Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration.

BackgroundOne potential mechanism for early superficial cartilage wear in normal joints is alteration of the lubricant content and quality of synovial fluid. The purpose of this study was to determine if the concentration and quality of the lubricant, hyaluronan, in synovial fluid: (1) was similar in left and right knees; (2) exhibited similar age-associated trends, whether collected postmortem or antemortem; and (3) varied with age and grade of joint degeneration.MethodsHuman synovial fluid of donors (23-91 years) without osteoarthritis was analyzed for the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5-7 MDa, 1-2.5 MDa, 0.5-1 MDa, and 0.03-0.5 MDa. Similarity of data between left and right knees was assessed by reduced major axis regression, paired t-test, and Bland-Altman analysis. The effect of antemortem versus postmortem collection on biochemical properties was assessed for age-matched samples by unpaired t-test. The relationships between age, joint grade, and each biochemical component were assessed by regression analysis.ResultsJoint grade and the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5-7 MDa, 1-2.5 MDa, and 0.5-1 MDa in human synovial fluid showed good agreement between left and right knees and were similar between age-matched patient and cadaver knee joints. There was an age-associated decrease in overall joint grade (-15 %/decade) and concentrations of hyaluronan (-10.5 %/decade), and hyaluronan in the molecular weight ranges of 2.5-7 MDa (-9.4 %/decade), 1-2.5 MDa (-11.3 %/decade), 0.5-1 MDa (-12.5 %/decade), and 0.03-0.5 MDa (-13.0 %/decade). Hyaluronan concentration and quality was more strongly associated with age than with joint grade.ConclusionsThe age-related increase in cartilage wear in non-osteoarthritic joints may be related to the altered hyaluronan content and quality of synovial fluid

Stock Composition of Some Sockeye Salmon, Oncorhynchus nerka, Catches in Southeast Alaska, Based on Incidence of Allozyme Variants, Freshwater Ages, and a Brain-Tissue Parasite

The incidence of four discrete characters of individual sockeye salmon -two genetically inherited proteins (PGM-1*and PGM-2*), freshwater age at migration, and the presence of the brain-tissue parasite Myxobolus arcticus-in weekly samples from two Alaskan fisheries (Noyes Island in 1986 and Sumner Strait in 1987) were used to infer stock composition of the catches based on corresponding character samples from 73 Alaskan and Canadian stocks. Estimated contributions of 13 stock groups, formed on the basis of character similarity of their members, were roughly consistent with expectations from tagging experiments, knowledge of stock magnitudes, and similar assessments from scales. Imprecision of the estimated contributions by the 13 stock groups limited their practical value; but variability was much reduced for combined estimated contributions by two inclusive categories, namely stock groups whose members had either high or low brainparasite prevalence. Noyes Island catches consisted predominantly of unparasitized fish, most of which were probably of Canadian origin. The majority of Sumner Strait catches consisted of parasitized fish, whose freshwater origins may have been in Alaska or Canada. (PDF file contains 27 pages.

Large inter-stock differences in catch size-at-age of mature Atlantic salmon observed by using genetic individual origin assignment from catch data

Genetic individual assignment of river stock of origin of mixed stock catch fish offers a tool to analyze size differences among river stocks. Data on the genetically identified river stock of origin of individual fish from commercial mixed stock catches were used to compare the catch size-at-age of mature Atlantic salmon catch fish (Salmo salar) from different rivers in the Baltic Sea. In this application of genetic mixed stock modeling, individual assignments of the river stock of origin were analyzed together with length- and weight-at-age data for individual catch fish. The use of four genetic stock identification based methods was compared for defining the length distributions of caught mature salmon in different river stocks. The catch data included information on maturing salmon in the northern Baltic Sea over the years 2000-2013. DNA microsatellite data on 17 loci and information on the smoltification age were used to assign spawners to their stock of origin. All of the compared methods for using probabilistic stock of origin data in our case yielded very similar estimates of the final mean length distributions of the stocks. The Bayesian mixture model yielded slightly more conservative estimates than the direct probability method, threshold method, or the modified probability method. The catch size between spawners of a same sex and age from river stocks differed significantly and the differences were large. The mean catch weight of 1-sea-winter old mature males in different rivers varied from 1.9 kg to 2.9 kg, from 5.1 kg to 7.5 kg for 2-sea-winter old males, from 5.0 kg to 7.2 kg for 2-sea-winter old females, and from 8.2 kg to 10.8 kg for 3-sea-winter-old females. The mean size of caught wild salmon spawners in each year-class was on average smaller than that of the hatchery-reared and sea ranched stocks

Comparing autonomous underwater vehicle (AUV) and vessel-based tracking performance for locating acoustically tagged fish

Autonomous underwater vehicles (AUV’s) are increasingly used to collect physical, chemical, and biological information in the marine environment. Recent efforts include merging AUV technology with acoustic telemetry to provide information on the distribution and movements of marine fish. We compared surface vessel and AUV tracking capabilities under rigorous conditions in coastal waters near Juneau, Alaska. Tracking surveys were conducted with a REMUS 100 AUV equipped with an integrated acoustic receiver and hydrophone. The AUV was programmed to navigate along predetermined routes to detect both reference transmitters at 20–500 m depths and tagged fish and crabs in situ. Comparable boat surveys were also conducted. Transmitter depth had a major impact on tracking performance. The AUV was equally effective or better than the boat at detecting reference transmitters in shallow water, and significantly better for transmitters at deeper depths. Similar results were observed for tagged animals. Red king crab, Paralithodes camtschaticus, at moderate depths were recorded by both tracking methods, while only the AUV detected Sablefish, Anoplopoma fimbria, at depths exceeding 500 m. Strong currents and deep depths caused problems with AUV navigation, position estimation, and operational performance, but reflect problems encountered by other AUV applications that will likely diminish with future advances, enhanced methods, and increased use

Distribution, Stock Composition and Timing, and Tagging Response of Wild Chinook Salmon Returning to a Large, Free-Flowing River Basin

Chinook Salmon Oncorhynchus tshawytscha returns to the Yukon River basin have declined dramatically since the late 1990s, and detailed information on the spawning distribution, stock structure, and stock timing is needed to better manage the run and facilitate conservation efforts. A total of 2,860 fish were radio-tagged in the lower basin during 2002–2004 and tracked upriver. Fish traveled to spawning areas throughout the basin, ranging from several hundred to over 3,000 km from the tagging site. Similar distribution patterns were observed across years, suggesting that the major components of the run were identified. Daily and seasonal composition estimates were calculated for the component stocks. The run was dominated by two regional components comprising over 70% of the return. Substantially fewer fish returned to other areas, ranging from 2% to 9% of the return, but their collective contribution was appreciable. Most regional components consisted of several principal stocks and a number of small, spatially isolated populations. Regional and stock composition estimates were similar across years even though differences in run abundance were reported, suggesting that the differences in abundance were not related to regional or stock-specific variability. Run timing was relatively compressed compared with that in rivers in the southern portion of the species’ range. Most stocks passed through the lower river over a 6-week period, ranging in duration from 16 to 38 d. Run timing was similar for middle- and upper-basin stocks, limiting the use of timing information for management. The lower-basin stocks were primarily later-run fish. Although differences were observed, there was general agreement between our composition and timing estimates and those from other assessment projects within the basin, suggesting that the telemetry-based estimates provided a plausible approximation of the return. However, the short duration of the run, complex stock structure, and similar stock timing complicate management of Yukon River returns

The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor

The orphan receptor CRF2-4 is a member of the class II cytokine receptor family (CRF2), which includes the interferon receptors, the interleukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF2-4, is located within a gene cluster on human chromosome 21 that comprises three interferon receptor subunits. To elucidate the role of CRF2-4, we disrupted the CRFB4 gene in mice by means of homologous recombination. Mice lacking CRF2-4 show no overt abnormalities, grow normally, and are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By ∼12 wk of age, the majority of mutant mice raised in a conventional facility developed a chronic colitis and splenomegaly. Thus, CRFB4 mutant mice recapitulate the phenotype of IL-10–deficient mice. These findings suggest that CRF2-4 is essential for IL-10–mediated effects and is a subunit of the IL-10 receptor

New Copy Number Variations in Schizophrenia

Genome-wide screenings for copy number variations (CNVs) in patients with schizophrenia have demonstrated the presence of several CNVs that increase the risk of developing the disease and a growing number of large rare CNVs; the contribution of these rare CNVs to schizophrenia remains unknown. Using Affymetrix 6.0 arrays, we undertook a systematic search for CNVs in 172 patients with schizophrenia and 160 healthy controls, all of Italian origin, with the aim of confirming previously identified loci and identifying novel schizophrenia susceptibility genes. We found five patients with a CNV occurring in one of the regions most convincingly implicated as risk factors for schizophrenia: NRXN1 and the 16p13.1 regions were found to be deleted in single patients and 15q11.2 in 2 patients, whereas the 15q13.3 region was duplicated in one patient. Furthermore, we found three distinct patients with CNVs in 2q12.2, 3q29 and 17p12 loci, respectively. These loci were previously reported to be deleted or duplicated in patients with schizophrenia but were never formally associated with the disease. We found 5 large CNVs (>900 kb) in 4q32, 5q14.3, 8q23.3, 11q25 and 17q12 in five different patients that could include some new candidate schizophrenia susceptibility genes. In conclusion, the identification of previously reported CNVs and of new, rare, large CNVs further supports a model of schizophrenia that includes the effect of multiple, rare, highly penetrant variants

Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission

The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5–20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca2+-activated K+ channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation