Intracellular pH in human skeletal muscle by 1H NMR.

We report here the in vivo observation of the imidazole protons (C-2 and C-4) of carnosine (beta-Ala-His) by 1H NMR at 4.7 T in human skeletal muscle. The relationship between the pH and chemical shift of the C-2 and C-4 resonances was determined analytically. These titration curves were used to measure the resting pH of human muscle in vivo, 7.01 x 0.04 (C-2 proton) and 6.97 +/- 0.10 (C-4 proton). An in vivo titration curve of the C-2 proton resonance was determined by interleaving 1H and 31P NMR spectra after exhaustive exercise, during which muscle pH recovers from an acidic value of 6.1. We observed excellent agreement between the pH values as determined by the C-2 resonance of carnosine and that of inorganic phosphate. Carnosine provides an excellent pH indicator since (i) its concentration is relatively stable and (ii) it allows measurement of proton metabolites and pH to be achieved through the same coil, thus enabling a better signal/noise ratio and better localization.     

Detecting intraannual dietary variability in wild mountain gorillas by stable isotope analysis of feces

We use stable isotope ratios in feces of wild mountain gorillas (Gorilla beringei) to test the hypothesis that diet shifts within a single year, as measured by dry mass intake, can be recovered. Isotopic separation of staple foods indicates that intraannual changes in the isotopic composition of feces reflect shifts in diet. Fruits are isotopically distinct compared with other staple foods, and peaks in fecal δ¹³C values are interpreted as periods of increased fruit feeding. Bayesian mixing model results demonstrate that, although the timing of these diet shifts match observational data, the modeled increase in proportional fruit feeding does not capture the full shift. Variation in the isotopic and nutritional composition of gorilla foods is largely independent, highlighting the difficulty for estimating nutritional intake with stable isotopes. Our results demonstrate the potential value of fecal sampling for quantifying short-term, intraindividual dietary variability in primates and other animals with high temporal resolution even when the diet is composed of C₃ plants.     

Statins may reduce femoral osteolysis in patients with total Hip arthroplasty

In experimental studies, statin use has been associated with reduction of osteoclastic activity and promotion of bone formation around implants. Moreover, a large clinical study recently reported a substantially reduced risk of revision for aseptic loosening among statin users with THA. Our objective was to evaluate the influence of statin use on the development of femoral osteolysis within 5 years after THA. We conducted a case‐cohort study including all THAs presenting with femoral osteolysis at the 5 year visit (cases) and compared them with those without osteolysis (controls). Cases and controls were identified from a cohort of primary THAs operated between 2001 and 2005. Seven hundred thirty‐five THAs were included, mean age 68 years. Five years after surgery osteolysis had developed around the femoral component of 40 THAs (5.4%). Ever‐use of statins was much less frequent among cases (5 of 40, 12.5%) than among controls (199 of 695, 28.6%). The crude risk ratio of femoral osteolysis among statin users was 0.36 (95% CI 0.14; 0.92). After adjusting for age, sex, activity level, BMI, diagnosis, bearing surface, and type of stem, the adjusted risk ratio was 0.38 (95% CI 0.15; 0.99). In conclusion, statin use was associated with a reduced risk of developing femoral osteolysis 5 years after THA. Statins may be useful for reducing the risk of implant failure following THA. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 814–820, 2013     

MELD-XI Scores Correlate with Post-Fontan Hepatic Biopsy Fibrosis Scores

We tested the hypothesis that MELD-XI values correlated with hepatic total fibrosis scores obtained in 70 predominately stable, post-Fontan patients that underwent elective cardiac catheterization. We found a statistically significant correlation between MELD-XI values and total fibrosis scores (p = 0.003). Thus, serial MELD-XI values may be an additional useful clinical parameter for follow-up care in post-Fontan patients.     

Suppressor of cytokine signaling in allergic inflammation

The immunopathological hallmark of allergic diseases is elevated total and allergen specific serum IgE levels along with inflammation. This inflammation results from the activation of a cadre of hematopoietic and nonhematopoetic cells. This coordinated activation is the result of the increased production of a variety of soluble factors including chemokines and cytokines. The magnitude and the duration of cytokine action will determine the response to an allergen, either mounting a low-grade immunologic response or resulting in exaggerated reaction such as asthma or atopic dermatitis. Thus, the action of cytokines is tightly regulated both developmentally and within the cell. The suppressor of cytokine signaling (SOCS) protein family represents a novel group of cytoplasmic negative feedback regulators of type I and II cytokines. Several of the signaling pathways regulated by SOCS proteins are important in allergic immune responses. Thus, SOCS proteins may be important regulators of atopy.     

Strong association between smoking and the risk of revision in a cohort study of patients with metal‐on‐metal total hip arthroplasty

Thus far the ability to predict who will develop early failure following the insertion of a metal‐on‐metal (MoM) bearing has been very limited. Our objective was to assess the effect of smoking on failure rates in patients with MoM bearing, compared with patients with ceramic‐on‐polyethylene (CoP) bearing. From a prospective hospital‐based registry we included all primary THAs operated upon between 1/2001 and 12/2011 with MoM or CoP bearings of the same cup design and head size (28 mm). We compared revision rates through 10/2013 classified by smoking status and type of bearing. We included 1,964 patients (median age 71, 57% women), 663 with MoM and 1,301 with CoP bearing. Mean follow‐up was 6.9 years (range 1.8–12.8). Revisions were required for 56 THAs. In patients with MoM bearing the adjusted incidence rate of revision among ever‐smokers was four times greater than among never‐smokers (95% CI 1.4–10.9). Among those with CoP bearing, the rate ratio was only 1.3 (95% CI 0.6–2.5). We found a strong association between smoking and increased failure of MoM THAs. In contrast, the association was weak for patients with CoP bearing. Smoking might be a trigger or an effect amplifier for adverse reactions to metal debris from MoM bearings. © 2014 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 32:762–768, 2014.     

In Vitro Comparison of Two Different Mechanical Circulatory Support Devices Installed in Series and in Parallel

This study investigates the novel approach of placing a ventricular assist pump in the descending aorta in series configuration with the heart and compares it with the two traditional approaches of left‐ventricle‐to‐ascending‐aorta (LV‐AA) and left‐ventricle‐to‐descending‐aorta (LV‐DA) placement in parallel with the heart. Experiments were conducted by using the in‐house simulator of the cardiovascular blood‐flow loop (SCVL). The results indicate that the use of the LV‐AA in‐parallel configuration leads to a significant improvement in the systemic and pulmonic flow as the level of continuous flow is increased; however, this approach is considered highly invasive. The use of the LV‐DA in‐parallel configuration leads to an improvement in the systemic and pulmonic flow at lower levels of continuous flow but at higher levels of pump support leads to retrograde flow. In both in‐parallel configurations, increasing the level of pump continuous flow leads to a decrease in pulsatility to a certain extent. The results of placing the pump in the descending aorta in series configuration show that the pressure drop upstream of the pump facilitates cardiac output as a result of afterload reduction. In addition, the pressure rise downstream of the pump may assist with renal perfusion. However, at the same time, the pressure drop generated at the proximal part of the descending aorta induces a slight drop in carotid perfusion, which would be autoregulated by the brain in a native cardiovascular system. The pulse wave analysis shows that placing the pump in the descending aorta leads to improved pulsatility in comparison with the traditional in‐parallel configurations.     

Enzymatic phosphorylation of muscle glycogen synthase: a mechanism for maintenance of metabolic homeostasis.

We recently analyzed experimental studies of mammalian muscle glycogen synthesis using metabolic control analysis and concluded that glycogen synthase (GSase) does not control the glycogenic flux but rather adapts to the flux which is controlled bv the activity of the proximal glucose transport and hexokinase steps. This model did not provide a role for the well established relationship between GSase fractional activity, determined by covalent phosphorylation, and the rate of glycogen synthesis. Here we propose that the phosphorylation of GSase, which alters the sensitivity to allosteric activation by glucose 6-phosphate (G6P), is a mechanism for controlling the concentration of G6P instead of controlling the flux. When the muscle cell is exposed to conditions which favor glycogen synthesis such as high plasma insulin and glucose concentrations the fractional activity of GSase is increased in coordination with increases in the activity of glucose transport and hexokinase. This increase in GSase fractional activity helps to maintain G6P homeostasis by reducing the G6P concentration required to activate GSase allosterically to match the flux determined by the proximal reactions. This role for covalent phosphorylation also provides a novel solution to the Kacser and Acarenza paradigm which requires coordinated activity changes of the enzymes proximal and distal to a shared intermediate, to avoid unwanted flux changes.