Role of CB2 cannabinoid receptor in the development of food addiction in male mice.

The endocannabinoid system plays an important role in multiple behavioral responses due to its wide distribution in the central nervous system. The cannabinoid CB1 receptor was associated to the loss of behavioral control over food intake occurring during food addiction. The cannabinoid CB2 receptor (CB2R) is expressed in brain areas canonically associated with addictive-like behavior and was linked to drug-addictive properties. In this study, we evaluated for the first time the specific role of the CB2R in food addiction by using a well-validated operant mouse model of long-term training to obtain highly palatable food. We have compared in this model the behavioral responses of wild-type mice, mutant mice constitutively lacking CB2R, and transgenic mice overexpressing CB2R. The lack of CB2R constitutes a protective factor for the development of food addiction and the impulsive and depressive-like behavior associated. In contrast, the overexpression of CB2R induces a vulnerable phenotype toward food addiction after long-term exposure to highly palatable chocolate pellets. Relevant transcriptomic changes were associated to resilience and vulnerability to food addiction depending on the genotype, which provides a mechanistic explanation for these behavioral changes. Therefore, CB2R may constitute a potential therapeutic target for the loss of eating control and the comorbid emotional effects associated to food addiction.

Prognostic accuracy of SIRS criteria, qSOFA score and GYM score for 30-day-mortality in older non-severely dependent infected patients attended in the emergency department.

The aim of this study was to determine the accuracy of systemic inflammatory response syndrome (SIRS), quick Sepsis-related Organ Failure Assessment (qSOFA) score and GYM score to predict 30-day mortality in older non-severely dependent patients attended for an episode of infection in the emergency department (ED). We performed an analytical, observational, prospective cohort study including patients 75 years of age or older, without severe functional dependence, attended for an infectious process in 69 Spanish EDs for 2-day three-seasonal periods. Demographic, clinical and analytical data were collected. The primary outcome was 30-day mortality after the index event. We included 1071 patients, with a mean age of 83.6 [standard deviation (SD) 5.6] years; 544 (50.8%) were men. Seventy-two patients (6.5%) died within 30 days. SIRS criteria ≥ 2 had a sensitivity of 65% [95% confidence interval (CI) 53.1-75.9] and a specificity of 49% (95% CI 46.0-52.3), a qSOFA score ≥ 2 had a sensitivity of 28% (95% CI 18.2-39.8) and a specificity of 94% (95% CI 91.9-95.1), and a GYM score ≥ 1 had a sensitivity of 81% (95% CI 69.2-88.6) and a specificity of 45% (95% CI 41.6-47.9). A GYM score ≥ 1 and a qSOFA score ≥ 2 were the cut-offs with the highest sensitivity (p < 0.001) and specificity (p < 0.001), respectively. The area under the curve (AUC) was 0.73 (95% CI 0.66-0.79; p < 0.001) for the GYM score, 0.69 (95% CI 0.61-0.76; p < 0.001) for the qSOFA score and 0.65 (95% CI 0.59-0.72; p < 0.001) for SIRS. A GYM score ≥ 1 may be the most sensitive score and a qSOFA score ≥ 2 the most specific score to predict 30-day mortality in non-severely dependent older patients attended for acute infection in EDs.

Extensive sequence analysis of CFTR, SCNN1A, SCNN1B, SCNN1G and SERPINA1 suggests an oligogenic basis for cystic fibrosis-like phenotypes.

The term cystic fibrosis (CF)-like disease is used to describe patients with a borderline sweat test and suggestive CF clinical features but without two CFTR(cystic fibrosis transmembrane conductance regulator) mutations. We have performed the extensive molecular analysis of four candidate genes (SCNN1A, SCNN1B, SCNN1G and SERPINA1) in a cohort of 10 uncharacterized patients with CF and CF-like disease. We have used whole-exome sequencing to characterize mutations in the CFTR gene and these four candidate genes. CFTR molecular analysis allowed a complete characterization of three of four CF patients. Candidate variants in SCNN1A, SCNN1B, SCNN1G and SERPINA1 in six patients with CF-like phenotypes were confirmed by Sanger sequencing and were further supported by in silico predictive analysis, pedigree studies, sweat test in other family members, and analysis in CF patients and healthy subjects. Our results suggest that CF-like disease probably results from complex genotypes in several genes in an oligogenic form, with rare variants interacting with environmental factors.

Detection criteria and preventive measures for occupational disease in the mines of Almaden (Spain).

This research focuses on the metallurgy and underground mining job positions in the historic mines of Almaden (Spain). We introduce a preventive methodology for hydrargyrism in work environments known by the name of Methodology for Operational Units Action Levels for Health Indicators (MUONAIS). The methodology allows critical levels to be established using environmental and clinical-biological indicators. The prevention plan concentrated on 15 job positions in the metallurgy department that employed more than 100 workers between the years 1986 and 1997. The development of this preventive methodology managed to keep workers' mercury levels below 60 µg/l in blood and 200 µg/l in urine, values that present no negative effects on human health. MUONAIS has proven very effective in protecting workers' health. During this period, some cases of micro-mercurialism were detected, yet were completely reversible, allowing us to affirm that the terrible disease of hydrargyrism was totally eradicated.

Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation.

The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx). METHODS: One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively. RESULTS: In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8). CONCLUSIONS: This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.

The APOA5-1131 T>C variant enhances the association between RBP4 and hypertriglyceridemia in diabetes.

BACKGROUND AND AIM: Type 2 diabetic patients have an increased prevalence of hypertriglyceridemia. RBP4 has been associated with insulin resistance and hypertriglyceridemia in obesity, the metabolic syndrome and type 2 diabetes. APOA5 is proposed to be a genetic modulator of triglycerides. The aim of this study was to evaluate the relationship between RBP4 plasma levels and lipid disturbances and to determine the impact of the APOA5-1131 T>C variant on this relationship in type 2 diabetic patients. METHODS AND RESULTS: A total of 165 type 2 diabetic patients were included in the study. RBP4 plasma levels and the APOA5-1131 T>C variant were determined and the complete lipid profile was assessed by sequential ultracentrifugation. RBP4 was positively correlated with triglyceride levels in plasma and with all the components of triglyceride-rich lipoproteins. Despite the fact that a statistically significant relationship between the APOA5 genetic variant and RBP4 plasma levels was not found, the hypertriglyceridemic effect of high RBP4 levels was enhanced by the presence of the APOA5-1131 T>C genetic variant. Correlation coefficients were 2-fold higher for TC carriers compared to TT carriers with regard to RBP4 plasma levels and all the components of triglyceride-rich lipoproteins. Those type 2 diabetic patients with high RBP4 plasma concentrations and who were TC carriers showed an increased incidence of hypertriglyceridemia (OR=7.46, P=0.010). CONCLUSION: RBP4 is associated with hypertriglyceridemia in type 2 diabetic patients. The RBP4 effect is conditioned by the presence of the APOA5-1131 T>C genetic variant.

Quality of life in end stage renal disease: a multicentre comparative study.

BACKGROUND: Quality of Life (QOL) in patients with End Stage Renal Disease (ESRD) is an important measure of dialysis adequacy. Health related QOL is an independent risk factor for mortality in ESRD. The Kidney Disease QOL questionnaire is a highly validated disease targeted instrument with global application. We sought to document QOL and the predictive factors in a cohort of patients with ESRD in Jamaica and Panama. METHODS: Two hundred patients were recruited consecutively from November 2006 - November 2007. Seventy patients were from a tertiary hospital based outpatient dialysis centre, the University Hospital of the West Indies (UHWI), and 40 patients from a private centre, Diabetes Association Renal Unit (DARU) both in Kingston, Jamaica. Ninety patients were consecutively recruited from a tertiary hospital based outpatient dialysis centre in Panama City, Panama. The Kidney Disease Quality of Life - Short Form Questionnaire was administered. Each QOL domain was scored from 0 - 100 with higher scores representing better rating. RESULTS: Mean age was 50 +/- 4 years, with no difference between the cohorts. Panama, however, had significantly higher parameters than the Jamaican cohorts: mean haemoglobin (Hb) 12.4g/dL (p = 0.004), mean serum albumin 45g/dL (p = 0.03) and Urea Reduction Ratio (URR) 78% (p = 0.004). Diabetes Association Renal Unit recorded mean Hb 11.4 +/- 1.3g/dL, mean serum albumin 42.1 +/- 2.3g/dL and URR 72%. The University Hospital of the West Indies documented mean Hb 11.2 +/- 2.4g/dL, mean serum albumin 41 +/- 4.5g/dL and URR 68%. All three cohorts had good overall QOL scores when compared with the reference population. Patients from Panama had higher overall QOL scores than Jamaican patients (p = 0.02). By centre, UHWI had higher overall QOL scores than DARU (p = 0.04). Burden of Kidney Disease domain recorded the lowest overall scores (Reference Population 49, DARU 19.0 (p = 0.001), UHWI 24.0 (p = 0.002), Panama 32.9 (p = 0.03). Patient Satisfaction scores were also significantly reduced across all cohorts (Reference population 72, DARU 52, UHWI 54, Panama 58). The University Hospital of the West Indies had significantly decreased dialysis staff encouragement (p = 0.003). The Diabetes Association Renal Unit noted significant reductions in general health (p = 0.04), physical functioning (p = 0.001), physical role (p = 0.001) and emotional role (p = 0.005) domains. Panama had the lowest overall physical functioning (p = 0.01), pain (p = 0.01) and social support (p = 0.04) scores. In the Panamanian cohort, age< 65 years (p = 0.0004). Hb > 11.1 g/dL (p = 0.01), albumin > 40g/dL (p = 0.01), URR > 65% (p = 0.03), race (p = 0.04), at least high school educational attainment (p = 0.01) and household yearly salaries > US$5000 (p = 0.002) predicted good QOL scores. These accounted for 55% of the variance. In the Jamaican cohort, however, younger age (p = 0.02), race (p = 0.001), higher URR (p = 0.01) and higher serum haemoglobin (p = 0.001) predicted higher QOL scores, accounting for only 40% of the variance. By modality, haemodialysis patients had significantly higher haemoglobin (p = 0.003) and albumin (p = 0.002) levels and ultimately higher overall QOL scores (p = 0.01). CONCLUSION: Overall, QOL is good in patients with ESRD. Domains of highest concern include Burden of Kidney Disease and Patient Satisfaction. The role of spirituality, depression and nutritional markers (eg prealbumin) needs to be assessed. Quality of Life must therefore be routinely documented in ESRD patients and targeted interventions implemented.

[Congenital disorder of glycosylation type 1b. Experience with mannose treatment]. / Defecto congénito de glucosilación tipo Ib. Experiencia en el tratamiento con manosa.

Congenital disorders of glycosylation (CDG) are recessively inherited multisystemic disorders resulting from several genetic defects affecting the assembly, transfer or processing of oligosaccharides onto proteins and other glycoconjugates. CDG type Ib is due to a deficiency of phosphomannose isomerase (PMI) encoded by the MPI gene. PMI catalyzes the interconversion of fructose-6-P and mannose-6-P. The clinical phenotype is characterized by gastro-intestinal and hepatic symptoms. In contrast to most CDG patients, there is no neurological affectation. It's a mannose treatable disorder. We report the first recognised case of CDG Ib in Spain. He presented at 6 months with hypoglycaemia, failure to thrive and hypertransaminasaemia. He subsequently developed an enteropathy with subtotal villous atrophy on biopsy. The %CDT was very high and he presented with a type 1 pattern in transferrin isoelectric focusing. PMI activity in fibroblasts was very deficient. Mutations in MPI gene at R219Q and R56fs were found. Clinical and biochemical parameters normalised after treatment with mannose 1 g/kg/day in 5 doses. CDG Ib should be considered in patients with hypoglycaemia, liver disease, enteropathy and hypercoagulability, in the absence of other common causes, and particularly if some of them are combined.

[Assessment of the severity scores in patients included in a sepsis code in an Emergency Departament]. / Valoración de escalas de gravedad en pacientes incluidos en un código sepsis en un servicio de urgencias hospitalario.

OBJECTIVE: The objective of the study is to determine the usefulness of the SOFA (Sequential Organ Failure Assessment), quick SOFA (qSOFA), LODS (Logistic Organ Dysfunction System) and EWS (Early Warning Score) scores to predict in-hospital mortality among septic patients attended in the emergency department; to evaluate what factors are associated with mortality; and develop a predictive model of in-hospital mortality. METHODS: Retrospective study including patients over 14 years of age included in the sepsis code of an Emergency Department of a University Hospital between November 2013 and September 2015. Demographic variables, hemodynamic and analytical variables, and in-hospital mortality were collected to obtain qSOFA, SOFA, LODS, EWS scores. Receiver operating characteristic curves were constructed for each score. Logistic regression was used to evaluate the probability of in-hospital mortality. RESULTS: A total of 349 patients were analyzed, median age 72.7 (range 86), males: 54.4%. The in-hospital mortality was 21.8%. AUC obtained: LODS: 0.73 (IC 95% 0.67-0.80; p<0.001), EWS: 0.73 (IC 95% 0.65-0.81; p<0.001), SOFA: 0.72 (IC 95% 0.65- 0.78; p<0.001), qSOFA: 0.67 (IC 95% 0.58-0.76; p<0.001). After the multivariate analysis, these were the independent factors associated with in-hospital mortality: Oxygen saturation ≤92%, Glasgow coma score <14, lactate ≥2mmol/L (p<0.05). Two prognostic models were generated: MPRO1: age, oxygen saturation ≤92% and Glasgow coma score <14, AUC: 0.78 (IC 95% 0.72-0.84; p<0.001) and MPRO2 formed by the previous ones and lactate ≥2mmol/L, AUC: 0.82 (IC 95% 0.76-0.87; p<0.001). CONCLUSIONS: SOFA score and the new developed scores could be useful in asses the risk of in-hospital mortality in patients included in the sepsis code.

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

[Prevalence of celiac disease in apparently healthy blood donors in the autonomous community of Madrid]. / Prevalencia de la enfermedad celiaca en donantes de sangre de la Comunidad de Madrid.

OBJECTIVE: The aim of this study was to determine the prevalence of celiac disease among the adult population of Madrid by measuring antibodies against tissue transglutaminase as serologic screening method. POPULATION AND METHODS: 2,215 subjects participated voluntarily in this study. All of them completed a clinical questionnaire. We determined the levels of total IgA and antibodies to tissue transglutaminase (tTG). An intestinal biopsy by endoscopy was proposed to all subjects who were tTG-positive. The histologic lesion was classified in accordance to Marsh. RESULTS: Three known CD cases were identified by the questionnaire. Eleven donors with tTG positivity were detected, all of them asymptomatic. Four subjects rejected the intestinal biopsy. Seven out of 11 positive subjects consented to undergo a duodenal biopsy -3 had villous atrophy and 4 had increased intraepithelial lymphocyte counts with normal villi. In our study the number of donors with biopsy-proven CD was 6, and the prevalence was 1/370. If we include the subcategories of gluten sensitive enteropathy (Marsh I), the prevalence would be 1/222. When we considered antibody positivity the prevalence of gluten sensitivity was 1 in 201, and it reached 1 in 158 when the three known CD cases were included. CONCLUSIONS: Data on CD prevalence in this study confirm that CD is a first-line healthcare problem that may warrant universal screening. We detected a high number of lymphocytic enteritis cases, and thus some sort of action is mandatory.

Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes.

Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB(1)mediated suppression of mast cell activation responses, CB(2)-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness.

RATIONALE: Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade. OBJECTIVES: The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs. METHODS: Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA). RESULTS: Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine. CONCLUSIONS: These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence. HIGHLIGHTS: • Topiramate increases the rewarding properties of cocaine in CPP • Topiramate alters dopaminergic signaling in the mesolimbic circuit • Topiramate delays the extinction of cocaine-induced CPP • TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine • Results show that it should limit the use of topiramate in cocaine-dependent subjects.

Association between maltreatment and polydrug use among adolescents.

Different studies have related sexual and physical abuse during childhood and adolescence to the development of substance abuse disorders. Nevertheless, we are not aware of the role that other more common maltreatment types, such as neglect, will play among the most risky pattern of consumption: the polydrug use. A clinical sample of 655 adolescents, divided into two groups: polydrug users and non-polydrug users, were assessed on their pattern of drug consumption, history of childhood maltreatment, current psychopathology and their family history of alcoholism. Polydrug users had a greater prevalence of all types of maltreatment, although the most associated to this group were sexual abuse and emotional neglect. Other relevant variables to adolescent consumption were: the diagnosis of depressive disorder, the presence of anxiety traits and the family history of alcohol dependence. Polydrug users have higher risks of having had problems during infancy and adolescence, such as maltreatment and other psychopathological conditions, with the addition of family history of alcoholism. Accordingly, practitioners should take into account that those variables may influence polydrug abuse because it is the most risky pattern for subsequent dependence of substances, and they should always be considered during treatment.

Pharmacological and biochemical interactions between opioids and cannabinoids.

Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans. A number of studies have shown that both types of drugs share several pharmacological properties, including hypothermia, sedation, hypotension, inhibition of both intestinal motility and locomotor activity and, in particular, antinociception. Moreover, phenomena of cross-tolerance or mutual potentiation of some of these pharmacological effects have been reported. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs. The present review addresses the recent advances in the study of pharmacological interactions between opioids and cannabinoids, focusing on two aspects: antinociception and drug addiction. The potential biochemical mechanisms involved in these pharmacological interactions are also discussed together with possible therapeutic implications of opioid-cannabinoid interactions.

[A project for the implementation of a unit-dose drug dispensation system in an intensive care unit]. / Proyecto de implantación del sistema de distribución de medicamentos en dosis unitarias en una unidad de cuidados intensivos.

OBJECTIVE: To describe the implementation of a unitary dose drug dispensation system (UDDDS) with computerized medical orders in an intensive care unit (ICU) including 10 multi-purpose offices, and to obtain a medication error index as an indicator of the process quality. METHOD: A UDDDS with computerized medical orders for intensive care was defined. By consensus among nurses, intensivists and pharmacists, the administration of high-risk drugs by perfusion or through a gastric tube was protocolized, and computerized medical orders were adapted to ICU dynamics, with both fluid therapy and enteral and parenteral nutrition becoming fully integrated. A prospective observational 8-month study with 15 cross-sectional time points was performed to estimate the overall error index and mean error per drug use process stage. The error index is estimated by dividing the number of errors into error opportunities, and is expressed as a percentage. RESULTS: Computerized medical orders favored compliance with consensus protocols defined in software programs at the pharmacy department, even though the degree of adhesion degree was not quantitized. They also allowed a validation of all medical prescriptions by a pharmacist before dispensation. The total number of errors detected during the study period was 86. Error opportunities were 26,695, and the overall error index was 0.32%. During the study an error occurred every 312.5 error opportunities.

The effect of short-photoperiod exposure on tuberoinfundibular dopamine neurons in male and female Syrian hamsters.

In male hamsters, exposure to a short photoperiod results in a significant decrease in median eminence (ME) dopamine (DA) concentrations. The mechanism responsible for this decrease in DA is unknown. The experiments described in this paper were designed to examine the effects of photoperiod on DA metabolism and synthesis in the ME to determine if a change in these processes is responsible for the short-photoperiod-induced decrease in ME DA concentrations. In the first experiment, the metabolism of DA in tuberoinfundibular dopamine (TIDA) neuronal terminals was determined by measuring ME concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC; a major metabolite of DA) and DA in male and female hamsters housed in long and short photoperiods. In both males and females, exposure to the short photoperiod induced a collapse of the reproductive system and a reduction in circulating prolactin. In males, but not in females, exposure to the short photoperiod reduced ME DA concentrations; however, DOPAC concentrations were not affected by photoperiod. Thus, the decrease in ME DA seen in males is not the result of an increase in DA metabolism. In the second experiment, tyrosine hydroxylase (TH) activity in the ME of males was determined by injecting animals housed in long and short photoperiods with a L-aromatic amino acid decarboxylase inhibitor (NSD 1015) and measuring 3,4-dihydroxyphenylalanine (DOPA). Consistent with Experiment 1, ME DA concentrations were significantly decreased in gonadally regressed males housed in a short photoperiod; however, ME DOPA accumulation was not affected. Thus, the observed decrease in DA is not the result of a decrease in TH activity in the ME. The results of the experiments presented here indicate that (1) in males but not females, the decrease in circulating prolactin seen in animals housed in a short photoperiod for 12 weeks is associated with a decrease in ME DA concentrations, and (2) the decrease in ME DA seen in males housed in a short photoperiod is not the result of an increase in DA metabolism or a decrease in synthesis by TIDA neurons.

[Interpretation of basic urinalysis in athletes]. / Interpretación del análisis básico de orina en el deportista.

Basic urinalysis is a quick and easy method to obtain diagnostic information on diseases that primarily affect the urinary system. However, performing intense physical exercise by healthy individuals can cause changes in various organs, particularly in the urinary tract. Hematuria and proteinuria are abnormalities commonly found after sports activity, This phenomenon can occur in non-contact sports as well as in contact sports. It is important to differentiate between benign alterations in sports practice and true pathological conditions, excluding misdiagnosis of kidney or lower urinary tract disease.

Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders.

Generalized peroxisomal disorders are severe congenital diseases that involve the central nervous system, leading to severe psychomotor retardation, retinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristically, plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids (VLCFAs) are affected. We found that patients with generalized peroxisomal disorders have a profound brain deficiency of docosahexaenoic acid (DHA; 22:6n-3) and low DHA concentrations in all tissues and the blood. Given the fundamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therapeutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl ester (DHA-EE) because of its high degree of purity at daily oral doses of 100-500 mg. This article summarizes the results of treatment of 13 patients with DHA-EE, with some follow-up evidence of clinical improvement. Supplementation with DHA-EE normalized blood DHA values within a few weeks. Plasmalogen concentrations increased in erythrocytes in most patients and after DHA concentrations were normalized, amounts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal in most cases. From a clinical viewpoint, most patients showed improvement in vision, liver function, muscle tone, and social contact. In 3 patients, normalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progressing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recommended, not only to alleviate symptoms in patients with life-threatening diseases, but also to clarify remaining questions regarding the role of DHA in health and disease.

Extinction of cocaine self-administration produces a differential time-related regulation of proenkephalin gene expression in rat brain.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.