Characterization of long-term motor deficits in the 6-OHDA model of Parkinson's disease in the common marmoset.

Research aimed at developing new therapies for Parkinson's disease (PD) critically depend on valid animal models of the disease that allows for repeated testing of motor disabilities over extended time periods. We here present an extensive characterization of a wide range of motor symptoms in the 6-OHDA marmoset model of PD when tested over several months. The severity of motor deficits was quantified in two ways: (i) through manual scoring protocols appropriately adapted to include species specific motor behavior and (ii) using automated quantitative motion tracking based on image processing of the digital video recordings. We show that the automated methods allow for rapid and reliable characterization of motor dysfunctions, thus complementing the manual scoring procedures, and that robust motor symptoms lasting for several months could be induced when using a two-stage neurotoxic lesioning procedure involving one hemisphere at a time. This non-human primate model of PD should therefore be well suited for long-term evaluation of novel therapies for treatment of PD

A framework for mapping, visualisation and automatic model creation of signal-transduction networks

An intuitive formalism for reconstructing cellular networks from empirical data is presented, and used to build a comprehensive yeast MAP kinase network. The accompanying rxncon software tool can convert networks to a range of standard graphical formats and mathematical models

Severe breastfeeding difficulties: Existential lostness as a mother—Women's lived experiences of initiating breastfeeding under severe difficulties

A majority of women in Sweden initiate breastfeeding but almost a quarter stop or wean the infant in the first few weeks after birth because of difficulties. In order to develop care that facilitates initiation of breastfeeding and enables mothers to realize their expectations concerning breastfeeding, it is necessary to understand what having severe breastfeeding difficulties means for women who experience them. The aim of this study is to describe the lived experiences of initiating breastfeeding under severe difficulties. A reflective lifeworld research design was used. Eight women, seven primiparous and one multipara, were interviewed within 2 months of giving birth. The essential meaning of the phenomenon is described as “Existential lostness as a mother forcing oneself into a constant fight”. This pattern is further explicated through its constituents; shattered expectations, a lost time for closeness, being of no use to the infant, being forced to expose oneself, and gaining strength through sharing. The results show that mothers with severe breastfeeding difficulties feel alone and exposed because of their suffering and are lost in motherhood. Thus, adequate care for mothers should enhance the forming of a caring relationship through sharing rather than exposing

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca(2+) handling is a key feature of HF pathophysiology. Restoring the Ca(2+) regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp(−/−)), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF

Word mining: metal names and the Indo-European dispersal

Horizon 2020(H2020)716732Descriptive and Comparative Linguistic

Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.

The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes