Increased Levels of Soluble Tumour Necrosis Factor Receptor-I (P55) and Decreased IgG1 Reactivities in HIV-1 Patients with Cytomegalovirus Disease

The purpose of the study was to investigate potential associations between tumour necrosis factor (TNF), soluble TNF receptors (sTNF-Rs), immunoglobulin (Ig)G subclasses and development of cytomegalovirus (CMV) disease amongst human immunodeficiency virus (HIV)-1 patients. We enrolled HIV-1 patients with CD4 counts less than 100/μl in a prospective study and followed them over 1 year for development of CMV disease. Concentrations of TNF, sTNF-RI, sTNF-RII and IgG subclass reactivities were measured by ELISA; levels of CMV pp65 antigenaemia were determined as numbers of pp65 expressing cells/100 000 cells and were measured by staining of leucocytes; and HIV-1 RNA loads were measured by polymerase chain reaction (PCR). Eighteen patients studied with CMV disease had higher levels of sTNF-RI than 18 similar patients without CMV disease. Concentrations of sTNF-RI correlated with levels of CMV antigenaemia in blood samples collected before the development of CMV disease. Patients with CMV disease had lower levels of IgG₁ reactivities to CMV than patients without CMV disease. We conclude that increased levels of sTNF-RI and decreased IgG₁ reactivities are associated with an increased risk of development of CMV disease among HIV-1 patients.     

Muscarinic modulation of calcium dependent plateau potentials in rat neostriatal neurons

Intracellular recording from neostriatal neurons in rat brain slices revealed effects of the acetylcholine (ACh) agonist carbachol (Cch, 1–10 mol/l), of the anticholinesterase physiostigmine (10 mol/l) and of the muscarinic antagonist atropine (10 mol/l) on plateau potentials elicited in the presence of K-blockers were Cadependent, elicited in the presence of K-blockers were Cadependent, since they persisted in Na-free solution, were resistant to tetrodotoxin (TTX, 3 mol/l) and blocked by Cd (0.1–0.5 mmol/l). Cch reduced the duration of the plateau potentials and made them more susceptible to fatigue. These effects were antagonized by atropine (1–10 mol/l), but not by Ba (100–200 mol/l) or 4-aminopyridine (4-AP, 0.5 mmol/l). Physostigmine (10 mol/l) had the same atropine-sensitive effects as Cch on the plateau potential. Atropine (10 mol/l), by itself, prolonged the duration of the plateau potential. High concentrations (100 mol/l) of Cch did not further reduce the duration of the plateau potential, instead, the duration re-increased with prolonged exposure. The re-increase of the plateau-spike duration was later masked by bursting activity. The opposing effects of low and high concentrations of Cch on the plateau potential duration corresponded to effects of this drug on intrastriatally evoked EPSPs in that low concentrations of Cch reduced the EPSP amplitude, but high concentrations re-increased it after a transient decrease. It is concluded that the muscarinic effect of Ach in the neostriatum is to modulate Ca-influx and that this effect is exerted in a tonic manner. On leave from absence from: Clinica Neurologica II, Universita di Roma. Tor Vergata, Roma, Italy.     

Postmenopausal estrogen administration suppresses muscle sympathetic nerve activity

The activity of the sympathetic nervous system shows gender-specific differences with lower sympathoneural activity to the muscle vascular bed in women compared with men, with this difference vanishing after menopause. The present study tested the hypothesis that estrogen exerts regulatory influence on the autonomic nervous system in postmenopausal women. Eleven healthy postmenopausal women (age, 58.5 +/- 1.0 yr; mean +/- SEM) were studied in a randomized double-blind crossover protocol with transdermal administration of 100 microgram/day estradiol (E(2)) or placebo (P) for 2 days. Muscle sympathetic activity (MSA), blood pressure, and heart rate were recorded at rest and during sympathoexcitatory maneuvers (apnea, cold pressor test). E(2) administration significantly increased serum E(2) to physiological levels (E(2), 469.5 +/- 51.5; P, 34.8 +/- 2.2 pmol/L; P < 0.05) and significantly lowered MSA (E(2), 30.1 +/- 3.0 vs. P 37.7 +/- 3.1 bursts/min; P < 0.05). At the same time, blood pressure and heart rate were not affected. MSA was significantly enhanced during apnea and the cold pressure test, and this physiological response to the maneuvers was not changed after estrogen supplementation. In conclusion, elevation of low postmenopausal estrogen levels to physiological premenopausal levels by transdermal E(2) administration supresses MSA. This effect is most likely the consequence of a direct E(2) effect on central nervous autonomic centers, which could explain the gender-specific differences in sympathetic outflow to the muscle vascular bed. The sympathoinhibitory estrogen effects could be important for beneficial cardiovascular effects of estrogen replacement therapy in postmenopausal women.     

Acute suppression of muscle sympathetic nerve activity by hydrocortisone in humans

In the present study, we examined the acute influence of hydrocortisone on human sympathetic nerve activity and cardiovascular parameters. Muscle sympathetic nerve activity (MSA), heart rate, and blood pressure were monitored in 8 healthy subjects (20 to 37 years old) before and after a bolus injection of 50 mg hydrocortisone followed by a continuous infusion at 50 mg/h during a period of 3 hours in a placebo-controlled, double-blind, crossover protocol. Recordings were performed at rest and during repeated transient sympathoexcitation induced by voluntary apneas. Resting MSA and endogenous serum cortisol concentrations were also measured in a larger study group (49 experiments, 25 subjects). During the experimental period, MSA burst number increased by 56% from the control level in the placebo group. In contrast, MSA was suppressed by 25% at the end of the hydrocortisone infusion, resulting in a significant treatment effect (P<0.05). In addition, sympathoexcitation during apnea was significantly reduced with hydrocortisone after 180 minutes. In parallel with the sympathetic outflow, blood pressure decreased in the hydrocortisone-treated group, whereas it rose in the placebo group (P<0.05 between groups). No correlation was found between basal MSA and basal cortisol levels. Our results indicate that pharmacological doses of hydrocortisone acutely influence MSA responses to short- and long-lasting environmental stimuli, whereas basal native cortisol levels do not appear to be tonically involved in the regulation of resting MSA. The suppressive hydrocortisone effect is most likely induced via supraspinal autonomic centers and cannot be explained by peripheral steroid mechanisms. The effect of elevated corticosteroid levels on sympathetic nerve discharge may be an important mechanism in cardiovascular adaptations to stress.     

Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products

Background and Objectives The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events. Material and Methods The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S‐2302 and S‐2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non‐activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa‐specific clotting assays, respectively. Results Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S‐2288, but not with S‐2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT. Conclusions Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE‐associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs.     

WIN 55,212-2 decreases the spatial spread of neocortical excitation in vitro

The 'intrinsic optical signal' was used to monitor neuronal network excitability. The cannabinoid receptor type 1 agonist WIN 55,212-2 reduced the intensity and the spatial spread of the intrinsic optical signal and prolonged its kinetics in the rat neocortex in vitro. These effects were antagonized by the cannabinoid receptor antagonist SR141716A. Thus, our results suggest that neocortical network activity is modulated via the activation of cannabinoid receptors. The decrease of neocortical network excitability in the present study is probably due to a decreased excitability of glutamatergic neurons.     

Isoflurane reduces glutamatergic transmission in neurons in the spinal cord superficial dorsal horn: evidence for a presynaptic site of an analgesic action

The minimum alveolar concentration (MAC) of a volatile anesthetic defines anesthetic potency in terms of a suppressed motor response to a noxious stimulus. Therefore, the MAC of an anesthetic might in part reflect depression of motor neuron excitability. In the present study we evaluated the effect of isoflurane (ISO) on neurons in the substantia gelatinosa driven synaptically by putative nociceptive inputs in an in vitro spinal cord preparation of the rat. Whole-cell patch-clamp recordings were performed in neurons with their soma in the substantia gelatinosa of transverse rat spinal cord slices. We investigated the effect of ISO on excitatory postsynaptic currents (EPSC) evoked by dorsal root stimulation (eEPSC), spontaneous (sEPSC), and miniature (mEPSC) EPSC. ISO reversibly reduced the amplitude of eEPSC to 39% +/- 22% versus control. ISO decreased the frequency of sEPSC and mEPSC to 39% +/- 26% and 63% +/- 7%. Neither the amplitudes nor the kinetics of mEPSC and sEPSC were altered by ISO. We conclude that ISO depresses glutamatergic synaptic transmission of putative nociceptive primary-afferent inputs, presumably by reducing the release of the excitatory transmitter. This effect may contribute to an antinociceptive action of volatile anesthetics at the spinal cord level. IMPLICATIONS: The present electrophysiological in vitro experiments provide evidence that the volatile anesthetic isoflurane reduces excitatory transmitter release at the first site of synaptic integration of nociceptive inputs, the spinal cord superficial dorsal horn. This effect may contribute to the anesthetic action of volatile anesthetics at the spinal cord level.     

Prehospital noninvasive pressure support ventilation for acute cardiogenic pulmonary edema.

Severe acute cardiogenic pulmonary edema (ACPE) can successfully be treated with noninvasive pressure support ventilation (NIPSV) in a clinical setting. Whether prehospital NIPSV starting early at patients' home and being continued until hospital arrival is feasible and improves ACPE emergency care is examined in this study. End points of the study were oxygen saturation at hospital admission and clinical outcome. Twenty-three patients suffering from severe cardiac pulmonary edema with severe dyspnea, an oxygen saturation of less than 90% and basal rales were included in this controlled prospective randomized trial. All patients received standard medical treatment and 10 patients were additionally treated with NIPSV (pressure support level, 12 cmH2O; positive endexpiratory pressure, 5 cmH2O; FiO2, 0.6) whereas the other patients received oxygen (8 l/min) via Venturi face mask. Improvement in oxygen saturation was significantly faster in the NIPSV group and oxygen saturation was higher at the time of the hospital admission (NIPSV=97.3+/-0.8%; standard=89.5+/-2.7%, P=0.002). A trend toward higher troponin T levels was seen in the standard treatment group. The need for intensive care treatment did not differ, and one patient of each treatment group died in hospital. No complications were noted during the treatment with NIPSV. Prehospital NIPSV is feasible and able to improve emergency management of ACPE.