Considering Intra-individual Genetic Heterogeneity to Understand Biodiversity

In this chapter, I am concerned with the concept of Intra-individual Genetic Hetereogeneity (IGH) and its potential influence on biodiversity estimates. Definitions of biological individuality are often indirectly dependent on genetic sampling -and vice versa. Genetic sampling typically focuses on a particular locus or set of loci, found in the the mitochondrial, chloroplast or nuclear genome. If ecological function or evolutionary individuality can be defined on the level of multiple divergent genomes, as I shall argue is the case in IGH, our current genetic sampling strategies and analytic approaches may miss out on relevant biodiversity. Now that more and more examples of IGH are available, it is becoming possible to investigate the positive and negative effects of IGH on the functioning and evolution of multicellular individuals more systematically. I consider some examples and argue that studying diversity through the lens of IGH facilitates thinking not in terms of units, but in terms of interactions between biological entities. This, in turn, enables a fresh take on the ecological and evolutionary significance of biological diversity

Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (≥300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time

A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

BACKGROUND: Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE), a novel extract of the plant Calendula Officinalis (Asteraceae). METHODS: An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. RESULTS: The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. CONCLUSION: These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation. The LACE extract presented in vivo anti-tumoral activity in nude mice against tumor growth of Ando-2 melanoma cells

The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

Background Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated.Methods The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells.Results PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation.Conclusion These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells.AGL was supported by FIS Postdoctoral Research Contract CP03/00111. Studies were partially supported by a grant from Kureha Chemical Industry (Japan)

Associations between HIV and Human Pathways Revealed by Protein-Protein Interactions and Correlated Gene Expression Profiles

BACKGROUND: AIDS is one of the most devastating diseases in human history. Decades of studies have revealed host factors required for HIV infection, indicating that HIV exploits host processes for its own purposes. HIV infection leads to AIDS as well as various comorbidities. The associations between HIV and human pathways and diseases may reveal non-obvious relationships between HIV and non-HIV-defining diseases. PRINCIPAL FINDINGS: Human biological pathways were evaluated and statistically compared against the presence of HIV host factor related genes. All of the obtained scores comparing HIV targeted genes and biological pathways were ranked. Different rank results based on overlapping genes, recovered virus-host interactions, co-expressed genes, and common interactions in human protein-protein interaction networks were obtained. Correlations between rankings suggested that these measures yielded diverse rankings. Rank combination of these ranks led to a final ranking of HIV-associated pathways, which revealed that HIV is associated with immune cell-related pathways and several cancer-related pathways. The proposed method is also applicable to the evaluation of associations between other pathogens and human pathways and diseases. CONCLUSIONS: Our results suggest that HIV infection shares common molecular mechanisms with certain signaling pathways and cancers. Interference in apoptosis pathways and the long-term suppression of immune system functions by HIV infection might contribute to tumorigenesis. Relationships between HIV infection and human pathways of disease may aid in the identification of common drug targets for viral infections and other diseases

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe