Reactivating and protective effects of Pro-2-PAM in mice poisoned with paraoxon

Acute toxicity of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride (Pro-2-PAM) in mice, its concentrations in blood and brain and its protective and reactivating effects in diethyl p-nitrophenyl phosphate (paraoxon) poisoning were determined. Comparative studies with N-methylpyridinium-2-aldoxime chloride (PAM-2 Cl) and a mixture of two oximes were also performed. Pro-2-PAM was much less toxic than was PAM-2 Cl. In contrast to this, the Pro-compound penetrates well into central nervous system (CNS), and effectively reactivates brain acetylcholinesterase (AChE) in vivo inhibited by paraoxon. The two oximes were equally effective in reactivating blood AChE. However, protective effects of Pro-2-PAM were unexpectedly lower than those of PAM-2 Cl. The observation suggests that there is no correlation between brain AChE reactivating power and protective effects of Pro-2-PAM. Contrary to the present belief, it seems that Pro-2-PAM undergoes slow conversion in vivo into its active form PAM-2 Cl. The possible use of Pro-2-PAM as a model oxime for penetration into CNS requires further evaluation with regard to therapy of organophosphorus poisoning.     

Radiofrequency catheter ablation of the bundle branch reentrant ventricular tachycardia

Bundle branch reentrant ventricular tachycardia (BBRVT) has a suitable anatomic substrate for radiofrequency catheter ablation. However, the experience with this treatment is still small. In the current study, we examined the safety and the long-term efficacy of radiofrequency ablation in the cure of patients with BBRVT. Four patients with BBRVT, identified during electrophysiological study, underwent temperature-controlled radiofrequency ablation of the right bundle branch (RBB). All of them had syncope and structural heart disease with reduced left ventricular ejection fraction. The baseline examination revealed an intraventricular block, prolonged HV interval and inducible sustained VT because of bundle branch reentry in all patients. RBB was successfully abolished in all patients after the delivery of 3 +/- 1 radiofrequency pulses. After ablation, a permanent pacemaker was implanted in one patient with significantly prolonged HV interval. All patients were free of BBRVT during a mean follow-up of 20 months. One patient received implantable cardioverter-defibrillator for myocardial VT five months after ablation. Two patients developed congestive heart failure. Radiofrequency catheter ablation of the RBB is a safe and highly effective therapeutic procedure for definitive cure of BBRVT. Long-term prognosis of these patients depends mainly on the underlying heart disease and the treatment of other VT.     

Light chain editors of anti-DNA receptors in human B cells

Receptor editing is a mechanism of self-tolerance used in newly generated B cells. The expressed heavy (H) or light (L) chain of an autoreactive receptor is replaced by upstream V genes which eliminate or modify autoreactivity. Editing of anti-DNA receptors has been characterized in anti-DNA transgenic mouse models including 3H9, 3H9/56R, and their revertant 3H9GL. Certain L chains, termed editors, rescue anti-DNA B cells by neutralizing or modifying DNA binding of the H chain. This editing mechanism acts on the natural H chain repertoire; endogenous H chains with anti-DNA features are expressed primarily in combination with editor L chains. We ask whether a similar set of L chains exists in the human repertoire, and if so, do they edit H chains with anti-DNA signatures? We compared the protein sequences of mouse editors to all human L chains and found several human L chains similar to mouse editors. These L chains diminish or veto anti-DNA binding when expressed with anti-DNA H chains. The human H chains expressed with these L chains also have relatively high arginine (Arg) content in the H chain complementarity determining region (H3), suggesting that receptor editing plays a role in establishing tolerance to DNA in humans.The antibody-combining site is formed by the interaction of the variable regions of the H and L chains; hence, replacement of either V changes the specificity of an antibody (Gay et al., 1993; Radic et al., 1993a; Tiegs et al., 1993). A characteristic feature of anti-DNA antibodies is that DNA contact is mediated primarily through the positively charged amino acid residue Arg in H-chain complementarity determining regions (CDRs; Jang et al., 1998; Radic et al., 1989, 1993b; Shlomchik et al., 1990). Hence, these Arg-containing H chains bind DNA regardless of most L chains (Ibrahim et al., 1995). However, several L chains in mouse can modify or veto DNA binding when paired with anti-DNA H chains (Li et al., 2001). These L chains are called editors and share functionally consequential structural characteristics such as a low isoelectric point (pI) and negatively charged aspartate residues (Asp) in CDRs (Li et al., 2001).Editor L chains were originally discovered in anti-DNA H-chain transgenic models (Gay et al., 1993; Radic et al., 1993a). The majority of peripheral B cells bearing anti-DNA transgenic H chains were paired with editor L chains, indicating that only those B cells that edited their receptors were allowed to migrate to the periphery. Editing of anti-DNA receptors also influences the endogenous mouse repertoire; antibodies which use editor L chains have characteristics of lupus anti-DNA antibodies—namely, a high frequency of H chains with Args in H3 (H3-Arg) (Kalinina et al., 2011).Here, we studied the human antibody repertoire to determine whether it contains L chains similar to the mouse editors, whether such human L chains silence or modify anti-DNA activity, and whether antibodies that express these L chains have a high frequency of H chains with H3 Arg relative to the total human antibody repertoire. We used mouse editor L chain sequences as a guideline for identifying human editor L chains. We focused on the prominent sequence characteristics of editors—namely, the number and location of Asps in L-chain CDRs. Using this criterion, we identified several potential human editor L chains. We tested the ability of the human editors to modify DNA binding by H chains derived from monoclonal anti-DNA antibodies and found that they can silence anti-DNA H chains from both humans and mice. Because the human H3s are generated by mechanisms similar to those in mice, we reasoned that the human endogenous H-chain repertoire might also include H3-Args. If editing of anti-DNAs is a tolerance mechanism which operates in humans, then we would expect that these Arg-containing H chains are preferentially expressed with human editor light chains. This is indeed the case. This finding provides an understanding of how tolerance to DNA is maintained and, importantly, how the B cell repertoire is shaped in humans.     

Burning controversies in NETs and autoimmunity: The mysteries of cell death and autoimmune disease

Abstract

The causes and mechanisms of autoimmune disease pose continuing challenges to the scientific community. Recent clues implicate a peculiar feature of neutrophils, their ability to release nuclear chromatin in the form of neutrophil extracellular traps (NETs), in the induction or progression of autoimmune disease. Efforts to define the beneficial versus detrimental effects of NET release have, as yet, only partially revealed mechanisms that guide this process. Evidence suggests that the process of NET release is highly regulated, but the details of regulation remain controversial and obscure. Without a better understanding of the factors that initiate and control NET formation, the judicious modification of neutrophil behaviour for medically useful purposes appears remote. We highlight gaps and inconsistencies in published work, which make NETs and their role in health and disease a puzzle that deserves more focused attention.     

The influence of decreased low-molecular-weight heparin nadroparin dose on diastolic blood pressure in patients on hemodialysis

The aim of present study was to assess the impact of decreasing single bolus dose of nadroparin on blood pressure in patients on hemodialysis (HD). Forty HD patients were included in this study. The bolus dose of nadroparin was decreased twice by 25%; this lower dose was maintained for last 4 weeks, during which the dose was adjusted. There were no significant differences between the first and the last predialysis: systolic blood pressure ([pre-SBP]; 131.05 ± 25.58 vs 125.92 ± 25.49 mm Hg; P = .133), diastolic blood pressure ([pre-DBP]; 73.82 ± 11.82 vs 72.89 ± 9.13 mm Hg; P = .653), and pulse pressure ([pre-PP]; 57.24 ± 20.39 vs 53.03 ± 21.20 mm Hg; P = .121). We found correlation between delta nadroparin and pre-DBP in the last HD (rho = 0.310; P = .031) but not between delta nadroparin and pre-SBP and pre-PP values. This is the first report of influence of nadroparin dose lowering on pre-DBP in HD patients.     

Does sublingual microscopy correlate with nailfold videocapillaroscopy in systemic sclerosis?

Clinical Rheumatology - In this study, we examine sublingual videomicroscopy and nailfold videocapillaroscopy (NVC) features in systemic sclerosis (SSc) patients presenting for routine care....     

Incidence of congenital rubella syndrome in 19 regions of Europe in 1980–1986

Twenty-five cases of congenital rubella syndrome were recorded in 1,458,126 live births in 19 EUROCAT birth defects registries from 1980 to 1986. During the study period, the incidence declined steadily from 3.50 to 0.41 per 100,000 births. Rubella infection occurred in 12 multiparous women indicating failure in immunization programme.Corresponding author.     

The temperature coefficient of the unperturbed dimensions of poly(pentachlorophenyl methacrylate)

Values of the temperature coefficient of the mean square unperturbed dimensions dln(r /dT) for poly(pentachlorophenyl methacrylate) are obtained from viscosity vs. temperature data under two different conditions: (a) viscosity determinations in several different solvents each at its Θ-temperature and (b) viscosity determinations in a thermodynamically good solvent with a similar chemical structure as compared to the repeating unit. An anomalous temperature dependence of the viscosity was observed in o-dichlorobenzene for this polymer. The results obtained from both conditions are compared and their limitations and interpretations are discussed.     

Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system

We focused on the therapeutic effect of the stable gastric pentadecapeptide BPC 157 and how its action is related to nitric oxide (NO) in persistent colocutaneous fistula in rats (at 5 cm from anus, colon defect of 5 mm, skin defect of 5 mm); this peptide has been shown to be safe in clinical trials for inflammatory bowel disease (PL14736) and safe for intestinal anstomosis therapy. BPC 157 (10 microg/kg, 10 ng/kg) was applied i) in drinking water until the animals were sacrificed at post-operative day 1, 3, 5, 7, 14, 21, and 28; or ii) once daily intraperitoneally (first application 30 min following surgery, last 24 h before sacrifice) alone or with N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg), L-arginine (200 mg/kg), and their combinations. Sulphasalazine (50 mg/kg) and 6-alpha-methylprednisolone (1 mg/kg) were given once daily intraperitoneally. BPC 157 accelerated parenterally or perorally the healing of colonic and skin defect, leading to the suitable closure of the fistula, macro/microscopically, biomechanically, and functionally (larger water volume sustained without fistula leaking). L-NAME aggravated the healing failure of colocutaneous fistulas, skin, and colon wounds (L-NAME groups). L-Arginine was effective only with blunted NO generation (L-NAME + L-arginine groups) but not without (L-arginine groups). All of the BPC 157 beneficial effects remained unchanged with blunted NO-generation (L-NAME + BPC 157 groups) and with NO substrate (L-arginine + BPC 157 groups) as well as L-NAME and L-arginine co-administration (L-NAME + L-arginine + BPC 157 groups). Sulphasalazine was only moderately effective, and corticosteroid even had an aggravating effect.