Transforming growth factor-beta trans-modulates the expression of colony stimulating factor receptors on murine hematopoietic progenitor cell lines

Transforming growth factor beta (TGF-beta) is a potent and selective growth inhibitor of early hematopoietic progenitors and leukemic cells. The cellular mechanism(s) underlying this antiproliferative effect is, however, currently unknown. In the present study, we demonstrate that TGF-beta inhibits the expression of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3), and granulocyte-CSF (G-CSF) receptors on murine factor-dependent and independent hematopoietic progenitor cell lines without a significant change in receptor affinity. A maximum reduction in GM-CSF receptor numbers of 65% to 77% was observed by 96-hour incubation with TGF-beta. The TGF- beta induced trans-down-modulation of GM-CSF receptors was prolonged, noncytotoxic but reversible, and not due to endogenous production of GM- CSF. The TGF-beta induced reduction in CSF receptor numbers preceded TGF-beta's growth inhibitory action. In addition, the ED50 (1 to 10 pmol/L) for TGF-beta's CSF receptor modulatory and antiproliferative effect was similar. The effect of TGF-beta on cell surface CSF receptor expression was specific, because the expression of other cell surface proteins (Ly 5 and Ly 17) was not affected by TGF-beta treatment, and because other growth inhibitors (tumor necrosis factor and interferon) did not affect CSF receptor expression. These data suggest that the downregulation of the growth of hematopoietic progenitor cells by TGF- beta involves reducing the cell surface expression on growth factor receptors.     

Multicentric reticulohistiocytosis: a rare cause of erosive arthropathy of the distal interphalangeal finger joints

BACKGROUND: Multicentric reticulohistiocytosis (MRH) is a rare systemic disease, presenting with typical skin abnormalities and erosive polyarthritis, which is often associated with malignancy. CASE REPORT: A case of MRH arthropathy, in which the typical nodular skin manifestation of the disease was absent, is described in a patient with a past history of breast cancer and no evidence of recurrent or new malignancy. RESULTS: Careful clinical and roentgenological evaluation disclosed important clues to differentiate this condition from other more common distal interphalangeal arthritides--namely, osteoarthritis and its "erosive" variant, rheumatoid arthritis, psoriatic arthritis, tophaceous gout, dialysis related hand arthropathy, and from the rarer fibroblastic rheumatism, all of which can be mimicked by MRH. Histopathology showed the characteristic histiocytic and multinucleated giant cell infiltrate with ground glass cytoplasm, and immunohistochemical analysis showed markers evocative of a monocyte/macrophage origin of MRH.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Detection of circulating crosslinked fibrin derivatives by a heat extraction-SDS gradient gel electrophoretic technique

A technique has been developed to identify and quantitate unique plasmic degradation products of crosslinked fibrin in plasma. In this method, fibrin derivatives are extracted by heat precipitation and dissolved with disulfide bond reduction, after which the crosslinked gamma-gamma chain remnants are identified by SDS-polyacrylamide gradient gel electrophoresis and quantitated by densitometric analysis. A heterogenous group of gamma-gamma chains with molecular weights between 100,000 and 76,000 daltons was identified in lysates of crosslinked fibrin during plasmic degradation in vitro. Three stages of crosslinked fibrin degradation have been arbitrarily defined based primarily on the extent of degradation of these gamma-gamma polypeptide chains. As little as 20 microgram of crosslinked fibrin digests added to 1 ml of normal plasma could be detected by the heat-extraction--gel- electrophoresis technique, identifying the gamma-gamma derivatives with molecular weights of 96,000, 86,000, 82,000, and 76,000 daltons. Plasmic derivatives of gamma-gamma chains were not found in normal plasma, but they were identified in the plasma of patients with disseminated intravascular coagulation and deep-vein thrombosis, both before and in increased quantity during successful thrombolytic therapy.     

Fat body mass, leptin and femur bone mineral density in hip-fractured women

Fat body mass (FBM) is a strong predictor of both bone mineral density (BMD) and risk of hip fracture, but the mechanisms responsible are not completely understood. We addressed whether leptin is the link between FBM and BMD in hip-fractured women. Sixty-two of 74 women with hip fractures were evaluated. Serum leptin was measured by radioimmunoassay, 23.4+/-9.1 days (mean+/-SD) after fracture occurrence. BMD and body composition were assessed by dual-energy X-ray absorptiometry (DXA). As expected, a positive linear correlation was found between FBM and both leptin (r=0.782; p<0.001) and femur BMD measured at five sites (r value ranging from 0.293 to 0.498 depending on the site of the femur BMD assessment, p<0.05). A positive correlation between leptin and BMD measured at the intertrochanteric area (r=0.259; p<0.05) but not at the other four sites was shown. At linear multiple regression [dependent variable = femur BMD; independent variables = age, weight, height, body mass index, fracture type, term fracture-DXA, Barthel index score, FBM, lean body mass, serum PTH, serum 25(OH)vitamin D and leptin], FBM was positively associated with BMD measured at all the five sites. The association between leptin and BMD was inverse and it was significant at four of the five sites of the BMD assessment. In conclusion, in a sample of hip-fractured women, the positive association between FBM and femur BMD was not explained by serum leptin. On the contrary, after adjustment for FBM and other confounding variables, an inverse association between leptin and BMD was found.     

Effect of phosphodiesterase inhibitors on Sertoli cell refractoriness: reversal of the impaired androgen aromatization

Responsiveness of the Sertoli cell after FSH pretreatment was evaluated in terms of androgen aromatization. Sertoli cell cultures were preincubated with FSH for 24 h, then cells were washed free of hormone and reincubated with FSH in the presence of androstendione. The estrogen accumulated in the medium was measured by RIA. Gonadotropin pretreatment produced a marked refractory state, and a second challenge with FSH did not produce an increase in androgen aromatization. A dose-response study showed that FSH pretreatment produced three separate effects on Sertoli cell steroidogenesis: an increased basal production of estrogen; a decreased maximal response when doses of 10 ng/ml FSH or higher were employed in the preincubation; and a decreased sensitivity of the Sertoli cell to FSH. In the last case, the ED50 was reduced approximately 3- to 5-fold. Such an impaired stimulation of androgen aromatization was no longer present when cells were incubated with the phosphodiesterase inhibitors methyl-isobutyl-xanthine (MIX). In the presence of this inhibitor, refractory cells responded to FSH better than the control cells. The possibility that MIX stimulated cAMP accumulation by acting as antagonist of purine receptor was ruled out by the finding that the nonxanthine phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)2-imidazolidinone (Ro 20-1724) also reverted the refractory state. Pretreatment of the Sertoli cells with FSH produced an impaired response in the second incubation also to isoproterenol, cholera toxin, and forskolin. The response to these compounds was apparently normal when cells were incubated in the presence of MIX or Ro 20-1724. Conversely, refractory cells responded to (Bu)2cAMP in a manner indistinguishable from the fully responsive control cells. These data demonstrate that FSH induces homologous and heterologous refractory states of the Sertoli cell reflected by an impaired estrogen production. The finding that phosphodiesterase inhibitors fully restore the FSH response suggests an important role of phosphodiesterase in the induction and/or maintenance of such refractoriness.     

Earliest Videofluoromanometric Pharyngeal Signs of Dysphagia in ALS Patients

The aim of this study was to find whether there are manometric pharyngeal changes that may have diagnostic and prognostic relevance in the amyotrophic lateral sclerosis (ALS) patient who does not show changes in contrast-medium oropharyngeal transit in a videofluoroscopic swallowing study. Ten ALS patients, with an ALS Severity Scale Score of at least 7, no need to change dietary habit, no aspiration and/or penetration, and no other changes in contrast-medium oropharyngeal transit, were collected from our institution’s database of videofluoromanometric swallowing studies. They were included in the study together with a group of 11 healthy volunteers. For each subject, 12 manometric items—7 for the pharyngeal phase and 5 for UES functionality—were evaluated. Statistically significant differences between the ALS patients and the healthy volunteers were found for pharyngeal contraction time of the upper region (median = 1,120, range = 880–1,420 vs. median = 970, range = 800–1,140), pharyngeal contraction time of the intermediate region (median = 1140, range = 960–1,360 vs. median = 770, range = 280–1,180), pharyngeal contraction time of the lower region (median = 1,320, range = 920–1,760 vs. median = 800, range = 620–1,780), and residual pressure after the relaxation of the UES (median = 2.2, range = ?20.2 to 27.8 vs. median = ?5.7, range = ?2.9 to 8.4). A videofluoromanometric swallowing study may show an increase in the pharyngeal contraction time and in residual pressure after relaxation of the UES in ALS patients without videofluoroscopic changes in contrast-medium oropharyngeal transit.     

Successful use of the Impella Recover LP 5.0 device for circulatory support during off-pump coronary artery bypass grafting

INTRODUCTION

Surgical coronary revascularization is being performed with ever increasing frequency in patients at high surgical risk. Off-pump coronary artery bypass grafting (OPCABG) is particularly appealing in such subjects, but may limit the options for concomitant mechanical circulatory support.

PRESENTATION OF CASE

We hereby report an original case of mechanical circulatory support with the Impella Recover LP 5.0 device during OPCABG in a 61-year-old gentleman with multiple comorbidities and severe left ventricular systolic dysfunction. Specifically, the soft tipped device did not impede surgical manipulation of the heart during the surgical procedure, providing uninterrupted circulatory support to the patient.

DISCUSSION

This clinical vignette supports the feasibility, safety and efficacy of the Impella Recover LP 5.0 device in patients undergoing OPCABG.

CONCLUSION

Pending further studies, use of the Impella Recover LP 5.0 device can be envisioned safely for OPCABG.     

Parathyroid-hormone variance is only marginally explained by a panel of determinants: a cross-sectional study of 909 hip-fracture patients

Several factors affect the levels of parathyroid hormone (PTH) in hip-fracture patients. We hypothesized that a panel of easily assessable determinants could account for both a substantial proportion of PTH variance and the occurrence of secondary hyperparathyroidism. We evaluated 909 of 981 hip-fracture inpatients admitted consecutively to our Rehabilitation division. In each patient we assessed PTH, 25-hydroxyvitamin D, albumin-adjusted total calcium, phosphate, magnesium, and creatinine on a fasting blood sample 21.3 ± 6.1 (mean ± SD) days after fracture occurrence. Glomerular filtration rate (GFR) was estimated by the 4-variable Modification of Diet in Renal Disease Study equation. Functional level was assessed using the Barthel index. On multivariate analysis, six factors (phosphate, albumin-adjusted total calcium, estimated GFR (eGFR), 25-hydroxyvitamin D, age, and magnesium) were significantly associated with PTH levels. Overall, the panel of variables accounted for 23.7 % of PTH variance. Among the 909 patients, 304 (33.4 %) had PTH levels exceeding the normal range. Six factors (phosphate, albumin-adjusted total calcium, eGFR, 25-hydroxyvitamin D, age, and Barthel index scores) were significantly associated with the category of PTH level (either normal or elevated). The model correctly classified 70.4 % of cases. For the optimal cut-off point, sensitivity was 80 % and specificity was 61 %. Data shows that six factors were significantly associated with PTH levels in hip-fracture inpatients. However, the six factors accounted for only 23.7 % of PTH variance and the presence or absence of secondary hyperparathyroidism was correctly categorized in a modest proportion of cases. We conclude that more knowledge is needed on the factors affecting PTH levels after hip fracture.