cocaine exposure during the first trimester of gestation. The cytogenetic analysis revealed a trisomy 8 mosaicism. The putative role of prenatal cocaine exposure and mosaicism for chromosome 8 in ACC are discussed. This report emphasizes the specific analysis of chromosome 8 by using fluorescence in situ hybridization as a complement to routine cytogenetic analysis for prenatal diagnosis of ACC.

Biochemical characterization and autoradiographic localization of [125I]endothelin-1 binding sites on trophoblast and blood vessels of human placenta.

The presence of endothelin binding sites in the human placenta raises the question of the precise localization of these receptors on well defined placental constituents. In order to find an answer to this problem various approaches were used. Specific binding sites for [125I] endothelin-1 (ET-1) were identified on human term placenta, not only on membranes of smooth muscles stem villi vessels, but also on trophoblastic plasma membranes prepared from trophoblast in culture. Scatchard analysis of binding data revealed a single class of high affinity binding sites with Kd values of 26 +/- 4 pmol/L for stem villi vessels and 126 +/- 4 pmol/L for trophoblast in culture, with maximum binding capacities of 681 +/- 61 and 224 +/- 53 fmol/mg protein, respectively. The anatomical localization of these binding sites was determined by in vitro autoradiography. Autoradiograms obtained from placental sections incubated with [125I]ET-1 indicate that [125I]ET-1 high affinity binding sites exist on placental stem villi vessels and on the trophoblastic layer of the villi. The latter localization was also found on autoradiograms of trophoblast in culture. The human placental syncytiotrophoblast is a polarized epithelium with the microvillous membrane, facing maternal blood space and the basal plasma membrane, facing fetal circulation. [125I]ET-1 high affinity binding sites are present on both membranes but the number of binding sites is higher on the basal plasma membrane. These findings lead to the suggestion that ET-1 may be involved in the regulation of the feto-placental circulation and may subserve specific trophoblastic functions.

Relationship between the liver and lymphocytotoxic alloantibodies in inbred rats. Specific absorption by nonparenchymal liver cells.

Liver allografts have a privileged status with regard to hyperacute rejection. In this experimental study, we have used extracorporeal liver hemoperfusion in sensitized rats in order to analyze reactions between lymphocytotoxic antibodies and the liver. In sensitized BN rats, a donor-specific (Lewis) extracorporeal liver hemoperfusion can delay hyperacute rejection of heart allografts and reduce the level of lymphocytotoxic antibodies. The decrease in the level of antibodies could be due to massive absorption of antibodies by the liver or to release of major histocompatibility complex antigens in a soluble form. Immunofluorescent examination of the hemoperfused liver revealed important deposits of C3 on Kupffer cells and of IgG on sinusoidal cells. On the contrary, in control rats in which a third-party (DA) liver hemoperfusion was performed, heart allograft survival was less prolonged, the decrease in the level of lymphocytotoxic antibodies was not significant, and the deposits of IgG and C3 were much less evident. The level of circulating immune complexes was unchanged after a donor-specific or a third-party liver hemoperfusion. These results support the hypothesis that resistance of the liver to hyperacute rejection might be due to a massive and nontoxic absorption of lymphocytotoxic antibodies on nonparenchymal liver cells.

Quantitative autoradiography of the rat brain vesicular monoamine transporter using the binding of [3H]dihydrotetrabenazine and 7-amino-8-[125I]iodoketanserin.

The binding of [3H]dihydrotetrabenazine, a specific ligand of the monoamine transporter present on serotonin and catecholamine synaptic vesicles, was studied on rat brain sections. The characteristics of binding (Kd = 5.0 nM, k1 = 0.13 x 10(6) M-1 s-1; k-1 = 0.66 x 10(-3) s-1) were similar to those previously observed on tissue homogenates. The rostrocaudal topographical distribution of dihydrotetrabenazine binding sites was analysed by quantitative autoradiography. High labelling was observed in regions richly innervated by monoaminergic systems: dopamine in the striatum and olfactory tubercles, noradrenaline in the striatal fissure and in the paraventricular and dorsomedial hypothalamus and serotonin in the lateral septum, islands of Calleja and suprachiasmatic nucleus. Cell bodies were also labelled in the substantia nigra and ventral tegmental area (dopamine), in locus coeruleus (noradrenaline) and in raphe nucleus (serotonin). The pituitary gland (particularly the neural lobe) and the pineal gland were also labelled. Low labelling was observed in various areas of the cerebral cortex and in the cerebellum. Unilateral 6-hydroxydopamine lesion of the substantia nigra dramatically reduced [3H]dihydrotetrabenazine labelling in the ipsilateral striatum. Moreover, ketanserin has recently been shown to possess a nanomolar affinity for the vesicular monoamine transporter, and autoradiographic localization of brain monoaminergic synaptic vesicles was also obtained by means of the derivative 7-amino-8-[125I]iodoketanserin in the presence of 5-hydroxytryptamine2 and alpha 1 antagonists, although the non-specific labelling was higher than with [3H]dihydrotetrabenazine. It is concluded that [3H]dihydrotetrabenazine may represent a valuable monoaminergic marker in in vitro autoradiographic studies.

Distribution of neurotensin binding sites in rat brain: a light microscopic radioautographic study using monoiodo [125I]Tyr3-neurotensin.

The topographic distribution of specifically labeled neurotensin binding sites was examined by light microscopic radioautography in rat brain sections incubated with monoiodo [125I]Tyr3-neurotensin. Preliminary experiments indicated that under the present experimental conditions [125I]neurotensin specifically binds to a single apparent population of sites with a dissociation constant of 7.7 +/- 0.3 nM, and that fixation of the labeled sections with glutaraldehyde ensures regionally proportional retention of more than 70% of bound [125I]neurotensin molecules. High concentrations of [125I]neurotensin binding sites were detected in the olfactory bulb and tubercle, parts of the neocortex, the lateral septum, the diagonal band of Broca, the caudate putamen, the amygdala, the dentate gyrus, the anterior dorsal nucleus of the thalamus, the suprachiasmatic nucleus of the hypothalamus, the medial habenula, the zona incerta, the substantia nigra and the ventral tegmental area. In certain areas, such as in the diagonal band of Broca, the substantia innominata, the nucleus basalis and the pars compacta of the substantia nigra, discrete accumulations of silver grains were apparent over neuronal perikarya and their proximal dendrites. In most areas, however, the label appeared more or less uniformly distributed over nerve cell bodies and surrounding neuropil. In several instances, the labeling conformed with the distribution of cell bodies of origin and terminal aborizations of specific projection systems, suggesting that neurotensin receptors might be distributed both proximally and distally on the plasma membrane of certain neurons. Such putative "neurotensinoceptive" projection systems might involve part of the mesostriatal, mesocortical and mesolimbic dopamine systems, as well as the raphe-prosencephalic serotonin system and the habenulo-interpeduncular and basal forebrain-cortical cholinergic systems. Finally, areas of dense [125I]neurotensin labeling often corresponded to zones previously shown to exhibit intense acetylcholinesterase staining, suggesting the existence of a possible link between the expression of neurotensin binding sites and that of acetylcholinesterase in certain neuronal populations.

Conservative management of patent ductus arteriosus in preterm infants.

We report our experience of medical treatment, chiefly based on prolonged artificial ventilation, of 33 preterm infants with PDA and heart failure whose survival rate was 88%. All of them had clinical criteria used by others to indicate surgical ligation of the ductus arteriosus. This conservative approach seems to give better results than surgical ligation, despite a high frequency of bronchopulmonary dysplasia among survivors.

Labor induction in women at term with mifepristone (RU 486): a double-blind, randomized, placebo-controlled study.

OBJECTIVE: To determine the efficacy and safety of mifepristone as an induction agent for the initiation of labor or as a cervical ripening agent in women at term. METHODS: Our study group contained 120 women at term (after 37.5 weeks' amenorrhea) who had clear clinical indications for labor induction. They were randomized to receive either 200 mg of mifepristone or placebo on days 1 and 2 of a 4-day observation period, with labor induction planned for day 4. Eight patients, three treated with mifepristone and five receiving placebo, had to be excluded from the survey because they required cesareans for medical reasons (fetal distress or maternal complications) less than 12 hours after taking the first tablet. RESULTS: Forty-one subjects entered spontaneous labor, 31 treated with mifepristone and ten in the control group (P < .001). Forty-five needed cervical maturation with prostaglandins on day 4, 13 of whom had received mifepristone and 32 of whom had been given placebo (P < .001). Thirteen women treated with mifepristone and 13 who had taken placebo had mature cervices sufficient for classic labor induction with oxytocin and amniotomy. Patients who delivered vaginally needed a much lower amount of oxytocin when mifepristone had been given, and the mean time interval between day 1 of the survey and the onset of labor was also significantly shorter in this group. CONCLUSION: Although more studies are needed, we have found mifepristone to be a safe, efficient, and suitable induction agent for initiation of labor in women at term.

Hyperprolactinemia-induced modifications in vasoactive intestinal peptide binding site densities in the rat central nervous system and pituitary gland: evidence for an interaction between estradiol-17 beta and prolactin effects.

Hyperprolactinemia was induced in ovariectomized rats by implanting estradiol-17 beta pellets, grafting extrapituitaries, or by a combination of both treatments. Subsequently, the effect of increasing plasma prolactin levels on both central and pituitary receptors for vasoactive intestinal peptide (VIP), a neuropeptide known to stimulate prolactin release was investigated. The results obtained by quantitative autoradiography show that the density of VIP binding sites is modified in restricted areas of the central nervous system (striatum, several cortical, thalamic and limbic structures) and in the pituitary in hyperprolactinemic animals. The present results suggest that changes in plasma prolactin levels may control VIP receptor site density in both brain and pituitary. Moreover, direct effects of estradiol-17 beta and possible interactions between estradiol-17 beta and prolactin are observed on both brain and pituitary VIP binding sites.

Characterization and autoradiographic distribution of vasoactive intestinal peptide binding sites in the rat central nervous system.

Biochemical characteristics and topographical distribution of mono-[125I )vasoactive intestinal peptide (VIP) binding sites in rat brain were studied on tissue sections and by quantitative autoradiography. Biochemical investigations show two classes of binding sites with a dissociation constant of 1.03 +/- 0.11 nM and 68 +/- 14 nM and a maximal binding capacity of 43.3 +/- 5.1 fmol/mg protein and 713 +/- 117 fmol/mg protein respectively. The order of potency of various peptides to inhibit 125I-VIP binding to brain sections is: VIP greater than PHI greater than secretin greater than VIP greater than hGRF. Autoradiography reveals the highest densities of binding sites in the pineal gland, the dentate gyrus of the hippocampus, the central amygdaloid nucleus and in various thalamic nuclei such as the mediodorsal, lateral posterior, submedius, dorsolateral and medial geniculate nuclei. Similar high densities are observed in the olfactory bulbs as well as in the suprachiasmatic and dorsomedial nuclei of the hypothalamus and in the superior colliculus. These data together with the distribution of the endogenous peptide suggest a physiological role for VIP both in the regulation of CNS activities and pituitary functions.

Characterization and autoradiographic distribution of neurotensin binding sites in the human brain.

The characteristics and topographical distribution of monoiodo 125I-Tyr3-neurotensin (NT) binding sites in normal human brain tissue were studied on brain sections and by quantitative autoradiography. Sections at the level of the substantia nigra show a dissociation constant and maximal binding capacity of 4.8 +/- 0.8 nM and 70 +/- 7 fmol/mg protein, respectively. High density of 125I-NT binding sites were mainly found in dopaminergic (DA)-rich areas such as the substantia nigra, the ventral tegmental area, the striatum and the nucleus accumbens, further supporting an interaction between NT and DA neurons in human brain.