Cue and Reward Evoked Dopamine Activity Is Necessary for Maintaining Learned Pavlovian Associations

Associating natural rewards with predictive environmental cues is crucial for survival. Dopamine (DA) neurons of the ventral tegmental area (VTA) are thought to play a crucial role in this process by encoding reward prediction errors (RPEs) that have been hypothesized to play a role in associative learning. However, it is unclear whether this signal is still necessary after animals have acquired a cue-reward association. In order to investigate this, we trained mice to learn a Pavlovian cue-reward association. After learning, mice show robust anticipatory and consummatory licking behavior. As expected, calcium activity of VTA DA neurons goes up for cue presentation as well as reward delivery. Optogenetic inhibition during the moment of reward delivery disrupts learned behavior, even in the continued presence of reward. This effect is more pronounced over trials and persists on the next training day. Moreover, outside of the task licking behavior and locomotion are unaffected. Similarly to inhibitions during the reward period, we find that inhibiting cue-induced dopamine (DA) signals robustly decreases learned licking behavior, indicating that cue-related DA signals are a potent driver for learned behavior. Overall, we show that inhibition of either of these DA signals directly impairs the expression of learned associative behavior. Thus, continued DA signaling in a learned state is necessary for consolidating Pavlovian associations.SIGNIFICANCE STATEMENT Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been suggested to be necessary for animals to associate environmental cues with rewards that they predict. Here, we use time-locked optogenetic inhibition of these neurons to show that the activity of these neurons is directly necessary for performance on a Pavlovian conditioning task, without affecting locomotor per se These findings provide further support for the direct importance of second-by-second DA neuron activity in associative learning.     

The study of MED12 gene mutations in uterine leiomyomas from Iranian patients

Tumor Biology - Uterine leiomyomas are the most common gynecologic benign tumors of the female genital tract that cause a variety of health problems including, abnormal menstrual bleeding, pelvic...     

Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects

Methimazole is an oral antithyroid compound that exhibits a skin-depigmenting effect when used topically. However, the effect of topical methimazole on thyroid function has not been reported. This study was aimed at assessing the safety of topical methimazole used to treat pigmented lesions, without affecting thyroid hormones due to systemic delivery. The pharmacokinetics of methimazole, either applied in the form of a 5% topical formulation to facial skin or taken orally in the form of a 5-mg tablet by 6 volunteers, were determined. In addition, the effect of long-term topical applications of 5% methimazole on the function of the thyroid gland in 20 patients with epidermal melasma was determined following 6 weeks of once-daily application. Cutaneous adverse effects of topical methimazole were determined. From 15 min up to 24 h after application, methimazole was undetectable in the serum of the individuals receiving single topical methimazole dosing. Methimazole, however, was detected in serum after 15 min of oral administration and remained detectable in serum up to 24 h after administration. Long-term topical methimazole applications in melasma patients did not induce any significant changes in serum TSH, free thyroxine and free triiodothyronine levels. Topical methimazole was well tolerated by the patients and did not induce any significant cutaneous side effects. Present data together with the previously shown non-cytotoxic and non-mutagenic characteristics of methimazole indicate that this agent could be considered as a safe skin-depigmenting compound for topical treatment of skin hyperpigmentary disorders in humans.     

Comparison of Contamination Passing Through Iranian and Non- Iranian Filters of Ultra Filtration Dialysis Machines in Patients With Hepatitis C

Background

Hepatitis C is one of the common infectious diseases throughout the world. About 170 million people worldwide are infected with Hepatitis C virus. The most common route of transmission is direct blood-to-blood contacts.

Objectives

This study conducted to compare the amount of contamination might be found in ultra-filtered liquid passed through 2 kinds of filters ps10 (Mediatex, Iran) and Lups (Bio brand, Germany).

Patients and Methods

To achieve the goal, infected dialysis patients in which hepatitis C virus infection was detected by Elisa and PCR were selected.

Results

As shown in data the first stage of PCR test using ps10 filters all samples were negative. In the second step performed in later dialysis steps (with Lups filters), no infection was recorded, too.

Conclusions

Our results showed that dialysis machines do not have an important role in transmission of hepatitis C infection and sanitation control in the environment of dialysis should be emphasized.     

Sambucus ebulus extract stimulates cellular responses in cutaneous leishmaniasis

This is the first study aiming to determine the therapeutic effects of the Sambucus ebulus aquatic extract as an antileishmanial herbal drug and evaluate the immune responses in Leishmania major major infected BALB/c mice. The antileishmanial activity of S ebulus aquatic extract was evaluated using MTT test as well as parasite rescue and transformation assay. Footpad swelling and parasite load of infected mice were measured by several techniques. The immune responses were evaluated by measuring the levels of IFN‐γ, IL‐4, nitric oxide and arginase. The results indicated that S. ebulus can significantly decrease L. major promastigotes and amastigotes viability, but it was not toxic to macrophages. The lesion size, parasite burden and the level of ARG decreased in the treated infected mice, while the IFN‐γ‐to‐IL‐4 ratio and the level of NO increased significantly. Altogether, the S. ebulus extract is an effective compound for killing Leishmania parasite without excessive toxicity to the host cells and can cure the CL by switching the host immune responses towards Th1 response. Thus, it may be a perfect therapeutic option for CL treatment.     

Ebselen is a new skin depigmenting agent that inhibits melanin biosynthesis and melanosomal transfer

We assessed the ability of ebselen, a glutathione peroxidase mimic, to reduce pigmentation in various models. In murine B16 melanocytes, 25 μm ebselen inhibited melanogenesis and induced a depolymerisation of actin filaments. In co-cultures of B16 melanocytes with BDVII keratinocytes, a pretreatment of melanocytes with ebselen resulted in a strong inhibition of melanosome transfer to keratinocytes, as shown under optical and electron microscopy. In reconstructed epidermis, topical 0.5% ebselen led to a twofold decrease of melanin without affecting the density of active melanocytes. A similar result was obtained with topical 0.5% ebselen in black guinea pig ears. Ebselen induced a decrease of epidermal melanin parallel to a localisation of melanin and melanosomes in the basal layer. Ebselen appears as a new depigmenting compound that inhibits melanin synthesis and melanosome transfer to keratinocytes.     

Should we think of Urbach-Wiethe disease in refractory epilepsy? Case report and review of the literature

Urbach-Wiethe disease (UWD) is an autosomal recessive disease characterized by both neurological and dermatological manifestations. Face specially eyelids are commonly involved. Alopecia, nail dystrophy and dental anomalies have been reported as less frequent symptoms. Some patients show evidences of epilepsy and psychiatric symptoms such as schizophrenia, mood disorders, and anxiety due to calcium deposits in different parts of the brain. In this report, we describe the case of a young woman affected by UWD presenting with neurological involvements and no dermatological manifestations. This patient is a unique case of UWD as she has partial seizures and hoarseness. Also we summarize relevant data from the literature.     

17-β-hydroxysteroid dehydrogenase type 3 deficiency in three adult Iranian siblings

17-β-hydroxysteroid dehydrogenase type 3 (17-β-HSD 3) deficiency is an autosomal recessive form of 46,XY disorder of sex development (DSD). To date, a total of 27 HSD17B3 gene mutations have been described in 46,XY patients exhibiting different phenotypes at birth and virilization at puberty, sometimes in association with gynecomastia. Herein, we investigate the 46,XY DSD in an Iranian family consisting of 7 siblings, 3 of which are affected and virilized at puberty. We clinically characterized these patients and performed direct DNA sequencing of the steroid 5-α-reductase type 2 (SRD5A2) and the HSD17B3 gene, respectively. We identified a homozygous mutation in the HSD17B3 gene (R80W; c.238C>G) in all affected siblings. No mutation was detected in the SRD5A2 gene. The detected mutation in the HSD17B3 gene was previously described in a newborn child, who died from other congenital malformations, and in a 12-year-old girl. Hence, our report adds novel value to the phenotype classification of 17-β-HSD 3 deficiency.     

5-Nitroimidazole-based 1,3,4-thiadiazoles: heterocyclic analogs of metronidazole as anti-Helicobacter pylori agents

A series of 5‐nitroimidazole‐based 1,3,4‐thiadiazoles were prepared and tested for antibacterial activity against Helicobacter pylori. The anti‐H. pylori activity of target compounds along with the commercially available antimicrobial metronidazole was evaluated by comparing the inhibition‐zone diameters determined by the paper disc diffusion bioassay. From our bioassay results against 20 clinical isolates it is evident that piperazinyl, 4‐methylpiperazinyl, 3‐methylpiperazinyl, and 3,5‐dimethylpiperazinyl analogs ( 6a , 6b , 6e , and 6f , respectively) and pyrrolidine derivative 7 had strong activity at 0.5 µg/disc (average of inhibition zone >20 mm) while metronidazole had no activity at this dose. Compound 6f containing the 3,5‐dimethylpiperazinyl moiety at the 2‐position of the 5‐(1‐methyl‐5‐nitro‐1H‐imidazol‐2‐yl)‐1,3,4‐thiadiazole skeleton was the most potent compound tested at low concentrations.