Systematic mechanism-orientated approach to chronic pancreatitis pain

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.     

Statins,plasma cholesterol,and risk of Parkinson's disease: A prospective study

Previous findings on the association of statins, plasma lipids, and Parkinson's disease (PD) are confounded by the fact that statins also affect lipid profiles. We prospectively examined plasma lipids and statin use in relation to PD in the Atherosclerosis Risk in Communities (ARIC) Study. Statin use and plasma lipids were assessed at baseline (visit 1, 1987‐89) and at three triennial visits thereafter (visits 2‐4) until 1998. Potential PD cases were identified from multiple sources and validated where possible. The primary analysis was limited to incident PD cases diagnosed between 1998 and 2008. Odds ratios and 95% confidence intervals were derived from multivariate logistic regression models. Statin use was rare at baseline (0.57%) but increased to 11.2% at visit 4. During this time frame, total‐cholesterol levels decreased, particularly among statin users. Fifty‐six PD cases were identified after 1998. Statin use before 1998 was associated with significantly higher PD risk after 1998 (odds ratio = 2.39, 95% confidence interval 1.11‐5.13) after adjusting for total cholesterol and other confounders. Conversely, higher total cholesterol was associated with lower risk for PD after adjustment for statin usage and confounders. Compared with the lowest tertile of average total cholesterol, the odds ratios for PD were 0.56 (0.30‐1.04) for the second and 0.43 (0.22‐0.87) for the third tertile (P_trend = 0.02). Statin use may be associated with a higher PD risk, whereas higher total cholesterol may be associated with lower risk. These data are inconsistent with the hypothesis that statins are protective against PD. © 2015 International Parkinson and Movement Disorder Society     

Monoclonal antibody BA-1 does not bind to hematopoietic precursor cells

Monoclonal antibody BA-1 binds to B lymphocytes, to cells from most cases of non-T acute lymphoblastic leukemia (ALL), and weakly to neutrophils. To determine whether BA-1 also reacts with hematopoietic progenitor cells (HPC), we studied the effect of removal of BA-1+ cells from human bone marrow on the proliferation in vitro of the trilineage precursor cell CFU-GEMM, and on the committed progenitor cells of granulopoiesis (CFU-C) and erythropoiesis (BFU-E/CFU-E). Complement- mediated cytotoxicity using BA-1 at concentrations far beyond those required to lyse BA-1+ bone marrow cells and ALL cells did not result in inhibition of colony formation in any of the assays. A rosette separation method, using ox red blood cells coated with BA-1, resulted in enrichment of HPC in the BA-1-depleted interface, whereas very few HPC were found in the BA-1-enriched pellet. Both methods indicate that BA-1 does not bind to HPC, although binding of the antibody to the lymphohematopoietic stem cell cannot be excluded yet. The high cytotoxic capacity of the IgM antibody BA-1, and the lack of reactivity with HPC, make the antibody particularly suitable for use in autologous bone marrow transplantation for patients with ALL.     

Biallelic neutrophil Na-antigen system is associated with a polymorphism on the phospho-inositol-linked Fc gamma receptor III (CD16)

Neutrophils express two distinct types of receptor for the Fc region of IgG, FcRII and FcRIII, in amounts of 10,000 to 20,000 FcRII (40 Kd) and 100,000 to 200,000 FcRIII (50 to 80 Kd) per neutrophil. We showed that the FcRIII exhibits genetically determined heterogeneity, detectable by differences in electrophoretic mobility with sodium dodecyl sulfate (SDS) as well as by reaction with antibodies against the biallelic neutrophil-specific antigen system NA. FcRIII was precipitated with an FcRIII-specific monoclonal antibody (MoAb) from the neutrophils of 35 donors. NA1NA1 donors expressed an FcRIII with a molecular weight (mol wt) of 50 to 65 Kd, NA1NA2 donors expressed an FcRIII with a mol wt of 50 to 80 Kd, and NA2NA2 donors expressed an FcRIII with a mol wt of 65 to 80 Kd. Statistical analysis showed that the electrophoretic heterogeneity corresponds with the NA polymorphism (k = 1). Sequential immunoprecipitation with a MoAb against NA1 and a MoAb against anti- FcRIII, followed by SDS-polyacrylamide gel electrophoresis (PAGE), showed that NA1-FcRIII is distinct from NA2-FcRIII. Moreover, immunoprecipitation with a MoAb against NA1 yielded a protein of 50 to 65 Kd, and immunoprecipitation with human anti-NA2 sera or an MoAb against NA2 yielded a protein of 65 to 80 Kd. Preincubation of NA1NA2 neutrophils with F(ab')2 fragments of an MoAb against anti-NA1 reduced binding of IgG dimers to these cells with about 50%, whereas it completely prevented binding of the dimers to NA1NA1 neutrophils. Inhibition experiments with the MoAb against NA2 yielded the same results for NA1NA2 cells, whereas binding of IgG dimers to NA2NA2 cells was completely prevented. Thus, the products of both NA alleles bind IgG. Immunoprecipitation from the medium of neutrophils either stimulated with formyl- methionyl-leucyl-phenylalanine (FMLP) or treated with glycosyl-phosphatidyl-inositol-specific phospholipase C (GPI- PLC) showed that both the NA1-FcRIII and the NA2-FcRIII are released from the cell surface, indicating that both forms of FcRIII have some structural features in common. Deglycosylation of FcRIII from homozygous donors yielded material that showed several bands on SDS- PAGE. GPI-PLC treatment of neutrophils indicated that all of this material is phosphatidyl-inositol linked.     

Expression and structure of CD22 in acute leukemia

The purpose of this study was to examine the expression and structure of CD22 in B cell precursor acute lymphoblastic leukemia (BCP-ALL), acute myeloid leukemia (AML), and T cell acute lymphoblastic leukemia (T-ALL). By using immunofluorescence microscopy and flow cytometry we observed that CD22 is expressed not only in the cytoplasm (as previously reported) but also on the cell surface of virtually all (15/16) BCP-ALL examined. CD22 that was biosynthetically labeled with 35S-cysteine and immunoprecipitated from the uncommon cytoplasmic CD22- positive/surface CD22-negative BCP-ALL cells was analyzed by single- dimension sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Our results indicated that the cytoplasmic form of CD22 comigrated with 125I/lactoperoxidase-labeled surface CD22. Therefore, cytoplasmic CD22 is probably a pool of fully processed glycoprotein. We also observed unusual cases of AML (approximately 20%) that expressed cytoplasmic CD22 based on immunofluorescent staining; however, biosynthetic labeling and immunoprecipitation revealed an apparently cross-reactive protein(s) of approximately 250 to 300 kd in AML cells. No T-ALL cell lines examined expressed either cytoplasmic or surface CD22. Thus, cytoplasmic and surface expression of bona fide CD22 appears restricted to B cells, which suggests that this molecule subserves a function unique to B cells.     

Prolonged benefit of nitroglycerin ointment on exercise tolerance in patients with angina pectoris.

The effect on exercise tolerance of 2 per cent nitroglycerin ointment and placebo was studied on the bicycle ergometer in 10 patients with angina pectoris, a positive exercise test, and documented coronary artery disease. After a control stress test sufficient to produce angina pectoris and > 1 mm. horizontal or downsloping ST segment depression, nitroglycerin ointment or placebo was administered in a random, double-blinded manner and stress tests were repeated at 1 hour and 3 hours. End points for the exercise stress test were angina and 1 mm. ST segment depression. Forty-eight hours later, stress tests were again performed at 1 hour and 3 hours after administration of the alternate preparation. Work load (watts) plus duration of exercise (minutes) were calculated for each stage of the bicycle ergometer protocol and exercise tolerance was expressed as the sum of this product for all stages completed.Nitroglycerin ointment produced a significant increase in exercise tolerance from a control value of 877 ± 129 watt-minutes to 1165 ± 173 watt-minutes at 1 hour and 1040 ± 137 watt-minutes at 3 hours. Duration of exercise also increased significantly after nitroglycerin ointment from 13.7 ± 1.4 minutes in the control stress test to 16.8 ± 1.4 minutes at 1 hour and 16.3 ± 1.2 minutes at 3 hours. Exercise induced ST segment depression decreased significantly at 1 hour and 3 hours after nitroglycerin ointment but not after the placebo.The placebo produced a small, but statistically significant, increase in exercise tolerance and duration of exercise at 1 hour after its application. However, these increases were significantly smaller than the one observed after nitroglycerin ointment. No changes were observed 3 hours after application of the placebo. Double product at peak exercise was unchanged after nitroglycerin or placebo ointments at 1 hour and 3 hours.These data indicate that nitroglycerin ointment is capable of producing an improvement in exercise tolerance and a reduction in the magnitude of exercise-induced ST segment depression up to 3 hours in patients with coronary artery disease and angina pectoris.     

Bedeutung von Mikrokalzifikationen in der Mammographie

Ohne Zusammenfassung     

Barbiturates depress currents through human brain calcium channels studied in Xenopus oocytes

Barbiturates have had wide use as sedatives, anesthetics and anticonvulsants. Among the sites implicated in the membrane action of barbiturates are the gamma-aminobutyric acidA receptor, receptors for excitatory amino acids and Ca and potassium channels. The expression in Xenopus oocytes of various ligand- and voltage-gated channels offers the opportunity for more-detailed studies of such neuroactive substances as the barbiturates. Using RNA from human temporal cortex, we obtained the expression of an omega-conotoxin-sensitive, dihydropyridine-resistant Ca channel in Xenopus oocytes. Under voltage clamp, barbiturates depressed both the peak current and the steady-state current through this Ca channel. Barbiturates had no effect on the shape of the current-voltage relation, nor did they cause a shift in the voltage-dependence of channel activation. However, both the rate of inactivation of open Ca channels, as well as the proportion of channels inactivated at steady state were increased by barbiturates. The IC50 for these effects was about 0.25 mM for the more potent barbiturates tested. These results are consistent with the hypothesis that sedative and anesthetic effects of barbiturates can be mediated in part by an action to depress Ca currents.