Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow

We review modeling of astrocyte ion dynamics with a specific focus on the implications of so-called spatial potassium buffering, where excess potassium in the extracellular space (ECS) is transported away to prevent pathological neural spiking. The recently introduced Kirchoff-Nernst-Planck (KNP) scheme for modeling ion dynamics in astrocytes (and brain tissue in general) is outlined and used to study such spatial buffering. We next describe how the ion dynamics of astrocytes may regulate microscopic liquid flow by osmotic effects and how such microscopic flow can be linked to whole-brain macroscopic flow. We thus include the key elements in a putative multiscale theory with astrocytes linking neural activity on a microscopic scale to macroscopic fluid flow.Comment: 27 pages, 7 figure

Neogenin expression may be inversely correlated to the tumorigenicity of human breast cancer

BACKGROUND: Neogenin is expressed in cap cells that have been suggested to be mammary stem or precursor cells. Neogenin is known to play an important role in mammary morphogenesis; however its relationship to tumorigenesis remains to be elucidated. METHODS: To compare the expression levels of neogenin in cells with different tumorigenicity, the expression levels in M13SV1, M13SV1R2 and M13SV1R2N1 cells, which are immortalized derivatives of type I human breast epithelial cells, were evaluated. Then we measured the expression level of neogenin in paired normal and cancer tissues from eight breast cancer patients. Tissue array analysis was performed for 54 human breast tissue samples with different histology, and the results were divided into four categories (none, weak, moderate, strong) by a single well-trained blinded pathologist and statistically analyzed. RESULTS: The nontumorigenic M13SV1 cells and normal tissues showed stronger expression of neogenin than the M13SV1R2N1 cells and the paired cancer tissues. In the tissue array, all (8/8) of the normal breast tissues showed strong neogenin expression, while 93.5% (43/46) of breast cancer tissues had either no expression or only moderate levels of neogenin expression. There was a significant difference, in the expression level of neogenin, in comparisons between normal and infiltrating ductal carcinoma (p < 0.001). CONCLUSION: Neogenin may play a role in mammary carcinogenesis as well as morphogenesis, and the expression may be inversely correlated with mammary carcinogenicity. The value of neogenin as a potential prognostic factor needs further evaluation

Conservation Patterns of HIV-1 RT Connection and RNase H Domains: Identification of New Mutations in NRTI-Treated Patients

Background: Although extensive HIV drug resistance information is available for the first 400 amino acids of its reverse transcriptase, the impact of antiretroviral treatment in C-terminal domains of Pol (thumb, connection and RNase H) is poorly understood. Methods and Findings: We wanted to characterize conserved regions in RT C-terminal domains among HIV-1 group M subtypes and CRF. Additionally, we wished to identify NRTI-related mutations in HIV-1 RT C-terminal domains. We sequenced 118 RNase H domains from clinical viral isolates in Brazil, and analyzed 510 thumb and connection domain and 450 RNase H domain sequences collected from public HIV sequence databases, together with their treatment status and histories. Drug-naıve and NRTI-treated datasets were compared for intra- and inter-group conservation, and differences were determined using Fisher’s exact tests. One third of RT C-terminal residues were found to be conserved among group M variants. Three mutations were found exclusively in NRTI-treated isolates. Nine mutations in the connection and 6 mutations in the RNase H were associated with NRTI treatment in subtype B. Some of them lay in or close to amino acid residues which contact nucleic acid or near the RNase H active site. Several of the residues pointed out herein have been recently associated to NRTI exposure or increase drug resistance to NRTI. Conclusions: This is the first comprehensive genotypic analysis of a large sequence dataset that describes NRTI-related mutations in HIV-1 RT C-terminal domains in vivo. The findings into the conservation of RT C-terminal domains may pave the way to more rational drug design initiatives targeting those regions

WT1 gene expression as a prognostic marker in advanced serous epithelial ovarian carcinoma: an immunohistochemical study

BACKGROUND: WT1 is a tumor suppressor gene responsible for Wilms' tumor. WT1 reactivity is limited to ovarian serous carcinomas. Recent studies have shown that WT1 plays an important role in the progression of disease and indicates a poorer prognosis of human malignancies such as acute myeloid leukemia and breast cancer. The aims of this study were to determine the survival and recurrence-free survival of women with advanced serous epithelial ovarian carcinoma in relation to WT1 gene expression. METHODS: The study accrued women over an 18-year period, from 1987–2004. During the study period, 163 patients were diagnosed with advanced serous epithelial ovarian carcinoma and had undergone complete post-operative chemotherapy, but the final study group comprised 99 patients. The records of these women were reviewed and the paraffin-embedded tissue of these women stained with WT1 immunostaining. Survival analysis was performed using Kaplan-Meier and Cox regression methods. RESULTS: Fifty patients showed WT1 staining and forty-nine did not. Five-year survival of non-staining and staining groups were 39.4% and 10.7% (p < 0.00005); five-year recurrence-free survival of these groups were 29.8% and ≤ 7.5% (p < 0.00005), respectively. For survival the HR of WT1 staining, adjusted for residual tumor and chemotherapy response, was 1.98 (95% CI 1.28–3.79), and for recurrence-free survival the HR was 3.36 (95% CI 1.60–7.03). The HR for recurrence-free survival was not confounded by any other variables. CONCLUSION: This study suggests that expression of WT1 gene may be indicative of an unfavorable prognosis in patients with advanced serous epithelial ovarian carcinoma

The design and protocol of acupuncture for migraine prophylaxis: A multicenter randomized controlled trial

Background: Many studies have already reported encouraging results in the prophylactic therapy of migraine by acupuncture, but there seems to be a lack of high quality randomized controlled trials from China. We design and perform a randomized controlled clinical trial to evaluate the efficacy of acupuncture compared with flunarizine in the prophylactic therapy of patients with migraine without aura in China. Methods: This trial is a multicenter, prospective, randomized controlled clinical trial. The 140 migraine patients are randomly allocated to two different groups. The acupuncture groups (n = 70) is treated with acupuncture and placebo medicine; while the control group (n = 70) is treated with sham acupuncture and medicine (Flunarizine). Both Flunarizine and placebo are taken 10 mg once per night for the first 2 weeks and then 5 mg once per night for the next 2 weeks. Patients in both groups receive 12 sessions of verum/sham acupuncture in 4 weeks. Discussion: The study design and the long term clinical practice of acupuncturists guarantee a high external validity for the results. The results of our trial will be helpful to supply the evidence on the efficacy of acupuncture for migraine prophylaxis in China. Trial Registration: The trial is registered at Controlled Clinical Trials: ISRCTN49839714.Medicine, Research &amp; ExperimentalSCI(E)0ARTICLEnull1

Serum and follicular fluid organochlorine concentrations among women undergoing assisted reproduction technologies

<p>Abstract</p> <p>Background</p> <p>Exposure to persistent organic pollutants, including polychlorinated biphenyls (PCBs) and organochlorine pesticides, is widespread among the general population. There is evidence of adverse effects on reproduction and early pregnancy in relation to organochlorine exposure but human studies remain limited. The increased use of assisted reproductive technologies (ART) presents unique opportunities for the assessment of environmental influences on early pregnancy outcomes not otherwise observable in humans, but studies need to be designed to maximize the efficiency of the exposure data collected while minimizing exposure measurement error.</p> <p>Methods</p> <p>The present study was conducted to assess the correlation between concentrations of organochlorines in serum and follicular fluid samples collected from a subset of women undergoing ART in a large study that took place between 1994 and 2003, as well as the temporal reliability of serum organochlorine concentrations among women undergoing multiple ART cycles in the study. PCB congeners (118, 138, 153, and 180), 1,1,1-trichloro-2,2-bis(<it>p</it>-chlorophenyl)ethane (p,p'-DDT), the DDT metabolite p,p'-DDE, hexachlorobenzene (HCB), oxychlordane, trans-nonachlor and mirex were measured in 72 follicular fluid samples and 265 serum samples collected from 110 women.</p> <p>Results</p> <p>Organochlorine concentrations in paired serum and follicular fluid samples were correlated, with Pearson and Spearman coefficients ranging from 0.60 to 0.92. Serum organochlorine concentrations were two- to three-fold greater than in follicular fluid, and a significant inverse trend was observed in the distribution of follicular fluid:serum ratios with increasing molecular weight of the compound (p-value for trend < 0.0001). Serum organochlorine concentrations were highly reliable over the course of several months, with intraclass correlation coefficients ranging from 0.86 to 0.98. Finally, there was evidence for a declining trend in organochlorine concentrations between samples collected between years 1994–1998 and those collected in 1999–2003.</p> <p>Conclusion</p> <p>Our results support the use of a single serum sample to adequately represent a more biologically relevant dose (concentrations in follicular fluid), as well as exposure levels over time, in epidemiological studies of ART outcomes in relation to organochlorine exposure.</p

Resolving confusions about jarrah dieback - don’t forget the plants

The name jarrah dieback has been used for two different disorders, leading to considerable confusion. It was coined in the 1940s to describe the sudden death of groups of jarrah (Eucalyptus marginata) trees in south western Western Australia, which occurred on poorly drained sites, following exceptionally heavy rainfall. In the 1960s these sites were shown to be infested by Phytophthora cinnamomi and jarrah deaths were attributed to it, even though it was only isolated from 5 % of sampled trees. Also the definition of jarrah dieback was expanded to include deaths of many other plants on infested sites, from which P. cinnamomi was more readily isolated. Jarrah trees die from severe water deficiency, indicating problems with water conduction through roots. Xylem vessel diameters vary along roots, being narrow at the root collar, while distally they are larger, providing water storage. Jarrah transpires vigorously during summer, accessing water at depth on sites with deep soil, but being more dependent on internally stored water when root systems are shallower. Following waterlogging, sapwood vessels become blocked with tyloses, reducing both conductivity and potential water storage; such trees may have insufficient water reserves for summer survival. In jarrah P. cinnamomi is unlikely to cause water deficiency because sapwood invasion is rapidly contained in healthy roots. Recent investigations into P. cinnamomi invasion and host responses in other plants show that it can potentially cause a vascular wilt in Banksia spp. and chronic, symptomless infections in herbaceous plants. Susceptibility to waterlogging damage, and/or mortality resulting from infection by P. cinnamomi can only be clarified by detailed knowledge of the hosts and their vulnerabilities. This is essential for making diagnoses, devising management strategies, and avoiding the confusions of the past

Genome-wide BAC-end sequencing of Cucumis melo using two BAC libraries

<p>Abstract</p> <p>Background</p> <p>Although melon (<it>Cucumis melo </it>L.) is an economically important fruit crop, no genome-wide sequence information is openly available at the current time. We therefore sequenced BAC-ends representing a total of 33,024 clones, half of them from a previously described melon BAC library generated with restriction endonucleases and the remainder from a new random-shear BAC library.</p> <p>Results</p> <p>We generated a total of 47,140 high-quality BAC-end sequences (BES), 91.7% of which were paired-BES. Both libraries were assembled independently and then cross-assembled to obtain a final set of 33,372 non-redundant, high-quality sequences. These were grouped into 6,411 contigs (4.5 Mb) and 26,961 non-assembled BES (14.4 Mb), representing ~4.2% of the melon genome. The sequences were used to screen genomic databases, identifying 7,198 simple sequence repeats (corresponding to one microsatellite every 2.6 kb) and 2,484 additional repeats of which 95.9% represented transposable elements. The sequences were also used to screen expressed sequence tag (EST) databases, revealing 11,372 BES that were homologous to ESTs. This suggests that ~30% of the melon genome consists of coding DNA. We observed regions of microsynteny between melon paired-BES and six other dicotyledonous plant genomes.</p> <p>Conclusion</p> <p>The analysis of nearly 50,000 BES from two complementary genomic libraries covered ~4.2% of the melon genome, providing insight into properties such as microsatellite and transposable element distribution, and the percentage of coding DNA. The observed synteny between melon paired-BES and six other plant genomes showed that useful comparative genomic data can be derived through large scale BAC-end sequencing by anchoring a small proportion of the melon genome to other sequenced genomes.</p

Team players against headache: multidisciplinary treatment of primary headaches and medication overuse headache

Multidisciplinary approaches are gaining acceptance in headache treatment. However, there is a lack of scientific data about the efficacy of various strategies and their combinations offered by physiotherapists, physicians, psychologists and headache nurses. Therefore, an international platform for more intense collaboration between these professions and between headache centers is needed. Our aims were to establish closer collaboration and an interchange of knowledge between headache care providers and different disciplines. A scientific session focusing on multidisciplinary headache management was organised at The European Headache and Migraine Trust International Congress (EHMTIC) 2010 in Nice. A summary of the contributions and the discussion is presented. It was concluded that effective multidisciplinary headache treatment can reduce headache frequency and burden of disease, as well as the risk for medication overuse headache. The significant value of physiotherapy, education in headache schools, and implementation of strategies of cognitive behavioural therapy was highlighted and the way paved for future studies and international collaboration

Transforming growth factor-β in breast cancer: too much, too late

The contribution of transforming growth factor (TGF)β to breast cancer has been studied from a myriad perspectives since seminal studies more than two decades ago. Although the action of TGFβ as a canonical tumor suppressor in breast is without a doubt, there is compelling evidence that TGFβ is frequently subverted in a malignant plexus that drives breast cancer. New knowledge that TGFβ regulates the DNA damage response, which underlies cancer therapy, reveals another facet of TGFβ biology that impedes cancer control. Too much TGFβ, too late in cancer progression is the fundamental motivation for pharmaceutical inhibition