MU Neurobehavioral Core Facility: Progressing from Molecules to Behavior

Neuroscience - Vision & Functional Brain Imaging Poster SessionAn important component of modern neuroscience research is the ability to measure systematically and objectively different aspects of behavior. Behavioral analysis is crucial to a strong neuroscience research program because it evaluates the impact of molecular or neurochemical changes on the functioning of the entire organism. Behavioral research can be used to validate the role of a neuroscientist's specific molecular target (e.g., receptor, gene, or enzyme) in a particular behavior (e.g., emotions, learning and memory, or locomotor activity) and subsequently create whole systems that a neuroscientist can use to study a particular pathological state (e.g., depression, drug addiction or obesity). A unique strength of the MU Translational Neuroscience Center is the presence of some “bench” scientists working at the molecular level in pathology, biochemistry and genetics in collaboration with neurobehavioral experts. The Center's modern facilities and trained personnel are available to the MU neuroscience community to help design, conduct and evaluate behavioral research. This will help translate research from the molecular laboratory to the human clinic. This poster will show a summary of the different aspects and tasks we plan to perform at the MU Neurobehavioral Core Facility

Studies in dipnoan structure

An examination of certain structures at an early stage in the development of the living Dipnoi is of interest and importance morphologically since this group is one of great antiquity and may on that account he expected to contain certain primitive features. In one genus particularly, Lepidosiren paradoxa, the tissue cells are of very large size and this fact makes for greater clarity in histological investigation than is the case in several other groups which do not possess this advantage. The following thesis deals with work, first of all, on the appendicular skeleton and considers the structure of the pectoral fin skeleton of Ceratodus forsteri and its hearing on the condition met with in certain other primitive vertebrates. The second part of the work concerns the axial skeleton and of this there are two aspects. One of these deals with the arrangement met with in the hinder part of the body of Lepidosiren and Protopterus, the other is an investigation into the origin of the sheaths surrounding the notochord in early stages

The definition of dietary fiber – discussions at the Ninth Vahouny Fiber Symposium: building scientific agreement

A definition for dietary fiber was adopted in June 2009 by the Codex Alimentarius Commission based on the recommendation for endorsement of the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) in November 2008. The definition listed three categories of carbohydrate polymers that are not hydrolyzed by the endogenous enzymes in the small intestine of humans. However, the definition left the inclusion of carbohydrates with degrees of polymerization (DP) in the range of 3 and 9 to the discretion of national authorities and left the ‘physiological effect(s) of benefit to health’ as undefined. The ILSI Europe and ILSI North America's committees on dietary carbohydrates organized a forum at the Ninth Vahouny Fiber Symposium in 2010 to discuss these implementation issues with the objective of building scientific consensus on how to resolve them. The results of this session are encouraging and indicated that the scientific community agrees on maintaining a worldwide consensus regarding the inclusion of non-digestible carbohydrates with ≥DP3 as dietary fiber and on a core, non-exhaustive list of beneficial physiological effects that dietary fibers have. These results are consistent with previous worldwide agreements

Identification of miRNA signatures associated with radiation-induced late lung injury in mice.

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident

Management of a Parturient with Preeclampsia and HELLP Syndrome Complicated by Gestational Diabetes Insipidus

Abstract HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) is considered to be a variant or severe form of pre-eclampsia, a life threatening complication of pregnancy. Gestational Diabetes Insipidus (GDI) can coexist with severe preeclampsia and HELLP syndrome. The combination of these two conditions presents a unique challenge to the anesthesiologist and the obstetric team, caring for this parturient. We present the case of a parturient with an unusual presentation of GDI, coexisting with severe preeclampsia and HELLP syndrome. She had two days history of polyuria and polydipsia as well as lethargy and rapidly rising serum sodium in addition to acute renal failure without any neurologic symptoms. Expeditious delivery of the baby and supportive management is essential for optimal outcomes. She underwent a repeat Cesarean section under combined spinal epidural (CSE) anesthesia. This patient was discharged on postoperative day five after clinical resolution of her signs and symptoms

The feasibility of preventing mother-to-child transmission of HIV using peer counselors in Zimbabwe

<p>Abstract</p> <p>Background</p> <p>Prevention of mother-to-child transmission of HIV (PMTCT) is a major public health challenge in Zimbabwe.</p> <p>Methods</p> <p>Using trained peer counselors, a nevirapine (NVP)-based PMTCT program was implemented as part of routine care in urban antenatal clinics.</p> <p>Results</p> <p>Between October 2002 and December 2004, a total of 19,279 women presented for antenatal care. Of these, 18,817 (98%) underwent pre-test counseling; 10,513 (56%) accepted HIV testing, of whom 1986 (19%) were HIV-infected. Overall, 9696 (92%) of women collected results and received individual post-test counseling. Only 288 men opted for HIV testing. Of the 1807 HIV-infected women who received posttest counseling, 1387 (77%) collected NVP tablet and 727 (40%) delivered at the clinics. Of the 1986 HIV-infected women, 691 (35%) received NVPsd at onset of labor, and 615 (31%) infants received NVPsd. Of the 727 HIV-infected women who delivered in the clinics, only 396 women returned to the clinic with their infants for the 6-week follow-up visit; of these mothers, 258 (59%) joined support groups and 234 (53%) opted for contraception. By the end of the study period, 209 (53%) of mother-infant pairs (n = 396) came to the clinic for at least 3 follow-up visits.</p> <p>Conclusion</p> <p>Despite considerable challenges and limited resources, it was feasible to implement a PMTCT program using peer counselors in urban clinics in Zimbabwe.</p

The Glycaemic Index-Food-Frequency Questionnaire: Development and validation of a food frequency questionnaire designed to estimate the dietary intake of glycaemic index and glycaemic load:An effort by the PREVIEW Consortium

Dietary glycaemic index (GI) and glycaemic load (GL) are indices used to quantify the effect of carbohydrate quality and quantity on postprandial glycaemia. GI/GL-health associations are widely studied but data on the validity of integrated GI/GL measurements are scarce. We evaluated the performance of a food-frequency questionnaire (FFQ) specifically developed to assess GI/GL. In total, 263 Dutch men and 212 women (aged 55 ± 11 years) completed a 58-item GI-FFQ, an 183-item general-FFQ and a 2-day 24 h-recall and donated blood for glycated haemoglobin (HbA1c) determination. The level of agreement between these methods was evaluated by (1) cross-classification, (2) correlations and (3) Bland and Altman plots. The three dietary assessment methods provided comparable mean intake estimates for total carbohydrates (range: 214–237 g/day), mono/disaccharides (100–107 g/day), polysaccharides (114–132 g/day), as well as bread, breakfast cereals, potatoes, pasta, rice, fruit, dairy, cakes/cookies and sweets. Mean (±SD) GI estimates were also comparable between the GI-FFQ (54 ± 3), general-FFQ (53 ± 4) and 24 h-recalls (53 ± 5). Mean (±SD) GI-FFQ GL (117 ± 37) was slightly lower than the general-FFQ GL (126 ± 38) and 24 h-recalls GL (127 ± 37). Classification of GI in quartiles was identical for the GI-FFQ and general-FFQ for 43% of the population (r = 0.58) and with 24 h-recalls for 35% of the population (de-attenuated r = 0.64). For GL, this was 48% (r = 0.65) and 44% (de-attenuated r = 0.74). Correlations between GI and HbA1c were low (r = −0.09 for GI-FFQ, r = −0.04 for general-FFQ and r = 0.07 for 24 h-recalls). In conclusion, compared to a general-FFQ and 24 h-recalls, the GI-FFQ showed a moderate to good relative validity for carbohydrates, carbohydrate-rich foods and GI/GL. No metric predicted HbA1c

Downregulation of MicroRNA-9 in iPSC-Derived Neurons of FTD/ALS Patients with TDP-43 Mutations

Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts

Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.

Background Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. Patients and methods AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Results Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and Conclusions Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management. ClinicalTrials.gov Id NCT02437318

G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Background: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Methods: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 mu g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.Results: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Conclusions: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors