Persistent organic pollutants have dose and CAG repeat length dependent effects on androgen receptor activity in vitro

Recently, the effect of exposure to persistent organic pollutants (POPs) on sperm concentration was only seen in men with a short androgen receptor (AR) gene CAG repeat. In order to investigate whether these effects could be observed also in vitro, we tested the impact of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (4,4′-DDE) on 5α-dihydrotestosterone activated ARs containing 16, 22 and 28 CAG repeats, respectively. Single exposure to 4,4′-DDE had the most pronounced effect on the AR activity containing 16 CAG repeats, whereas 28 CAG was the most sensitive variant when a mixture of the two compounds was added. Thus, our in vitro results have confirmed the in vivo data indicating a CAG repeat length dependent effect of endocrine disrupters on the AR activity.     

Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (∼30%) and slow onset of action (2–4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3–5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.     

Predicting the Effects of Anti-angiogenic Agents Targeting Specific VEGF Isoforms

Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, whose effect on cancer growth and development is well characterized. Alternative splicing of VEGF leads to several different isoforms, which are differentially expressed in various tumor types and have distinct functions in tumor blood vessel formation. Many cancer therapies aim to inhibit angiogenesis by targeting VEGF and preventing intracellular signaling leading to tumor vascularization; however, the effects of targeting specific VEGF isoforms have received little attention in the clinical setting. In this work, we investigate the effects of selectively targeting a single VEGF isoform, as compared with inhibiting all isoforms. We utilize a molecular-detailed whole-body compartment model of VEGF transport and kinetics in the presence of breast tumor. The model includes two major VEGF isoforms, VEGF(121) and VEGF(165), receptors VEGFR1 and VEGFR2, and co-receptors Neuropilin-1 and Neuropilin-2. We utilize the model to predict the concentrations of free VEGF, the number of VEGF/VEGFR2 complexes (considered to be pro-angiogenic), and the receptor occupancy profiles following inhibition of VEGF using isoform-specific anti-VEGF agents. We predict that targeting VEGF(121) leads to a 54% and 84% reduction in free VEGF in tumors that secrete both VEGF isoforms or tumors that overexpress VEGF(121), respectively. Additionally, 21% of the VEGFR2 molecules in the blood are ligated following inhibition of VEGF(121), compared with 88% when both isoforms are targeted. Targeting VEGF(121) reduces tumor free VEGF and is an effective treatment strategy. Our results provide a basis for clinical investigation of isoform-specific anti-VEGF agents.     

Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients

BackgroundTherapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients.MethodsOne hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA (rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone givenasmonotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2.ResultsThe three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment.ConclusionsThe present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients.     

Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle‐Aged and Elderly Men: Results From the European Male Aging Study (EMAS)

Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle‐aged and elderly European men. Men 40–79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 ± 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 ± 18.9 dB/Mhz, SOS was 1550.2 ± 34.1 m/s, and BMD was 0.542 ± 0.141 g/cm². Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (β =?0.016, p = ?0.005) and homozygotes (β = ?0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.     

Isolated Flinders Sensitive Line rats have decreased dopamine D2 receptor mRNA

Social isolation has profound effects on animal behavior and dopamine systems. We investigated the effect of social isolation on the dopamine receptor and neuropeptide mRNAs in the brain reward system in an animal model of depression, the Flinders Sensitive Line rats and Sprague-Dawley controls. We demonstrate that socially isolated but not group housed Flinders sensitive line rats had lower dopamine D2 receptor mRNA levels compared with Sprague-Dawley rats. Isolated and group housed Flinders Sensitive Line rats had higher levels of dopamine D1 receptor and substance P and enkephalin but not dynorphin mRNAs when compared with Sprague-Dawley rats. Our findings of decreased dopamine D2 receptor levels in socially isolated Flinders Sensitive Line rats suggest that low D2 receptor expression may play a role in pathophysiology of depression.     

The first record of Elaphostrongylus alces larvae in moose in Poland and their development to the invasive stage

BACKGROUND: This is the first record of the first stage larvae of Elaphostrongylus alces in moose in Poland. MATERIAL AND METHODS: The 75 faecal samples (5 g) from moose in Kampinos National Park were examined using Baermann method. RESULTS: The prevalence of E. alces larvae in feaces samples was 37%. The maximal intensity reached 294 larvae. 20 larvae of the first stage and 27 larvae of the third stage were measured. The comparison of their dimensions with the results obtained by Lankester, shows that they represent E. alces.     

Radioimmunotherapy in follicular lymphomas, a retrospective analysis of the Polish Lymphoma Research Group's (PLRG) experience

BACKGROUND: Ibritumomab is an (90)Yttrium ((90)Y) labelled radioimmunoconjugate registered to treat follicular lymphoma relapsing or refractory after Rituximab therapy. Combining the specificity of anti CD20 monoclonal antibodies with the efficacy of radiotherapy, it is particularly effective in patients with advanced stages of disease with generalized lymphadenopathy. MATERIAL AND METHODS: Twenty-one patients with follicular lymphoma, after failing 2-5 lines of previous treatment, were subjected to radioimmunotherapy in three Polish Lymphoma Research Group (PLRG) centres. Ibritumomab infusion was followed by 2 doses of Rituximab (250 mg/m(2) at day -7 and 0) to enhance its biodistribution. Radioimmunoconjugate was prepared in the Nuclear Medicine Departments of participating centres based on patient weight and full blood count results (14.8 MBq/kg, max 1200 MBq, reduced to 11.1 MBq/kg in cases with blood platelet 100,000-150,000 or leukocytes 1500-2000). 14.8 MBq/kg (0.4 mCi/kg) 100 thousand to 149 thousand/mm(3) platelets 11.1 MBq/kg (0.3 mCi/kg) RESULTS: The primary endpoint of the study was the assessment of response rate and haematological toxicity. Objective responses were observed in all patients, with 10 partial and 12 complete regressions. Cytopenia, starting 3-4 weeks after radioimmunotherapy, reflected haematological toxicity - the only important side effect. Thrombocytopenia was more pronounced, with platelet counts of < 50,000/ul in every second patient. One patient developed myelodysplastic syndrome 21 months after the procedure. After the medium time of follow up over 2 years, 2 patients died. Median progression free survival (secondary study endpoint) was 15 months. CONCLUSIONS: Ibritumomab radioimmunotherapy is an efficient method of palliation treatment of heavily pre-treated follicular lymphoma patients, failing numerous previous treatment lines. Earlier application increases the number of complete responses and prolongs progression free survival.