Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Patient-reported outcome metrics following total knee arthroplasty are influenced differently by patients' body mass index.

PURPOSE: This study investigated the impact of body mass index (BMI) on improvement in patient outcomes (pain, function, joint awareness, general health and satisfaction) following total knee arthroplasty (TKA). METHODS: Data were obtained for primary TKAs performed at a single centre over a 12-month period. Data were collected pre-operatively and 12-month postoperatively with the Oxford Knee Score (OKS) measuring pain and function, the EQ-5D-3L measuring general health status, the Forgotten Joint Score-12 (FJS-12) measuring joint awareness and a single question on treatment satisfaction. Change in scores following surgery was compared across the BMI categories identified by the World Health Organization (< 25.0, 25.0-29.9, 30.0-34.9, 35.0-39.9 and ≥ 40.0). Differences in postoperative improvement between the BMI groups were analysed with an overall Kruskal-Wallis test, with post hoc pairwise comparisons between BMI groups with Mann-Whitney tests. RESULTS: Of 402 patients [mean age 70.7 (SD 9.2); 55.2% women] 15.7% were normal weight (BMI < 25.0), 33.1% were overweight (BMI 25.0-29.9), 28.2% had class I obesity (BMI 30.0-34.9), 16.2% had class II obesity (BMI 35.0-39.9), and 7.0% had class III obesity (BMI ≥ 40.0). Postoperative change in OKS (n.s.) and EQ-5D-3L (n.s.) was not associated with BMI. Higher BMI group was associated with less improvement in FJS-12 scores (p = 0.010), reflecting a greater awareness of the operated joint during activity in the most obese patients. Treatment satisfaction was associated with BMI category (p = 0.029), with obese patients reporting less satisfaction. CONCLUSIONS: In TKA patients, outcome parameters are influenced differently by BMI. Our study showed a negative impact of BMI on postoperative improvement in joint awareness and satisfaction scores, but there was no influence on pain, function or general health scores. This information may be useful in terms of setting expectations expectation in obese patients planning to undergo TKA. LEVEL OF EVIDENCE: Level 1.

Directional selection effects on patterns of phenotypic (co)variation in wild populations.

Phenotypic (co)variation is a prerequisite for evolutionary change, and understanding how (co)variation evolves is of crucial importance to the biological sciences. Theoretical models predict that under directional selection, phenotypic (co)variation should evolve in step with the underlying adaptive landscape, increasing the degree of correlation among co-selected traits as well as the amount of genetic variance in the direction of selection. Whether either of these outcomes occurs in natural populations is an open question and thus an important gap in evolutionary theory. Here, we documented changes in the phenotypic (co)variation structure in two separate natural populations in each of two chipmunk species (Tamias alpinus and T. speciosus) undergoing directional selection. In populations where selection was strongest (those of T. alpinus), we observed changes, at least for one population, in phenotypic (co)variation that matched theoretical expectations, namely an increase of both phenotypic integration and (co)variance in the direction of selection and a re-alignment of the major axis of variation with the selection gradient.

Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation.

Post-operative Oxford knee score can be used to indicate whether patient expectations have been achieved after primary total knee arthroplasty.

PURPOSE: The aim of this study was to identify threshold values in the post-operative Oxford knee score (OKS) and change in the score for achievement of specific patient expectations and satisfaction, and whether failure to meet specific patient expectations influenced the rate of satisfaction after total knee arthroplasty (TKA). METHODS: Prospectively complied data for 322 primary TKA were used. Patient demographics, and pre- and post-operative (1 year) OKS, and expectation fulfilment were collected. Patient satisfaction was also assessed 1 year post-operatively. RESULTS: Patient pre-operative expectations varied in prevalence and differed according to gender, age, and severity of knee symptoms according the OKS. Fulfilment of patient expectations was variable and was dependent upon the specific expectation; the majority of patients achieved their expectation of pain relief and improved ability to walk (>70%), however, few fulfilled their expectation to kneel or squat (<25%). The threshold according to the post-operative OKS at which these expectations were achieved varied by more than ten points, ranging from ≥31 for pain relief to ≥42 for kneeling. Failure to fulfil patient expectations, for 15 of the 17 assessed, significantly increased the risk of dissatisfaction at 1 year (p < 0.05). CONCLUSION: The post-operative OKS can be used to predict the point at which the greatest proportion of patient expectations is achieved. Some expectations, however, are rarely fulfilled after a TKA and patients should be made aware of this pre-operatively which may improve their satisfaction post-operatively. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

Mega prosthetic distal femoral arthroplasty for non-tumour indications: does the indication affect the functional outcome and survivorship?

PURPOSE: To report the functional outcome, implant survival, and patient mortality after mega prosthetic distal femoral arthroplasty according to the surgical indication. METHODS: A prospective database was compiled for 45 consecutive patients undergoing distal femoral arthroplasty, of which 26 had fractures of the distal femur (group 1) and 19 underwent revision of a total knee arthroplasty (group 2). There were 17 males and 28 females with a median age of 74.5 years. Short form (SF)-12 scores were recorded pre-operatively (before the fracture or revision) and 1 year post-operatively, at which point a Toronto Extremity Salvage Score (TESS) was also obtained. Length of hospital stay and return to place of domicile was obtained from the hospital database. Mortality status was obtained from the General Register Office for Scotland. No patient was lost to follow-up. RESULTS: The 1-year physical (52.4) and mental (63.4) components of the SF-12 score and the TESS (70.5 %) did not significantly differ between the groups (n.s.). The fracture group, however, had a longer length of stay (8 vs. 19 days, p = 0.001) and were also less likely to return to their original domicile (odds ratio 9.5, p = 0.02). The overall implant survival rate was 85 % at 5 years, which was worse for the fracture group (80 vs. 90 %, n.s.). The 5-year mortality rate for the revision group was 17 %, whereas the fracture group demonstrated a greater mortality rate of 43 % (n.s.). CONCLUSION: The functional outcome, revision rate, and mortality of patients undergoing distal femoral arthroplasty for non-tumour reasons are not influenced by indication, but patients undergoing surgery for fractures of the distal femur have a longer length of stay and are less likely to return home. Distal femoral arthroplasty should be considered as a management option for non-tumour salvage procedures of the distal femur. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

Characterization of hydrogen responsive nanoporous palladium films synthesized via a spontaneous galvanic displacement reaction.

A model is presented regarding the mechanistic properties associated with the interaction of hydrogen with nanoporous palladium (np-Pd) films prepared using a spontaneous galvanic displacement reaction (SGDR), which involves PdCl(2) reduction by atomic Ag. Characterization of these films shows both chemical and morphological factors, which influence the performance characteristics of np-Pd microcantilever (MC) nanomechanical sensing devices. Raman spectroscopy, uniquely complemented with MC response profiles, is used to explore the chemical influence of palladium oxide (PdO). These combined techniques support a reaction mechanism that provides for rapid response to H(2) and recovery in the presence of O(2). Post-SGDR processing via reduction of PdCl(2)(s) in a H(2) environment results in a segregated nanoparticle three-dimensional matrix dispersed in a silver layer. The porous nature of the reduced material is shown by high resolution scanning electron microscopy. Extended grain boundaries, typical of these materials, result in a greater surface area conducive to fast sorption/desorption of hydrogen, encouraged by the presence of PdO. X-ray diffraction and inductively coupled plasma-optical emission spectroscopy are employed to study changes in morphology and chemistry occurring in these nanoporous films under different processing conditions. The unique nature of chemical/morphological effects, as demonstrated by the above characterization methods, provides evidence in support of observed nanomechanical response/recovery profiles offering insight for catalysis, H(2) storage and improved sensing applications.

Defining ruminal and total-tract starch degradation for adult dairy cattle using in vivo data.

Literature was searched for studies performed in adult dairy cattle that simultaneously measured starch degradability in the rumen (RSDeg) and starch digestion in the total tract to compute postruminal starch digestion (PRSDig). Forty-one studies with 161 dietary treatments were used to form the data set. Of these diets, the major starch source was corn for 83 diets, small grain for 58 diets, and sorghum for 8 diets. Corn RSDeg was more variable than other sources. As measured in vivo across all starch sources, the percent RSDeg was influenced only by the amount of starch consumed, with the amount of degradation being approximately 75% at low starch intakes and decreasing to about 60% when 4 kg or more of starch were consumed. Small grain starch had greater RSDeg than corn or sorghum starch, which were approximately equal. The PRSDig of corn and small grain starches were approximately equal, but sorghum was about 15% less. Across all diets, models derived from the Cornell Net Carbohydrate Protein System predicted percentage of total-tract digestibility of starch very accurately, but overpredicted RSDeg and, as a result, underpredicted percent PRSDig. Calculation of RSDeg using a French model predicted the mean RSDeg with greater accuracy but less precisely. The relative differences in RSDeg percent among starch sources was correctly predicted by these models. A model using a revised rate of digestion as a way of combining effects of starch type and processing was developed, which predicted corn starch RSDeg and PRSDig with greater accuracy than nutrition models but only slightly better than using the mean observed degradation or the French calculation. Inaccuracies in prediction of RSDeg may be due mainly to processing effects and particle sizes, but these were not well reported in literature studies and were difficult to estimate. More accurate assessment of RSDeg and PRSDig will require better and more consistent reporting of grain processing. Based on this study, the French calculation is the most accurate of the models examined, although adjustments will be required to improve accuracy.

Multifocal primary bone sarcoma in the elderly: a rare case and review of the literature.

To our knowledge there are no reports of a primary multifocal spindle cell sarcoma affecting both long bones of the lower limb in an elderly patient. An 83-year-old man presented with a progressively painful right ankle, without a history of trauma. Radiographs demonstrated a pathological fracture through a mixed lytic and sclerotic lesion in the distal tibia. Staging investigations, including bone scintigraphy and magnetic resonance imaging, revealed a second lytic lesion in the right distal femur. A provisional diagnosis of metastatic disease was favoured and intramedullary nailing was considered. However, computed tomography of the chest, abdomen and pelvis, and relevant blood tests revealed no evidence of a primary malignancy. Open biopsy of the tibial lesion showed high-grade pleomorphic spindle cells consistent with a primary bone sarcoma. The patient was treated successfully with a right trans-femoral amputation. In conclusion, we recommend early bone biopsy to allow accurate diagnosis and appropriate skeletal management in elderly patients.

A Cost-Utility Analysis of Robotic Arm-Assisted Total Hip Arthroplasty: Using Robotic Data from the Private Sector and Manual Data from the National Health Service.

Purpose: The aim was to assess the cost-effectiveness of robotic arm-assisted total hip arthroplasty (rTHA) compared with manual total hip arthroplasty (mTHA) and to assess the influence of annual volume on the relative cost-effectiveness of rTHA. Methods: A database of both rTHA (n = 48 performed in a private centre) and mTHA (n = 512 performed in the National Health Service) was used. Patient demographics, preoperative Oxford hip score, forgotten joint score, EuroQol 5-dimensional 3-level (EQ-5D), and postoperative EQ-5D were recorded. Two models for incremental cost-effectiveness ratios using cost per quality-adjusted life year (QALY) for rTHA were calculated based on a unit performing 100 rTHAs per year: 10-year follow-up and a lifetime time horizon (remaining life expectancy of a 69-year-old patient). Results: When adjusting for confounding factors, rTHA was independently associated with a 0.091 (p=0.029) greater improvement in the EQ-5D compared to mTHA. This resulted in a 10-year time horizon cost per QALY for rTHA of £1,910 relative to mTHA, which increased to £2,349 per QALY when discounted (5%/year). When using the 10-year time horizon cost per QALY was approximately £3,000 for a centre undertaking 50 rTHAs per year and decreased to £1,000 for centre undertaking 200 rTHAs per year. Using a lifetime horizon, the incremental unadjusted cost per QALY gained was £980 and £1432 when discounted (5%/year) for rTHA compared with mTHA. Conclusions: Despite the increased cost associated with rTHA, it was a cost-effective intervention relative to mTHA due to the associated greater health-related quality of health gain, according to the EQ-5D outcome measure.

Exposure to climate change drives stability or collapse of desert mammal and bird communities.

High exposure to warming from climate change is expected to threaten biodiversity by pushing many species toward extinction. Such exposure is often assessed for all taxa at a location from climate projections, yet species have diverse strategies for buffering against temperature extremes. We compared changes in species occupancy and site-level richness of small mammal and bird communities in protected areas of the Mojave Desert using surveys spanning a century. Small mammal communities remained remarkably stable, whereas birds declined markedly in response to warming and drying. Simulations of heat flux identified different exposure to warming for birds and mammals, which we attribute to microhabitat use. Estimates from climate projections are unlikely to accurately reflect species' exposure without accounting for the effects of microhabitat buffering on heat flux.

Negative energy balance and hepatic gene expression patterns in high-yielding dairy cows during the early postpartum period: a global approach.

In high-yielding dairy cows the liver undergoes extensive physiological and biochemical changes during the early postpartum period in an effort to re-establish metabolic homeostasis and to counteract the adverse effects of negative energy balance (NEB). These adaptations are likely to be mediated by significant alterations in hepatic gene expression. To gain new insights into these events an energy balance model was created using differential feeding and milking regimes to produce two groups of cows with either a mild (MNEB) or severe NEB (SNEB) status. Cows were slaughtered and liver tissues collected on days 6-7 of the first follicular wave postpartum. Using an Affymetrix 23k oligonucleotide bovine array to determine global gene expression in hepatic tissue of these cows, we found a total of 416 genes (189 up- and 227 downregulated) to be altered by SNEB. Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with widespread changes in gene expression classified into 36 gene networks including those associated with lipid metabolism, connective tissue development and function, cell signaling, cell cycle, and metabolic diseases, the three most significant of which are discussed in detail. SNEB cows displayed reduced expression of transcription activators and signal transducers that regulate the expression of genes and gene networks associated with cell signaling and tissue repair. These alterations are linked with increased expression of abnormal cell cycle and cellular proliferation associated pathways. This study provides new information and insights on the effect of SNEB on gene expression in high-yielding Holstein Friesian dairy cows in the early postpartum period.

Sagittal alignment of the cemented femoral component in revision total knee arthroplasty influences the anterior and posterior condylar offset: Stem length does not affect these variables.

BACKGROUND: The position of the femoral component can influence knee kinematics by altering the posterior (PCO) and anterior condylar offset (ACO). The primary aim of this study was to assess whether the length of the cemented stem influences the sagittal position of the femoral component after revision total knee arthroplasty (rTKA). The secondary aim was to determine the influence of the sagittal position on PCO and ACO. METHODS: There were 172 consecutive patients over a seven-year period that underwent rTKA with a cemented semi-constrained prosthesis. The 172 patients were separated into two groups: 115 with short stems (50 mm) and 57 with longer stems (100 or 150 mm). Using rotationally acceptable lateral radiographs, the degree of flexion(+)/extension(-) of the femoral components, PCO, and ACO were measured. RESULTS: There was no significant difference (p > 0.25) between the two groups for sagittal position, PCO, or ACO. The average flexion of the femoral component with short stems was 2.2 ±â€¯4.1° and 2.2 ±â€¯3.4° for long stems (difference = 0.0, 95% confidence intervals (CI) -1.3 to 1.2). The average PCO ratio was 1.02 ±â€¯0.15 for short stems and 0.99 ±â€¯0.17 for long stems (difference = 0.03, 95% CI -0.02 to 0.08). The average ACO ratio was at 0.07 ±â€¯0.08 for short stems and 0.08 ±â€¯0.08 for long stems (difference = 0.01, 95% CI -0.01 to 0.04). There was a significant correlation between sagittal alignment of the femoral component and PCO (flexion increased PCO, r = 0.39, p < 0.0001) and ACO (flexion decreased ACO, r = -0.34, p < 0.0001). CONCLUSIONS: Cemented stem length does not influence the position of femoral component in the sagittal axis, PCO, or ACO. Surgical technique and sizing of the femoral component may be more predictive.

Robotic-assisted unicompartmental knee arthroplasty has a greater early functional outcome when compared to manual total knee arthroplasty for isolated medial compartment arthritis.

AIMS: The primary aim of the study was to compare the knee-specific functional outcome of robotic unicompartmental knee arthroplasty (rUKA) with manual total knee arthroplasty (mTKA) for the management of isolated medial compartment osteoarthritis. Secondary aims were to compare length of hospital stay, general health improvement, and satisfaction between rUKA and mTKA. METHODS: A powered (1:3 ratio) cohort study was performed. A total of 30 patients undergoing rUKA were propensity score matched to 90 patients undergoing mTKA for isolated medial compartment arthritis. Patients were matched for age, sex, body mass index (BMI), and preoperative function. The Oxford Knee Score (OKS) and EuroQol five-dimension questionnaire (EQ-5D) were collected preoperatively and six months postoperatively. The Forgotten Joint Score (FJS) and patient satisfaction were collected six months postoperatively. Length of hospital stay was also recorded. RESULTS: There were no significant differences in the preoperative demographics (p ⩾ 0.150) or function (p ⩾ 0.230) between the groups. The six-month OKS was significantly greater in the rUKA group when compared with the mTKA group (difference 7.7, p < 0.001). There was also a greater six-month postoperative EQ-5D (difference 0.148, p = 0.002) and FJS (difference 24.2, p < 0.001) for the rUKA when compared to the mTKA. No patient was dissatisfied in the rUKA group and five (6%) were dissatisfied in the mTKA, but this was not significant (p = 0.210). Length of stay was significantly (p < 0.001) shorter in the rUKA group (median two days, interquartile range (IQR) 1 to 3) compared to the mTKA (median four days, IQR 3 to 5). CONCLUSION: Patients with isolated medial compartment arthritis had a greater knee-specific functional outcome and generic health with a shorter length of hospital stay after rUKA when compared to mTKA.Cite this article: Bone Joint Res 2019;9(1):15-22.

Pleiotropic effects of negative energy balance in the postpartum dairy cow on splenic gene expression: repercussions for innate and adaptive immunity.

Increased energy demands to support lactation, coupled with lowered feed intake capacity results in negative energy balance (NEB) and is typically characterized by extensive mobilization of body energy reserves in the early postpartum dairy cow. The catabolism of stored lipid leads to an increase in the systemic concentrations of nonesterified fatty acids (NEFA) and beta-hydroxy butyrate (BHB). Oxidation of NEFA in the liver result in the increased production of reactive oxygen species and the onset of oxidative stress and can lead to disruption of normal metabolism and physiology. The immune system is depressed in the peripartum period and early lactation and dairy cows are therefore more vulnerable to bacterial infections causing mastitis and or endometritis at this time. A bovine Affymetrix oligonucleotide array was used to determine global gene expression in the spleen of dairy cows in the early postpartum period. Spleen tissue was removed post mortem from five severe NEB (SNEB) and five medium NEB (MNEB) cows 15 days postpartum. SNEB increased systemic concentrations of NEFA and BHB, and white blood cell and lymphocyte numbers were decreased in SNEB animals. A total of 545 genes were altered by SNEB. Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with NRF2-mediated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, natural killer cell signaling, p53 signaling, downregulation of IL-15, BCL-2, and IFN-gamma; upregulation of BAX and CHOP and increased apoptosis with a potential negative impact on innate and adaptive immunity.

Assessing substitution patterns, rates and homoplasy at HVRI of Steller sea lions, Eumetopias jubatus.

Despite the widely recognized incidence of homoplasy characterizing this region, the hypervariable region I (HVRI) of the mitochondrial control region is one of the most frequently used genetic markers for population genetic and phylogeographic studies. We present an evolutionary analysis of HVRI and cytochrome b sequences from a range-wide survey of 1031 Steller sea lions, Eumetopias jubatus, to quantify homoplasy and substitution rate at HVRI. Variation in HVRI was distributed across 41 variable sites in the 238-bp segment examined. All variants at HVR1 were found to be transitions. However, our analyses suggest that a minimum of 101 changes have actually occurred within HVRI with as many as 18 substitutions occurring at a single site. By including this hidden variation into our analyses, several instances of apparent long-range dispersal were resolved to be homoplasies and 8.5-12% of observed HVRI haplotypes were found to have geographic distributions descriptive of convergent molecular evolution rather than identity by descent. We estimate the rate of substitution at HVRI in Steller sea lions to be approximately 24 times that of cytochrome b with an absolute rate of HVRI substitution estimated at 27.45% per million years. These findings have direct implications regarding the utility of HVRI data to generate a variety of evolutionary genetic hypotheses.

U1 precursors: variant 3' flanking sequences are transcribed in human cells.

Using RNase protection and oligonucleotide hybridization experiments, we have shown that U1 precursors are derived by transcription of 3' flanking sequences. A labeled SP6 transcript of one of the true U1 genes (pD2) was able to protect a subset of the 3' flanking sequences present in HeLa cytoplasmic U1 RNA. However, not all U1 precursors were protected using this probe, suggesting that variant U1 precursor 3' tail sequences are expressed in HeLa cells. This conclusion has been confirmed by hybridization of HeLa RNA samples with specific oligonucleotide probes representing variant U1 3' flanking sequences. Interestingly, these variant tail sequences contain the putative Sm antigen binding site, A(U)3-6G. The conservation of this flanking sequence through evolution suggests a possible functional role for these precursor tails in ordering protein binding to U1 RNA.

Watching fat digestion.

During fat digestion a number of physicochemical events can be seen directly by light microscopy. Under simulated physiological conditions, hydrolysis of emulsified fat droplets by human pancreatic lipase in the presence of colipase and bile salt micelles proceeds with the sequential formation of two visible product phases. A lamellar liquid crystalline or crystalline phase containing calcium and ionized fatty acid forms first; this is followed by the production of a "viscous isotropic" phase composed predominantly of monoglycerides and protonated fatty acids.

Differences in the expression of genes involved in the somatotropic axis in divergent strains of Holstein-Friesian dairy cows during early and mid lactation.

Differences in genetic selection criteria for dairy cows internationally have led to divergence in the Holstein-Friesian breed. The objective of this study was to compare hepatic expression of genes of the somatotropic axis in the North American Holstein-Friesian and the New Zealand Holstein-Friesian strains of dairy cow at early and mid lactation. Mature cows of both the North American Holstein-Friesian (n = 10) and New Zealand Holstein-Friesian (n = 10) strains were selected. Liver tissue was collected by percutaneous punch biopsy from all cows at 35 and 140 d postpartum, representing early and mid lactation, respectively. Total RNA was extracted and the hepatic expression of genes involved in the control of the somatotropic axis was examined. Abundance of insulin-like growth factor (IGF)-1 mRNA was greater in the New Zealand strain, concomitant with a tendency for increased expression of acid-labile subunit mRNA. Across strains, mRNA abundance of IGF-binding protein-1, IGF-binding protein-2, and growth hormone receptor 1A decreased from d 35 to 140 postpartum, whereas expression of IGF-1 and acid-labile subunit tended to increase. Abundance of suppressor of cytokine signaling-3 mRNA was increased at d 140 postpartum. Both the strain of Holstein-Friesian cow and the stage of lactation influenced expression of genes controlling the somatotropic axis in hepatic tissue.

Central sulcus is a barrier to causal propagation in epileptic networks.

the functional interactions of different brain regions are dependent of their underlying structural connectivity. These interactions are important for normal brain activity as well as in epileptic disorders where spontaneous epileptic discharges are generated. To understand the effects of brain topography on both normal and epileptic functional networks, we evaluated propagation frequency with respect to geodesic distance and the specific role of sulcal patterns in modulating these functional connections. We implemented a multimodal approach combining Electrocorticography (ECoG) and magnetic resonance imaging (MRI) to evaluate the relationships between epileptic and non-epileptic networks as they are related to structural connectivity in the human brain. We analyzed interictal ECoG along with MRI 3D reconstructions from seven epileptic patients and found that interictal full-dataset network propagations travel to both nearby and distant cortical locations, however with longer distance the propagations occurrence attenuates dramatically. We also discovered that the central sulcus acts as a strong barrier allowing only 30% of the propagation to cross central sulcus whereas the rest of the 70% propagations are observed on the same side of the sulcus. Epileptic spike propagations, however, were more highly localized with significantly less distant spread and had further reduction in spread across sulci. This is a novel approach to explore the structural influence of brain topography on the functional network and would help understand the interaction of different brain regions and how these are altered in patients with epilepsy. This approach could assist physician decision making during epilepsy surgery by revealing an appropriate brain network and cortical interactions.