Induced hypoglycemia for 48 hours indicates differential glucose and insulin effects on liver metabolism in dairy cows

Hypoglycemia is a characteristic condition of early lactation dairy cows and is subsequently dependent on, and may affect, metabolism in the liver. The objective of the present study was to investigate the effects of induced hypoglycemia, maintained for 48 h, on metabolic parameters in plasma and liver of mid-lactation dairy cows. The experiment involved 3 treatments, including a hyperinsulinemic hypoglycemic clamp (HypoG, n=6) to obtain a glucose concentration of 2.5 mmol/L, a hyperinsulinemic euglycemic clamp (EuG, n=6) in which the effect of insulin was studied, and a control treatment with a 0.9% saline solution (NaCl, n=6). Blood samples for measurements of insulin, metabolites, and enzymes were taken at least once per hour. Milk yield was recorded and milk samples were collected before and after treatment. Liver biopsies were obtained before and after treatment to measure mRNA abundance by real-time, quantitative reverse transcription-PCR of 12 candidate genes involved in the main metabolic pathways. Milk yield decreased in HypoG and NaCl cows, whereas it remained unaffected in EuG cows. Energy-corrected milk yield (kg/d) was only decreased in HypoG cows. In plasma, concentration of beta-hydroxybutyrate decreased in response to treatment in EuG cows and was lower (0.41+/-0.04 mmol/L) on d 2 of the treatment compared with that in HypoG and NaCl cows (on average 0.61+/-0.03 mmol/L, respectively). Nonesterified fatty acids remained unaffected in all treatments. In the liver, differences between treatments for their effects were only observed in case of mitochondrial phosphoenolpyruvate carboxykinase (PEPCKm) and glucose-6-phosphatase (G6PC). In HypoG, mRNA abundance of PEPCKm was upregulated, whereas in EuG and NaCl cows, it was downregulated. The EuG treatment downregulated mRNA expression of G6PC, a marked effect compared with the unchanged transcript expression in NaCl. The mRNA abundance of the insulin receptor remained unaffected in all treatments, and no significant treatment differences were observed for genes related to lipid metabolism. In conclusion, low glucose concentrations in dairy cows affect liver metabolism at a molecular level through upregulation of PEPCKm mRNA abundance. Metabolic regulatory events in the liver are directed, apart from hormones, by the level of metabolites, either in excess (e.g., free fatty acids) or in shortage (e.g., glucose).

Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells

It is increasingly recognised that chronically activated glia contribute to the pathology of various neurodegenerative diseases, including glaucoma. One means by which this can occur is through the release of neurotoxic, proinflammatory factors. In the current study, we therefore investigated the spatio-temporal patterns of expression of three such cytokines, IL-1β, TNFα and IL-6, in a validated rat model of experimental glaucoma. First, only weak evidence was found for increased expression of IL-1β and TNFα following induction of ocular hypertension. Second, and much more striking, was that robust evidence was uncovered showing IL-6 to be synthesised by injured retinal ganglion cells following elevation of intraocular pressure and transported in an orthograde fashion along the nerve, accumulating at sites of axonal disruption in the optic nerve head. Verification that IL-6 represents a novel marker of disrupted axonal transport in this model was obtained by performing double labelling immunofluorescence with recognised markers of fast axonal transport. The stimulus for IL-6 synthesis and axonal transport during experimental glaucoma arose from axonal injury rather than ocular hypertension, as the response was identical after optic nerve crush and bilateral occlusion of the carotid arteries, each of which is independent of elevated intraocular pressure. Moreover, the response of IL-6 was not a generalised feature of the gp130 family of cytokines, as it was not mimicked by another family member, ciliary neurotrophic factor. Finally, further study suggested that IL-6 may be an early part of the endogenous regenerative response as the cytokine colocalised with growth-associated membrane phosphoprotein-43 in some putative regenerating axons, and potently stimulated neuritogenesis in retinal ganglion cells in culture, an effect that was additive to that of ciliary neurotrophic factor. These data comprise clear evidence that IL-6 is actively involved in the attempt of injured retinal ganglion cells to regenerate their axons.

Sweat test in patients with glucose-6-phosphate-1-dehydrogenase deficiency

BACKGROUND: A false-positive sweat test in patients with deficiency of glucose-6-phosphate-1-dehydrogenase (EC 1.1.1.49; G6PD) is repeatedly reported. METHODS: Sweat chloride or conductivity was measured in 11 patients with G6PD deficiency. RESULTS: Mean (SD) chloride level (n = 8, median age 9.2 years, range 1.9-48.5) was 18.8 (9.6 mmol/l) and, mean (SD) sodium level was 26.0 (10.0 mmol/l), respectively, and mean (SD) conductivity (n = 3, median age 6.6 years, range 1.9-40.5) was 34.3 (6.5 mmol/l). CONCLUSION: In sweat of 11 patients with G6PD deficiency we did not find any abnormality. The reason for alleged false-positive sweat test in patients with G6PD deficiency is not known and we were unable to identify any original reference. It appears that tables of putative false-positive sweat tests in several disease states have been directly "copied and pasted" from one paper or textbook to another without verifying the original literature, a phenomenon one can call "chain citation".

Relationship between heart rate variability, interleukin-6, and soluble tissue factor in healthy subjects

Decreased heart rate variability (HRV) has been associated with an increased risk of atherosclerosis. We hypothesized that a decrease in frequency domains of resting HRV would be associated with elevated plasma levels of interleukin (IL)-6 and soluble tissue factor (sTF) both previously shown to prospectively predict atherothrombotic events in healthy subjects. Subjects were 102 healthy and unmedicated black and white middle-aged men and women. We determined IL-6 and sTF antigen in plasma and HRV measures from surface electrocardiogram data using spectral analysis. All statistical analyses controlled for age, gender, ethnicity, smoking status, blood pressure, and body mass index. Low amounts of low frequency (LF) power (beta=-0.31, p=0.007) and high frequency (HF) power (beta=-0.36, p=0.002) were associated with increased amounts of IL-6, explaining 7% and 9% of the variance, respectively. Interactions between LF power and IL-6 (p=0.002) and between HF power and IL-6 (p=0.012) explained 8% and 5%, respectively, of the variance in sTF. Post hoc analyses showed associations between IL-6 and sTF when LF power (beta=0.51, p<0.001) and HF power (beta=0.48, p<0.001) were low but not when LF power and high HF power were high. The findings suggest that systemic low-grade inflammatory activity is associated with a decrease in HRV. Furthermore, there was a positive relationship between plasma levels of IL-6 and sTF antigen when HRV was low. Inflammation and related hypercoagulability might particularly contribute to atherothrombotic events in a setting of decreased HRV.

A regioselective palladium-free protocol for accessing unsymmetrical biaryls through ring transformation of 6-aryl-~-pyrones

A regioselective synthesis of unsymmetrical biaryls with electron withdrawing or donating substituents is described and illustrated by carbanion-induced ring transfonnation of 6-aryl-a-pyrones with methoxyacetone in excellent yield. Our methodology is an alternative to classical organometal-catalyzed aryl-aryl coupling reactions and can be applied to the synthesis of functionally demanding naphthyl biaryls for the development of new ligands for asymetric synthesis

Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury

The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the matrix, and the microstructure of matrix itself can be dramatically altered by joint injury and the subsequent inflammatory response. We studied the transport into cartilage of a 48 kDa anti-IL-6 antigen binding fragment (Fab) using an in vitro model of joint injury to quantify the transport of Fab fragments into normal and mechanically injured cartilage. The anti-IL-6 Fab was able to diffuse throughout the depth of the tissue, suggesting that Fab fragments can have the desired property of achieving local delivery to targets within cartilage, unlike full-sized antibodies which are too large to penetrate beyond the cartilage surface. Uptake of the anti-IL-6 Fab was significantly increased following mechanical injury, and an additional increase in uptake was observed in response to combined treatment with TNFα and mechanical injury, a model used to mimic the inflammatory response following joint injury. These results suggest that joint trauma leading to cartilage degradation can further alter the transport of such therapeutics and similar-sized macromolecules.

Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury.

BACKGROUND: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion, reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be implanted to monitor ICP, there is no clinically proven method for determining a patient's risk for developing this pathology. METHODS: In the present study, we employed antibody array and Luminex-based screening methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers and in severe TBI patients (GCS RESULTS: Consistent with previous reports, we observed sustained increases in IL-6 levels in TBI patients irrespective of their ICP status. However, the group of patients who subsequently experienced ICP >or= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of injury as compared to the patients whose ICP remained 128 pg/ml correctly identified 85% of isolated TBI patients who subsequently developed elevated ICP, and values between these cut-off values correctly identified 75% of all patients whose ICP remained CONCLUSIONS: Our results suggest that serum IL-6 can be used for the differential diagnosis of elevated ICP in isolated TBI.

OXA-48 carbapenemase-producing Salmonella enterica serovar Kentucky isolate of sequence type 198 in a patient transferred from Libya to Switzerland

Here, we report a case of OXA-48-producing Salmonella enterica serovar Kentucky of sequence type 198 (ST198) from perianal screening cultures of a patient transferred from Libya to Switzerland. The blaOXA-48 gene was carried by Tn1999.2 and located on an ∼60-kb IncL/M plasmid. This Salmonella strain also possessed the blaVEB-8, aac(6)-Ib, tet(A), sul1, and mphA resistance genes and substitutions in GyrA (Ser83Phe and Asp87Asn) and ParC (Ser80Ile). This finding emphasizes that prompt screening strategies are essential to prevent the dissemination of carbapenemase producers imported from countries where they are endemic.

Lattice NRQCD study of in-medium bottomonium states using Nf = 2+1, 48³ × 12 HotQCD configurations

The behavior of bottomonium state correlators at non-zero temperature, 140.4(β = 6.664) ≤ T ≤ 221(β = 7.280) (MeV), where the transition temperature is 154(9) (MeV), is studied, using lattice NRQCD on 48³ ×12 HotQCD HiSQ action configurations with light dynamical Nf = 2+1 (mu,s/ms = 0.05) staggered quarks. In order to understand finite temperature effects on quarkonium states, zero temperature behavior of bottomonium correlators is compared based on 32⁴ (β = 6.664,6.800 and 6.950) and 48³ ×64 (β = 7.280) lattices. We find that temperature effects on S-wave bottomoniumstates are small but P-wave bottomoniumstates show a noticeable temperature dependence above the transition temperature.

Revisiting the Nd-142 deficits in the 1.48 Ga Khariar alkaline rocks, India

The 146Sm–142Nd system plays a central role in tracing the silicate differentiation of the Earth prior to 4.1 Ga. After this time, given its initial abundance, the 146Sm can be considered to be extinct. Upadhyay et al. (2009) reported unexpected negative 142Nd anomalies in 1.48 Ga rocks of the Khariar nepheline syenite complex (India) and inferred that an early enriched, low-Sm/Nd reservoir must have contributed to the mantle source rocks of the Khariar complex. As 146Sm had been effectively extinct for about 2.6 billion years before the crystallisation of the Khariar samples, this Nd signature should have remained isolated from the convective mantle for at least that long. It was thus suggested that the source rock of Khariar samples had been sequestered in the lithospheric root of the Indian craton. Using a different chemical separation method, and a different Thermal Ionization Mass Spectrometry (TIMS) analysis protocol, the present study attempted to replicate these negative 142Nd anomalies, but none were found. To determine which data set is correct, we investigated three possible sources of bias between them: imperfect cancellation of Faraday collector efficiencies during multidynamic TIMS analysis, rapid sample fractionation between the sequential measurement of 146Nd/144Nd and 142Nd/144Nd, and non-exponential law behaviour resulting from so-called “domain mixing.” Incomplete cancellation of collector efficiencies was found unlikely to cause resolvable biases at the estimated level of variation among collector efficiencies. Even in the case of highly variable efficiency and resolvable biases, there is no reason to suspect that they would reproducibly affect only four rocks out of 10 analysed by Upadhyay et al. (2009). Although domain mixing may explain apparent “reverse” fractionation trends observed in some TIMS analyses, it cannot be the cause of the apparent negative anomalies in the study of Upadhyay et al. (2009). It was determined that rapid mass fractionation during the course of a multidynamic TIMS analysis can bias all measured Nd ratios. After applying an approximate correction for this effect, only one rock from Upadhyay et al. (2009) retained an apparent negative 142Nd anomaly. This, in conjunction with our new, anomaly-free data set measured at fractionation rates too low to cause bias, leads to the conclusion that the anomalies reported by Upadhyay et al. (2009) are a subtle and reproducible analytical artefact. The absence of negative 142Nd anomalies in these rocks relaxes the need for a mechanism (other than crust formation) that can isolate a Nd reservoir from the convective mantle for billions of years.

Na 1 Nachlass Max Horkheimer, 48 - Korrespondenzen u.a. an Thorsten Sellin (p. I 22, 227-395)

2 Briefe zwischen Luther L. Gobbel und Max Horkheimer, 28.09.1938, 03.10.1938; 2 Briefe zwischen Russell M. Story und Max Horkheimer, 15.03.1938; 1 Brief von Max Horkheimer an Ralph E. Boothby, 14.03.1938; 1 Brief von Max Horkheimer an Roswell G. Ham, 13.01.1938; 2 Briefe von Carl Schurz von der Memorial Foundation Philadelphia an Max Horkheimer, 1940; 7 Briefe zwischen Helen Schuster und Max Horkheimer, 1936, 1937, 1947-1948; 1 Brief von Liesel Schwaibold an Max Horkheimer, 19.01.1937; 6 Briefe zwischen Ph. Schwartz und Max Horkheimer, 1936-1937; 4 Briefe zwischen Ph. Schwart an Ludwig Jekels, 1936, 1937; 1 Brief von Ph. Schwartz an Karl Landauer,; 1 Brief von Eugen Schwarz an den Vater von Max Horkheimer, 08.12.1937; 1 Brief von Max Horkheimer an Eugen Schwarz, 31.12.1937; 5 Briefe zwischen Olga Therese Schwarz und Max Horkheimer, 1942; 8 Briefe zwischen Alfred Schweizer und Max Horkheimer, 1940-1941; 1 Lebenslauf von Arthur Heinrich Schweitzer und 1 Bericht über Arthur Heinrich Schweitzer; 1 Brief von Josef Schwoner an Max Horkheimer, 20.06.1941; 1 Brief von Max Horkheimer an L. H. Seelye, 01.04.1935; 1 Brief von Max Horkheimer an Dora Segall-Ziegellaub, 01.10.1935; 6 Briefe zwischen Matyes Seiber und Max Horkheimer, Juli 1936, 1936; 2 Briefe zwischen Alfred Seidenmann und Max Horkheimer, 29.02.1940, 12.03.1940 sowie Briefwechsel mit dem American Freinds Service Committee, Phiadelphia; 2 Briefe zwischen dem American Friends Service Committee und Max Horkheimer, 12.09.1940; 3 Rundschreiben von der Selbsthilfe Deutscher Ausgewanderter New York, 1937-1938; Antworten auf einen Fragebogen des Selective Service Occupational Questionnaire von Max Horkheimer, 27.10.1942; 1 Brief vom Selfhelp of Emigres from Central Europe an Margot von Mendelssohn, 22.12.1948; 8 Briefe zwischen Edwin R. A. Seligman und Max Horkheimer, 1938-1939; 1 Brief von Max Horkheimer an Eustace Seligman, 11.03.1940; 1 Brief von Seligmann und Cia an Friedrich Pollock, 06.04.1936; 2 Brife zwischen Milton C. Seligman und Max Horkheimer, 1947; 1 Brief Stephen Schäfer an Thorsten Sellin, 07.02.1939; 17 Briefe zwischen Thorsten Sellin und Max Horkheimer, 1938-1941; 1 Brief von der Sherwin Cody School of English an Max Horkheimer, 06.02.1939; 3 Briefe und 1 Beilage zwischen Edward A. Shils und Max Horkheimer, 1938; 10 Briefe zwischen James T. Shotwell und Max Horkheimer, 01.07.1940-1941;