Usefulness of B-type natriuretic peptide levels to predict left ventricular filling pressures in patients with body mass index >35, 31 to 35, and < or =30 kg/m2

Noninvasive left ventricular (LV) pressure estimation in obese patients has not been well described. Simultaneous B-type natriuretic peptide (BNP) and echocardiographic Doppler examinations were performed in patients with dyspnea undergoing cardiac catheterization. Patients were divided into body mass index (BMI) >35 (markedly obese), 31 to 35 (obese), and < or =30 kg/m2 (nonobese). BNP levels and mitral early diastolic/tissue Doppler annular velocity (E/Ea) were compared with invasively measured LV end-diastolic and pre-atrial (pre-A) pressures. Seventy-two patients were studied. Except for BMI, LV mass index, and LV diastolic dimension, there were no significant differences in baseline, echocardiographic Doppler, or hemodynamic characteristics among the groups. However, BNP was significantly lower in markedly obese compared with obese and nonobese patients (116 +/- 187 vs 241 +/- 674 and 277 +/- 352 pg/ml, respectively; p = 0.03). BNP did not correlate with LV pre-A pressure in markedly obese patients (R = 0.13, p = 0.47), whereas BNP significantly correlated with this variable in the obese (R = 0.64) and nonobese (R = 0.58) groups. Mitral E/Ea significantly correlated with LV pre-A and LV end-diastolic pressures in all BMI groups. In markedly obese patients with dyspnea, BNP did not correlate with invasively measured LV filling pressure, whereas this correlated in obese and nonobese patients. However, mitral E/Ea significantly correlated with LV filling pressures in all BMI groups. In conclusion, BNP is not recommended for LV filling pressure estimation in ambulatory patients with dyspnea with BMI >35 kg/m2.     

The innate immune system in transplantation

The vertebrate innate immune system consists of inflammatory cells and soluble mediators that comprise the first line of defense against microbial infection and, importantly, trigger antigen-specific T and B cell responses that lead to lasting immunity. The molecular mechanisms responsible for microbial non-self recognition by the innate immune system have been elucidated for a large number of pathogens. How the innate immune system recognizes non-microbial non-self, such as organ transplants, is less clear. In this review, we approach this question by describing the principal mechanisms of non-self, or ‘damaged’ self, recognition by the innate immune system (pattern recognition receptors, the missing self theory, and the danger hypothesis) and discussing whether and how these mechanisms apply to allograft rejection.     

Embryonic chimerism does not induce tolerance in an invertebrate model organism

In colonial marine invertebrates, allorecognition restricts somatic fusion and thus, chimerism, to histocompatible individuals. Little is understood, however, about how invertebrates respond to chimerism formed across histocompatibility barriers or whether embryonic exposure to histoincompatible cells induces allotolerance. We here evaded natural allorecognition barriers by generating well mixed embryonic chimeras of Hydractinia symbiolongicarpus (Cnidaria:Hydrozoa) and developed molecular markers to detect chimerism in both histocompatible and histoincompatible settings. Histocompatible chimeras exhibited markedly higher growth rates and survivorship than histoincompatible pairings. Histoincompatible chimeras were unstable, with chimerism being undetectable by 4 wk of age. In contrast, colonies generated from histocompatible pairings remained chimeric at markedly higher frequencies and longer durations. Histoincompatible chimeras that lost detectable chimerism retained the fusibility/rejection characteristics of the remaining component of the chimera but not that of the lost component. Chimerism across histocompatibility barriers in an invertebrate model organism was unstable and did not induce tolerance.     

Stem cell based delivery of IFN-beta reduces relapses in experimental autoimmune encephalomyelitis

Interferon-beta (IFN-beta), an approved treatment of multiple sclerosis (MS), produces only partial clinical responses. IFN-beta therapy has been limited by its short serum half-life and limited ability to cross the blood brain barrier. We have developed a means of delivering the IFN-beta gene both systemically and into the central nervous system (CNS) using bone marrow stem cells (BMSCs) as a vehicle and examined the therapeutic efficacy of this approach in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. A retroviral expression vector (pLXSN-IFNbeta) was used to stably transfect virus producer PA317 cells to generate retrovirus containing the IFN-beta gene which then was used to transduce BMSCs. IFN-beta engineered BMSCs were transplanted (i.v.) into mice that then were immunized with proteolipoprotein (PLP) to initiate EAE. IFN-beta-engineered BMSCs transplanted mice showed a significant inhibition of EAE onset, and the overall clinical severity was less compared to control groups. IFN-beta delivery strongly reduced infiltration of mononuclear cells possibly by inhibiting cell adhesion molecules. Reduced demyelination and increased remyelination were also observed in the IFN-beta treated group. Furthermore, inhibition of the pro-inflammatory cytokines TNF-alpha, IFN-gamma and IL-12 and enhanced expression of the anti-inflammatory cytokines IL-10, IL-4 and TGF-beta was observed in CNS tissue. In addition, mice receiving IFN-beta had reduced apoptosis and increases in growth promoting factors including BDNF, CNTF, PDGF and VEGF. These results suggest that BMSCs can be used as vehicles to deliver the IFN-beta into the CNS. This is a potentially novel therapeutic approach which might be used in MS and other diseases of the CNS in which drug access is limited.     

Inhibitory effects from various types of dorsal column and raphe magnus stimulations on nociceptive withdrawal flexion reflexes

Most of the clinical and research reports agree about the analgesic effects of dorsal column (DC) stimulation, but there is no unanimity about the neural mechanisms involved in this stimulation. The aim of the present study was to compare the effects of segmental and rostral activation of the DCs and to investigate whether these effects are mediated through a brainstem spinal loop. Decerebrate-decerebellate cats were subjected to selective DC lesions at C(1) and C(3) spinal cervical levels and their reflex reactions to natural or electrical nociceptive stimuli were monitored either as withdrawal flexion reflexes or as motorneuronal discharges. Conditioning stimulation was performed as train of shocks (100 Hz, for 1 to 10 min or 300 Hz for 30 ms) applied on the DCs either rostral (DCr) or caudal (DCc) to the spinal lesions or on the raphe magnus (RM). Conditioning trains for 5-10 min applied on DCr inhibited the withdrawal flexion reflexes recorded as toe flexion (90% of the control). Comparisons of the effects of DCr, DCc or RM of conditioning stimuli were made on the discharges of 110 motorneurons recorded in isolated ventral root fibers. Conditioning stimulation applied to DCc produced short lived inhibition (in about 60%) or facilitation (in about 30% of the neurons) while DCr or RM conditioning produced inhibition in 90% of neurons which outlasted the duration of the conditioning trains. It was also shown that repetitive application of conditioning train on either DCr or RM resulted in longer duration of inhibition than that observed following DCc conditioning. We conclude that the stronger inhibition of motorneuronal discharges, evoked by nociceptive stimuli, is obtained by rostral activation of the DCs and that long term effects of DCst are mediated through a DC-brainstem-spinal loop.