Effects of airborne World Trade Center dust on cytokine release by primary human lung cells in vitro.

There are continuing concerns regarding the respiratory health effects of airborne particulate matter (PM) after the destruction of the World Trade Centre (WTC). We examined cytokine (interleukin [IL]-8, IL-6, tumor necrosis factor-alpha) release by primary human lung alveolar macrophages (AM) and type II epithelial cells after exposure to WTC PM2.5 (indoor and outdoor), PM10-2.5 (indoor), and PM53-10 (outdoor), fractionated from settled dusts within 2 months of the incident. There was an increase in AM cytokine/chemokine release at 5 and/or 50 microg/well WTC PM, which fell at 500 microg/well. Type II cells did not release tumor necrosis factor-alpha, and the increase in IL-8 and IL-6, although significant, was lower than that of AM. Respirable PM generated by the WTC collapse stimulates inflammatory mediator release by lung cells, which may contribute to the increased incidence of respiratory illness since September 11th 2001.

The myelotoxicity of chloramphenicol: in vitro and in vivo studies: II: In vivo myelotoxicity in the B6C3F1 mouse.

1. Chloramphenicol continues to be widely used in many parts of the world despite its known haematotoxicity. Until now, elucidation of the mechanisms involved and any attempt at amelioration of the toxic effects have been hampered by the lack of an animal model. 2. In this study neither acute nor chronic administration of chloramphenicol as its succinate ester in the drinking water produced anaemia in mice as assessed by changes in peripheral blood parameters. 3. Chloramphenicol could not be detected in the bone marrow when the antibiotic was administered either in the drinking water or by gavage, although it was detected in the serum. 4. In marrow taken from mice after chloramphenicol succinate administration and cultured in vitro, depression of the differentiation of immature committed erythroid progenitors occurred 15 min after administration of the antibiotic by gavage. However, recovery was beginning to occur at 48 h after administration of chloramphenicol succinate at 50 and 200 mg/kg and this was then followed by an 'overshoot' response at the higher dose. A toxic effect was therefore achieved in the bone marrow but this was probably masked in the peripheral blood by enhanced proliferation. 5. Morphological evidence of apoptosis was seen in erythroid and myeloid precursors in mice treated with 200 mg/kg. 6. The data suggest that the effect of chloramphenicol was at the differentiation stage of the committed marrow progenitor cells rather than at the replication stage of the stem cells and therefore this response appears to mimic the reversible bone marrow depression seen in the treated patient.

Physiologic estradiol replacement therapy and cardiac structure and function in normal postmenopausal women: a randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: To assess the effect of estradiol (E2) replacement therapy on cardiac structure and function in healthy postmenopausal women. METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover study of 31 healthy postmenopausal female volunteer study subjects (55-65 years) using 12 weeks of micronized E2 replacement therapy (2 mg/day). Echocardiography and Doppler techniques were used to assess the cardiac effects of E2 at rest and during graded bicycle ergometry. RESULTS: Crossover analysis demonstrated no carryover effects of estrogen treatment (which increased serum E2 15-fold to 37.6 pmol/L) on the cardiac characteristics measured. Estradiol treatment did not affect measurements of systolic function, diastolic function, left ventricular mass, or pulmonary artery pressure at rest or during bicycle ergometry. Left ventricular end-diastolic volume at rest was slightly higher with E2 treatment (P = .03). However, this change was not reflected by changes in stroke volume, ejection fraction, or cardiac output. CONCLUSIONS: Estrogen replacement therapy, which results in physiologic serum concentrations, does not affect cardiac structure or function in normal postmenopausal women after 12 weeks of treatment.

Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity.

Use of the antihistamine terfenadine has been associated with QT prolongation and torsade de pointes. One possible mechanism is blockade of cardiac potassium channels. We therefore characterized the effects of terfenadine on potassium currents recorded from isolated human cardiac myocytes. We demonstrated terfenadine block of the transient outward current and a novel, ultra-rapidly activating, delayed rectifier K+ current (IKur), which is very sensitive to 4-aminopyridine. IKur is probably produced by the protein product of Kv1.5a, a Shaker-like potassium channel cDNA cloned from human heart. We also compared terfenadine blockade of fHK (Kv1.5a) currents stably expressed in a human embryonic kidney cell line with terfenadine blockade of IKur in human atrial myocytes. Using the patch-clamp technique, we found that terfenadine produced a time-dependent reduction in Kv1.5a current that was consistent with blockade from the cytoplasmic side of the channel. The terfenadine-sensitive Kv1.5a current in human embryonic kidney cells was similar to the 4-aminopyridine-sensitive current in human atrial myocytes. In addition to blockade of the transient outward current and IKur, terfenadine at clinically relevant concentrations blocked both the rapidly and slowly activating components of the delayed rectifier in human atrial myocytes. Blockade of these K+ currents may contribute to the cardiotoxicity associated with terfenadine usage.

Rescue of lethal subunits into functional K+ channels.

In a chimeric, voltage-dependent K+ channel (CHM), the valine at position 369 and the leucine at position 374 interact within the pore or P-region to regulate ion permeation and block. Here we show that the point mutation, CHM V369L, abolished channel function whereas previous experiments showed that CHM V369 and CHM V369I are functional. Coinjection of "lethal" CHM V369L cRNA with CHM L374V cRNA but not CHM cRNA generated functional heteromultimers. The whole-cell Rb+/K+ conductance ratio was 2.98 +/- 0.43 for CHM L374V and was reduced to 0.87 +/- 0.04 for the coexpressed CHM V369L and CHM L374V subunits. When single-channel currents were recorded, a single class of CHM V369L/CHM L374V heteromultimers was identified. This class was readily distinguishable from CHM L374V homomultimers by K+ conductance, gating, and blockade by internal tetraethylammonium. Coinjection experiments at various RNA ratios suggest that the CHM V369L/CHM L374V heteromultime, assuming it to be a tetramer, was composed of three CHM L374V subunits and one CHM V369L subunit. It appears that in the critical P-region of CHM position 369 may tolerate only one leucine.

The use of pulse oximetry in post-operative hypoxaemia in patients after propofol induction of anaesthesia.

Pulse oximetry was used to measure changes in oxygen saturation in the early post-operative phase in three groups of 50 patients in whom anaesthesia was induced with propofol. One group breathed room air during induction and anaesthesia was maintained with halothane whereas the other two groups both breathed oxygen during induction and anaesthesia was maintained with either halothane inhalation or a propofol infusion. In 59 patients distributed fairly evenly between the three groups the oxygen saturation fell below 90%; the mean minimum oxygen saturation was 91.7 +/- 0.3 and the mean time at which it occurred was 3.9 +/- 0.4 min after the anaesthetic was withdrawn. Neither the inhalation of oxygen during induction nor the anaesthetic technique affected the decrease in postoperative oxygen saturation but the infusion group took significantly longer to recover consciousness.

Electrical and mechanical responses after neuromuscular blockade with vecuronium, and subsequent antagonism with neostigmine or edrophonium.

Six unpremedicated patients who had given their informed consent were given vecuronium 0.08 mg kg-1 before elective surgery. Recovery from neuromuscular blockade was measured electrically and mechanically. Neuromuscular blockade was antagonized 1 h after the administration of vecuronium with two doses of neostigmine 2.5 mg (three patients) or edrophonium 0.5 mg kg-1 (three patients). Although the onset of initial recovery was similar, subsequent recovery was faster when measured electrically (EMG) than when measured mechanically. Recovery appeared to be faster in younger patients. Reintroduction of neuromuscular blockade occurred after the second dose of neostigmine 2.5 mg, given to antagonize the block. This did not occur after either dose of edrophonium 0.5 mg kg-1.

Recovery of respiration after neuromuscular blockade with alcuronium.

Alcuronium 0.2 mg kg-1 was given to six patients to investigate the simultaneous recovery of breathing and peripheral neuromuscular function. Anaesthesia was maintained with 66% nitrous oxide in oxygen supplemented with 0.5% halothane, and the patients were ventilated to normocarbia. Patients were disconnected from the ventilator after the reappearance of the tetanic response. This response returned at a mean time of 19.2 min after the injection of alcuronium and oxygenation was maintained thereafter by means of apnoeic diffusion. Spontaneous breathing returned at a mean time of 23.6 min after the injection of alcuronium. Sixty minutes after the administration of alcuronium, respiratory exchange was judged adequate, and at that time neuromuscular function was still markedly depressed with a tetanic height less than 25% of control. It was concluded that, because of the slow recovery of neuromuscular function, alcuronium should be reserved for the longer surgical procedure.

Antagonism of atracurium-induced neuromuscular blockade by neostigmine or edrophonium.

Antagonism of atracurium-induced neuromuscular blockade by neostigmine or edrophonium has been studied using the tetanic (50 Hz) and train-of-four (2 Hz) or single twitch responses of the adductor pollicis muscle in 22 anaesthetized patients. A further nine patients not given an anticholinesterase acted as a control group. In two groups (six patients for each anticholinesterase) in whom antagonism was attempted at 95-98% blockade of the tetanic response, recovery of the tetanic response after two or three doses of edrophonium 0.75 mg kg-1 i.v. was not statistically different from that in the control group; recovery after two doses of neostigmine 2.5 mg i.v. was significantly faster (P less than 0.001). Recovery of the single twitch response after antagonism with edrophonium, although longer than that with neostigmine (P less than 0.01), was significantly shorter than in the control group (P less than 0.05). When edrophonium is given at the commencement of recovery, the initial rapid antagonism of tetanic block is not sustained, whereas antagonism by neostigmine is more persistent and the recovery phase is significantly shortened. In a further two groups of patients (n = 5) given atracurium 0.3 mg kg-1 i.v., antagonism was not attempted until the peak height of the tetanic contraction had reached approximately 50% of the control value.(ABSTRACT TRUNCATED AT 250 WORDS)