Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia

Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca²⁺, P_i, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)₂-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P<0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.     

Isolation and characterization of plasma membrane-associated cortical granules from sea urchin eggs

Cortical granules, which are specialized secretory organelles found in ova of many organisms, have been isolated from the eggs of the sea urchins Arbacia punctulata and Strongylocentrtus pupuratus by a simple, rapid procedure. Electron micropscope examination of cortical granules prepared by this procedure reveals that they are tightly attached to large segments of the plasma membrane and its associated vitelline layer. Further evidence that he cortical granules were associated with these cell surface layers was obtained by (125)I-labeling techniques. The cortical granule preparations were found to be rich in proteoesterase, which was purified 32-fold over that detected in a crude homogenate. Similarly, the specific radioactivity of a (125)I-labeled, surface glycoprotein was increased 40-fold. These facts, coupled with electron microscope observations, indicate the isolation procedure yields a preparation in which both the cortical granules and the plasma membrane-vitelline layer are purified to the same extent. Gel electrophoresis of the membrane-associated cortical granule preparation reveals the presence of at least eight polypeptides. The major polypeptide, which is a glycotprotein of apparent mol wt of 100,000, contains most of the radioactivity introduced by (125)I-labeling of the intact eggs. Lysis of the cortical granules is observed under hypotonic conditions, or under isotonic conditions if Ca(2+) ion is present. When lysis is under isotonic conditions is induced by addition of Ca(2+) ion, the electron-dense contents of the granules remain insoluble. In contrast, hypotonic lysis results in release of the contents of the granule in a soluble form. However, in both cases the (125)I-labeled glycoprotein remains insoluble, presumably because it is a component of either the plasma membrane or the vitelline layer. All these findings indicate that, using this purified preparation, it should be possible to carry out in vitro studies to better define some of the initial, surface-related events observed in vivo upon fertilization.     

Aggregation-dependent turnover of flagellar adhesion molecules in chlamydomonas gametes

Previous studies on flagellar adhesion in chlamydomonas (Snell, W. and S. Roseman. 1979. J. Biol. Chem. 254:10820-10829.) have shown that as gametes adhere to flagella isolated from gametes of the opposite mating type, the adhsiveness of the added flagella but not of the gametes is lost. The studies reported here show that the addition of protein synthesis inhibitors (cycloheximide [CH] or anisomycin) to the medium of such cell- flagella mixtures causes the cells to lose their adhesiveness. This loss, however, occurs only after the cells have interacted with 4-8 flagella/cell and does not occur if the cells are kept in CH (7 h) without aggregating. The availability of an impotent (imp) mating type plus (MT(+)) mutant (provided by U.W. Goodenough), which adheres but is unable to undergo the fusion that normally follows adhesion, made it possible to determine whether a similar loss of adhesiveness occurs in mixtures of matting type minus (mt(-)) and imp mt(+) gametes. In the absence of inhibitor, mt(-) and imp mt(+) gametes adhered to each other (without fusing) for several hours; however, in the presence of CH or anisomycin, the gametes began to de-adhere 35 min after mixing, and, by 90 min, 100 percent of the cells were single again. This effect was reversible, and the rapid turnover of cells were single again. This effect was reversible, and the rapid turnover of molecules involved in adhesion occurred only during adhesion inasmuch as gametes pretreated for 4 h with CH were able to aggregate in CH for the same length of time as nonpretreated cells aggregated in CH. By the addition of CH at various times after the mt(-) and imp mt(+) gametes were mixed, measurements were made of the “pool size” of the molecules involved in adhesion. The pool reached a minimum after 25 min of aggregation, rapidly increased for the next 25 min, and then leveled off at the premixing level. These results suggest that flagellar adhesion in chlamydomonas causes modification of surface molecules (receptors, ligands), which brings about their inactivation and stimulates their replacement.     

Fallopian Tube Prolapse after Hysterectomy: A Systematic Review

Background

Prolapse of the fallopian tube into the vaginal vault is a rarely reported complication that may occur after hysterectomy. Clinicians can miss the diagnosis of this disregarded complication when dealing with post-hysterectomy vaginal bleeding.

Objectives

We performed a systematic review in order to describe the clinical presentation, therapeutic management and outcome of fallopian tube prolapse occurring after hysterectomy.

Search Strategy

A systematic search of MEDLINE and EMBASE references from January 1980 to December 2010 was performed. We included articles that reported cases of fallopian tube prolapse after hysterectomy. Data from eligible studies were independently extracted onto standardized forms by two reviewers.

Results

Twenty-eight articles including 51 cases of fallopian tube prolapse after hysterectomy were included in this systematic review. Clinical presentations included abdominal pain, dyspareunia, post- coital bleeding, and/or vaginal discharge. Two cases were asymptomatic and diagnosed at routine checkup. The surgical management reported comprised partial or total salpingectomy, with vaginal repair in some cases combined with oophorectomy using different approaches (vaginal approach, combined vaginal-laparoscopic approach, laparoscopic approach, or laparotomy). Six patients were initially treated by silver nitrate application without success.

Conclusions

This systematic review provided a precise summary of the clinical characteristics and treatment of patients presenting with fallopian tube prolapse following hysterectomy published in the past 30 years. We anticipate that these results will help inform current investigations and treatment.     

Role of the orbital prefrontal cortex in choice between delayed and uncertain reinforcers: a quantitative analysis

'Inter-temporal choice' refers to choice between two or more outcomes that differ with respect to their sizes, delays, and/or probabilities of occurrence. According to the multiplicative hyperbolic model of inter-temporal choice, the value of a reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its delay and the odds against its occurrence. These functions, each of which contains a single discounting parameter, are assumed to combine multiplicatively to determine the overall value of the reinforcer. The model gives rise to a quantitative methodology for analysing inter-temporal choice, based on a family of linear null equations which describe performance under conditions of indifference, when the values of the reinforcers are assumed to be equal. This approach was used to examine the effect of lesions of the orbital prefrontal cortex (OPFC) on inter-temporal choice in rats. Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC or sham lesions. They were trained to press two levers (A and B) for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of a pellet after a delay d(A) with a probability P=0.5; a press on B resulted in delivery of a pellet with a probability P=1 after a delay d(B). d(B) was increased progressively across successive blocks of six trials in each session, while d(A) was manipulated systematically across phases of the experiment. The indifference delays, d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d(B(50)) versus d(A) were derived, and the parameters of the function compared between the groups. In both groups, d(B(50)) increased linearly with d(A). The slope of the linear function was significantly steeper in the lesioned group than in the sham-lesioned group, whereas the intercept did not differ significantly between the groups. Analysis based on the relevant null equation indicated that the lesion of the OPFC increased the rate of both delay and odds discounting. Possible implications of the results for interpreting the effects of OPFC lesions on inter-temporal choice behaviour in man are discussed.     

Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690]

Background

Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect.

Methods

Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.

Results

No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period.

Conclusions

Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.     

Evolutionary distances for protein-coding sequences: modeling site- specific residue frequencies

Estimation of evolutionary distances from coding sequences must take into account protein-level selection to avoid relative underestimation of longer evolutionary distances. Current modeling of selection via site-to-site rate heterogeneity generally neglects another aspect of selection, namely position-specific amino acid frequencies. These frequencies determine the maximum dissimilarity expected for highly diverged but functionally and structurally conserved sequences, and hence are crucial for estimating long distances. We introduce a codon- level model of coding sequence evolution in which position-specific amino acid frequencies are free parameters. In our implementation, these are estimated from an alignment using methods described previously. We use simulations to demonstrate the importance and feasibility of modeling such behavior; our model produces linear distance estimates over a wide range of distances, while several alternative models underestimate long distances relative to short distances. Site-to-site differences in rates, as well as synonymous/nonsynonymous and first/second/third-codon-position differences, arise as a natural consequence of the site-to-site differences in amino acid frequencies.      

Early steps in plastid evolution: current ideas and controversies

Some nuclear‐encoded proteins are imported into higher plant plastids via the endomembrane (EM) system. Compared with multi‐protein Toc and Tic translocons required for most plastid protein import, the relatively uncomplicated nature of EM trafficking led to suggestions that it was the original transport mechanism for nuclear‐encoded endosymbiont proteins, and critical for the early stages of plastid evolution. Its apparent simplicity disappears, however, when EM transport is considered in light of selective constraints likely encountered during the conversion of stable endosymbionts into fully integrated organelles. From this perspective it is more parsimonious to presume the early evolution of post‐translational protein import via simpler, ancestral forms of modern Toc and Tic plastid translocons, with EM trafficking arising later to accommodate glycosylation and/or protein targeting to multiple cellular locations. This hypothesis is supported by both empirical and comparative data, and is consistent with the relative paucity of EM‐based transport to modern primary plastids.