Effects of chronic treatment with valproate on serotonin-1A receptor binding and function

Valproate is effective in treating bipolar disorder characterized by rapid cycling or acute mania, although the mechanism of action is unclear. In contrast to other treatments for depression, 21 days of treatment in rats with valproate (100, 200 or 400 mg/kg) did not significantly alter the hypothermia induced by 8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors. Treatment with valproate also had no effect on radioligand binding to serotonin-1A, serotonin-2 or -adrenergic receptors. Based on these animal studies in frontal cortex and hippocampus, the therapeutic benefit of valproate in mood disorders does not appear to involve adaptive changes in serotonin-1A, serotonin-2 or -adrenergic receptor number.     

Customer exposure to MTBE, TAME, C6 alkyl methyl ethers, and benzene during gasoline refueling.

We studied customer exposure during refueling by collecting air samples from customers' breathing zone. The measurements were carried out during 4 days in summer 1996 at two Finnish self-service gasoline stations with "stage I" vapor recovery systems. The 95-RON (research octane number) gasoline contained approximately 2.7% methyl tert-butyl ether (MTBE), approximately 8.5% tert-amyl methyl ether (TAME), approximately 3.2% C6 alkyl methyl ethers (C6 AMEs), and 0.75% benzene. The individual exposure concentrations showed a wide log-normal distribution, with low exposures being the most frequent. In over 90% of the samples, the concentration of MTBE was higher (range <0.02-51 mg/m3) than that of TAME. The MTBE values were well below the short-term (15 min) threshold limits set for occupational exposure (250-360 mg/m3). At station A, the geometric mean concentrations in individual samples were 3.9 mg/m3 MTBE and 2. 2 mg/m3 TAME. The corresponding values at station B were 2.4 and 1.7 mg/m3, respectively. The average refueling (sampling) time was 63 sec at station A and 74 sec at station B. No statistically significant difference was observed in customer exposures between the two service stations. The overall geometric means (n = 167) for an adjusted 1-min refueling time were 3.3 mg/m3 MTBE and 1.9 mg/m3 TAME. Each day an integrated breathing zone sample was also collected, corresponding to an arithmetic mean of 20-21 refuelings. The overall arithmetic mean concentrations in the integrated samples (n = 8) were 0.90 mg/m3 for benzene and 0.56 mg/m3 for C6 AMEs calculated as a group. Mean MTBE concentrations in ambient air (a stationary point in the middle of the pump island) were 0.16 mg/m3 for station A and 0.07 mg/m3 for station B. The mean ambient concentrations of TAME, C6 AMEs, and benzene were 0.031 mg/m3, approximately 0.005 mg/m3, and approximately 0.01 mg/m3, respectively, at both stations. The mean wind speed was 1.4 m/sec and mean air temperature was 21 degreesC. Of the gasoline refueled during the study, 75% was 95 grade and 25% was 98/99 grade, with an oxygenate (MTBE) content of 12.2%.     

Estrogen-regulated non-reproductive behaviors and breast cancer risk: Animal models and human studies

The possible role of personality patterns and psychosocial factors in breast cancer has been studied extensively, through both human and animal experiments. The data are conflicting, and the conclusions controversial. This review will serve two purposes. First, we present evidence that behavioral patterns most commonly linked to breast cancer risk are at least partly regulated by estrogens. This section will suggest that some estrogen-regulated behaviors may be markers of increased breast cancer risk. Second, we will briefly review recent findings in animals connecting psychosocial factors to cancer. We also will address the plausible biological mechanisms. The literature suggests that estrogens, particularly when exposure occurs during the critical developmental periods, such as in utero, puberty, pregnancy, and menopause, influence affective behaviors and increase breast cancer risk. The affective behaviors include depression, aggression, and alcohol intake. Thus, psychosocial and personality factors do not necessarily have a direct impact on breast cancer risk; instead, estrogens have a dual effect on behavior and on the breast.     

Botulinum toxin injection as an adjunct when planning hand surgery in children with spastic hemiplegia

The usefulness of botulinum toxin A treatment when planning hand surgery in eight children with spastic hemiplegia was evaluated. The hand function of the children was assessed before and after treatment using a test battery consisting of quantitative and qualitative functional assessment. The results of preoperative botulinum treatment supported surgical intervention in four children and serial botulinum treatment in three children. In one child, the preoperative botulinum treatment provided no additional information. We conclude that preoperative botulinum A treatment in most children with spastic hemiplegia, for whom hand surgery is being considered, identifies the patients who would not benefit from the planned surgery or for whom the functional benefit would probably not outweigh the burden of surgical procedure and postoperative rehabilitation.     

Chlamydial antibodies and risk of prostate cancer.

OBJECTIVE: We assessed the risk of prostate cancer by exposure to Chlamydia trachomatis. METHOD: Seven hundred thirty eight cases of prostate cancer and 2,271 matched controls were identified from three serum sample banks in Finland, Norway, and Sweden by linkage to the population based cancer registries. RESULTS: A statistically significant inverse association (odds ratio, 0.69; 95% confidence interval, 0.51-0.94) was found. It was consistent by different serotypes and there was a consistent dose-response relationship. CONCLUSION: C. trachomatis infection is not likely to increase the risk of prostate cancer. Whether the inverse relationship is true or due to difficulties in measuring the true exposure in prostatic tissue by serology, confounders or other sources of error remain open.     

A combined analysis of genome-wide association studies in breast cancer

In an attempt to identify common disease susceptibility alleles for breast cancer, we performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls. Tests for association were performed for 285,984 SNPs. Evidence for association with SNPs in genes in specific pathways was assessed using a permutation-based approach. We confirmed associations with loci reported by previous GWAS on 1p11.2, 2q35, 3p, 5p12, 8q24, 10q23.13, 14q24.1 and 16q. Six SNPs with the strongest signals of association with breast cancer, and which have not been reported previously, were typed in two further studies; however, none of the associations could be confirmed. Suggestive evidence for an excess of associations was found for genes involved in the regulation of actin cytoskeleton, glycan degradation, alpha-linolenic acid metabolism, circadian rhythm, hematopoietic cell lineage and drug metabolism. Androgen and oestrogen metabolism, a pathway previously found to be associated with the development of postmenopausal breast cancer, was marginally significant (P = 0.051 [unadjusted]). These results suggest that further analysis of SNPs in these pathways may identify associations that would be difficult to detect through agnostic single SNP analyses. More effort focused in these aspects of oncology can potentially open up promising avenues for the understanding of breast cancer and its prevention.     

Patulin Detoxification by Recombinant Manganese Peroxidase from Moniliophthora roreri Expressed by Pichia pastoris

The fungal secondary metabolite patulin is a mycotoxin widespread in foods and beverages which poses a serious threat to human health. However, no enzyme was known to be able to degrade this mycotoxin. For the first time, we discovered that a manganese peroxidase (MrMnP) from Moniliophthora roreri can efficiently degrade patulin. The MrMnP gene was cloned into pPICZα(A) and then the recombinant plasmid was transformed into Pichia pastoris X-33. The recombinant strain produced extracellular manganese peroxidase with an activity of up to 3659.5 U/L. The manganese peroxidase MrMnP was able to rapidly degrade patulin, with hydroascladiol appearing as a main degradation product. Five mg/L of pure patulin were completely degraded within 5 h. Moreover, up to 95% of the toxin was eliminated in a simulated patulin-contaminated apple juice after 24 h. Using Escherichia coli as a model, it was demonstrated that the deconstruction of patulin led to detoxification. Collectively, these traits make MrMnP an intriguing candidate useful in enzymatic detoxification of patulin in foods and beverages.     

Integration of ER protein quality control mechanisms defines β cell function and ER architecture

Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.     

A rare case of metastatic pancreatic adenocarcinoma presenting as a pulmonary embolism from nonbacterial thrombotic endocarditis

Nonbacterial thrombotic endocarditis (NBTE) also called, "Marantic endocarditis" occurs due to an underlying hypercoagulable state causing tissue damage and upregulation of the coagulation cascade, with noninfective vegetation formation on heart valves. Mitral and aortic valves are most commonly involved. NBTE is rare, with an incidence of 1.6%, with 65 cases identified during a 10-year autopsy analysis. The most common malignancies associated with NBTE include gynecological cancers, lung cancer, gastric cancer, and pancreatic cancers with adenocarcinoma histology being the greatest risk. Herein, we present a rare case of a 55-year-old male who presented with acute hypoxic respiratory failure secondary to pulmonary embolism due to nonbacterial thrombotic endocarditis. He was found to have advanced pancreatic adenocarcinoma on further investigation of the 2.2 cm hypodense cystic mass in the distal pancreatic body and tail, and complex liver masses which were incidentally found on computed tomography angiography (CTA) of the chest. This is a rare phenomenon and clinicians have to consider the hypercoagulable state associated with cancers, particularly pancreatic adenocarcinoma, and the risk of NBTE.