OptiPharm: An evolutionary algorithm to compare shape similarity.

Virtual Screening (VS) methods can drastically accelerate global drug discovery processes. Among the most widely used VS approaches, Shape Similarity Methods compare in detail the global shape of a query molecule against a large database of potential drug compounds. Even so, the databases are so enormously large that, in order to save time, the current VS methods are not exhaustive, but they are mainly local optimizers that can easily be entrapped in local optima. It means that they discard promising compounds or yield erroneous signals. In this work, we propose the use of efficient global optimization techniques, as a way to increase the quality of the provided solutions. In particular, we introduce OptiPharm, which is a parameterizable metaheuristic that improves prediction accuracy and offers greater computational performance than WEGA, a Gaussian-based shape similarity method. OptiPharm includes mechanisms to balance between exploration and exploitation to quickly identify regions in the search space with high-quality solutions and avoid wasting time in non-promising areas. OptiPharm is available upon request via email.

Overflow of dopamine and cholecystokinin in rat nucleus accumbens in response to acute drug administration.

Cholecystokinin octapeptide (CCK-8) coexists with dopamine (DA) in rat mesencephalic neurons that project to the nucleus accumbens. To obtain indices of corelease, microdialysis probes were placed in the posterior nucleus accumbens of anesthetized rats, which were then injected acutely (s.c.) with drugs that exert known effects on DA neuronal function. Microdialysis samples were assayed for DA and CCK-8 to determine the differential overflow of these cotransmitters in response to drug treatment. Haloperidol (0.5 mg/kg), d-amphetamine (1 mg/kg), and TCP (5 mg/kg) preferentially increased DA overflow, whereas morphine (5 mg/kg) elicited marked increases in the overflow of both DA and CCK-8. These results suggest that the release of accumbal DA and CCK-8 can be differentially regulated by drug treatment.

[Mumps epidemic in the health area of Toledo with immunization intervention. Estimation of vaccine effectiveness]. / Epidemia de parotiditis en el área sanitaria de Toledo con intervención mediante inmunización. Estimación de la efectividad de la vacuna.

BACKGROUND: The aim of this study was to describe a mumps epidemic occurred among school children in Toledo, Spain, between 1993 and 1994 were vaccination was undertaken as control measure, and to estimate vaccine efficacy under field conditions. MATERIAL AND METHODS: Attack rates for vaccinated (at 15 months of age) and unvaccinated population were calculated. A retrospective cohort study was designed to estimate vaccine efficacy. RESULTS: A total of 19 outbreaks in different schools were declared. 216 cases and 4,059 contacts, between 10-17 years old, were investigated. The attack rate for the school population was 5.3%. By age, the highest attack rate was for those in the 12-13 age group (7.9%). Estimated vaccine efficacy was 76% (95% confidence interval 66-87%) for the whole study population: For children among 10-13 years old it was 87% (95% confidence interval 76-93%), and 46% (95% confidence interval 20-70%) for those aged 14-17 years. CONCLUSIONS: Vaccination is a good control measure in mumps outbreaks (the attack rate for the study population was 5.1%). Vaccine efficacy was high for the 10-13 age group and in agreement with the results of seroepidemiological studies.

Homologous conditioned medium enhances expression of TRH in hypothalamic neurons in primary culture.

Primary cultures of hypothalamic cells maintained in the presence of serum were either kept with homologous conditioned medium (CM) (i.e. only half of the medium was removed at each medium change) or without (total medium change). In cultures with homologous CM, TRH levels were increased. The effects of CMs from various intervals of the primary culture were tested. The strongest increases of TRH levels were obtained with CM from cultures enriched with hypothalamic glia.

[Study of 2 food poisoning outbreaks in Mora (Toledo) with the same source of infection]. / Investigación de dos brotes de toxiinfección alimentaria en Mora (Toledo) con una fuente de infección común.

BACKGROUND: The occurrence of an outbreak needs an immediate investigation, because on it depends the necessary measures to control the spread of the epidemic, and it is also the way of knowing the causal factor. We present the results of the investigation of two food poisoning outbreaks (outbreak A and outbreak B) occurred in Mora (Toledo). Both outbreaks were reported at the same time, the source of infection was the same and the total number of exposed people was 620. METHODS: A case-control study was carried out. A standardised questionnaire for food poisoning outbreaks was used to collect the data. Data were analysed using classic methods and also logistic regression models. RESULTS: A total of 236 individuals were interviewed (119 for outbreak A and 117 for outbreak B), 146 of them were cases (73 in each outbreak). The mean incubation period was of 26.18 (+/- 12.35) and 25.2 (+/- 19.9) hours respectively. The main symptoms were diarrhoea, fever and abdominal pain. The mean age of the cases was 43.42 (+/- 17.03) years old for outbreak A and 42.4 (+/- 19.9) for outbreak B. The statistical analysis showed a significant association between the intake of cake and the disease (adjusted odds ratio = 25.00; 95% confidence interval = 6,4996.15 for outbreak A and adjusted odds ratio = 64.62; 95% confidence interval = 8.10-515.3 for outbreak B). We also obtained a laboratory confirmation showing the presence of Salmonella Entérica I, Infantis 6.7:r:1.5 in samples of cases, cake and samples of the person who prepared the cake. CONCLUSIONS: The logistic regression model, used for the analysis was useful to detect and summarise data in a more efficient manner than simple stratified analysis. The collaboration of the Primary Health Care professionals contributed to the success of the investigation.

In vitro TRH release from hypothalamus slices varies during the diurnal cycle.

We have previously described a daily rhythm in thyrotropin releasing hormone (TRH) and TRH mRNA in the rat hypothalamus. To determine whether TRH release fluctuates in a diurnal manner, we have measured basal and potassium stimulated release from hypothalamic slices, and compared it to release from olfactory bulb slices, during the diurnal cycle. Basal TRH release was higher at 7:00 h than at any other time (1:00, 13:00 or 19:00 h) in either hypothalamus or olfactory bulb. The ratio of stimulated over basal release was higher in the hypothalamus at 19:00 h, when TRH content was highest. Potassium stimulated TRH release from olfactory bulb was not different from basal release at any time. TRH release fluctuations were not due to a rhythm of extracellular inactivation: the activity of pyroglutamyl aminopeptidase II, an ectoenzyme responsible for TRH inactivation, was constant throughout the cycle. Our data demonstrate that diurnal variations of TRH release occur in vitro and that the enhanced responsiveness to potassium stimulation in hypothalamus is correlated with increased levels of peptide.

Suckling and cold stress rapidly and transiently increase TRH mRNA in the paraventricular nucleus.

Thyrotropin releasing hormone (TRH) is released from the median eminence in response to neural stimuli evoked by different physiologic conditions (i.e. cold stress or suckling). The paraventricular nucleus (PVN) synthesizes pro-TRH and responds to negative thyroid hormone feedback. With the aim of determining if TRH biosynthesis is regulated in coordination with its release, we quantified TRH mRNA levels in PVN and in preoptic area-anterior hypothalamus (POA-AH) of rats sacrificed at different times during cold (0.5, 1, 2 or 6 h) or suckling (15, 30 and 60 min) stimulus; TRH-like immunoreactivity (TRH-LI) in medial basal hypothalamus (MBH) and in POA-AH as well as corticosterone, triiodothyronine and prolactin levels in serum were also measured. Increases of serum hormones were observed in both paradigms as has been reported. MBH TRH-LI content decreased during suckling by 33% (p < 0.01) after 1 h, but did not change after cold stimulation. At short stimulation times, PVN TRH mRNA levels were 85% (30 min of suckling) and 97% (1 h in the cold) higher than their respective controls, decreasing to normal after 1-2 h. In the POA-AH, another TRH synthesizing region not involved in TRH hypophysiotropic function, a similar transient enhancement of TRH mRNA (146%) was observed only in cold stimulated animals after 30 min, consistent with its suggested role in thermogenesis. These results show a fast and transient response of TRH mRNA in PVN evoked by a neural stimulus.

Pre-natal development of the adrenal gland in the mallard duck (Anas platyrhynchos).

The differentiating nephrotome in the 10-day-old mallard duck embryo is able to synthesize corticosterone, aldosterone and deoxycorticosterone even though an adrenal anlage cannot be identified histologically until the 12th day of incubation. At this time, sudanophilic cells containing much smooth endoplasmic reticulum and numerous mitochondria with tubular cristae are located adjacent to the developing mesonephros. Chromaffin cells appear in this region on about the 14th day of embryogenesis. A discrete glandular structure containing measurable quantities of corticosteroids can be identified on the 15th day, and during the next 2 days the tissue becomes encapsulated. Concomitantly, the ACTH-inducible rates of corticosteroid hormone synthesis increase several fold. The corticotropic responsiveness of the developing adrenal steroidogenic tissue increases progressively during the remainder of embryogenesis.

Changes in the adrenal steroidogenic responsiveness of the mallard duck (Anas platyrhynchos) during early post-natal development.

1. Plasma concentrations of corticosterone (B), aldosterone (Aldo) and deoxycorticosterone (DOC) were measured in mallard ducklings immediately before and after exposure to acute immobilization stress. 2. Except for transient declines in B and DOC between the 4th and 14th days after hatching, the resting concentration of each hormone did not change significantly during post-natal development. 3. The stress-induced in Aldo was maximal at hatching while maximal increases in B and DOC did not occur until one day later. 4. Thereafter the magnitude of the stress-induced increases in the concentrations of all of the hormones decreased steadily and on the 21st and 28th days after hatching only B increased significantly in response to stress.

Effects of short-term changes in electrolyte intake on the adrenal steroidogenic responses of juvenile mallard ducks (Anas platyrhynchos).

1. Adjusting the Na+ and K+ intake of juvenile mallard ducks caused the plasma concentrations of corticosterone (B) and aldosterone (Aldo) to increase independently of one another, but none of these changes in electrolyte intake had a significant effect on the deoxycorticosterone (DOC) concentration. 2. With the exception of DOC in birds consuming the control diet, the plasma concentration of each hormone, regardless of diet, increased significantly following exposure to stress. 3. Stress-induced increases in Aldo concentration were greatest in birds given diets containing low concentrations of Na+. 4. Unlike the mammal and some other species of birds, Na+ may be the primary secretagogue responsible for the regulation of both corticosterone and aldosterone synthesis in the mallard duck.