Susceptibility and resistance to environmental carcinogens in the development of carcinoma of the lung

Eight selected cases are presented to show different effects of the environment on the lung. Some appear to lack resistance to environmental carcinogens. The variations in response and an assessment of the carcinogens involved are discussed. Further study of these poorly understood etiologic factors is needed.     

Computerized photo-plethysmography of the finger

A microcomputer system for studying photo-plethysmography of the finger (PPF) was designed and applied to 50 non-premedicated healthy boys (one to ten years old) undergoing general anaesthesia (halothane in 70% N₂O, with mechanical ventilation) for outpatient inguinal hernia repair. The purpose of this study was to assess the accuracy of computerized estimations of the photo-plethysmographic (arterial waves) amplitude and to evaluate whether or not PPF allows discrimination between two different surgical stimuli (skin incision, and manipulation of the spermatic cord). When anaesthesia was stable for at least five minutes (end-tidal halothane=1.25–1.5%;PetCO₂=32–38 mmHg; SpO₂≥98%; rectal temperature=36.3–37°C; ambient operating room temperature=20–21°C), and immediately before the skin incision, computerized estimations of the photo-plethysmographic (arterial waves) amplitudes (PPA) were recorded and saved for later comparison with direct (manual) measurements of the plethysmographic tracing, using an arbitrary scale of 0–255 units. Also, the values of PPA, systolic blood pressure, and pulse rate recorded immediately before the skin incision were later compared with the maximum changes in these same values recorded 30–90 sec after skin incision, and 30–90 sec after manipulation (traction + dissection) of the spermatic cord. Six boys (three to ten years old) stayed quiet enough, during induction of anaesthesia by mask, to allow regression analysis of PPA, systolic blood pressure, and pulse rate (Y) on end-tidal halothane/70% N₂O (X). Computerized estimations tended to give a higher reading, by between 0.2 to 0.8 units, than direct measurements. Spearman and Kendall correlations showed that computerized and direct measurements were associated (P<0.0001), the Kolmogorov-Smirnov’s test revealed that the two distributions were identical (P=1), the mean difference between computerized and direct estimations of the PPA was 0.52±1.08 units, and the limits of agreement (?1.6 and 2.6 units) were small enough to be confident that computerized (automatic) estimations of PPA can be used for clinical purposes. Skin incision caused a smaller decrease of PPA (24%) than manipulation of the spermatic cord (37%). Changes in PPA were more pronounced than changes in systolic blood pressure or pulse rate (P<0.05). Linear regressions and Fisher’s exact test (two-tailed) showed that, during induction of anaesthesia with halothane in 70% N₂O by mask (n=6), changes in end-tidal halothane concentration were related more to changes in PPA than to changes in systolic blood pressure and/or in pulse rate (P<0.05). In conclusion, computerized PPF allows discrimination between two different surgical stimuli, provides quantification of the sympathetic response to preoperative anxiety, and may be useful for studying pre-anaesthetic sedation.     

Low flow veno-venous ECMO: an experimental study

Clinical use of extracorporeal membrane oxygenation (ECMO) and carbon dioxide removal (ECCO 2R) have become well established techniques for the treatment of severe respiratory failure; however they require full cardiopulmonary bypass, representing major procedures with high morbidity. We theorized the possibility of an efficient low flow veno-venous extracorporeal membrane gas exchange method. Four mongrel 12 kg dogs were submitted to veno-venous extracorporeal membrane gas exchange via a jugular dialysis catheter using a low flow (10 ml/min) roller pump and a membrane oxygenator for a period of four hours. Respiratory rate was set at 4 breaths/min with a FiO 2 of 21% and ventilatory dead space was increased. Adequate gas exchange was obtained (pO 2139, pCO 224, Sat 99.4%), without major hemodynamic changes or hematuria. Our results demonstrate the feasibility of a low flow, less aggressive system. Further research should be considered.     

Adenosine inhibits L-type Ca2+ current and catecholamine release in the rabbit carotid body chemoreceptor cells

In an in vitro preparation of the intact carotid body (CB) of the rabbit, adenosine (100 microM) inhibited hypoxia-induced catecholamine release by 25%. The specific A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 microM) prevented the inhibition and increased the response to hypoxia further. In isolated chemoreceptor cells from the same species, adenosine inhibited voltage-dependent Ca2+ currents by 29% at 1 microM (concentration producing half-maximal inhibition, IC50 = 50 nM). This inhibition was mimicked by R(-)N6-(2-phenylisopropyl)-adenosine and 2-chloroadenosine (1 microM), two purinergic agonists poorly active at the intracellular ('P') site, and persisted in the presence of dipyridamole (a blocker of adenosine uptake; 1 microM) and was fully inhibited by 8-phenyltheophylline (10 microM). The A1 antagonists DPCPX (10 microM) and 8-cyclopentyl-1,3-dimethylxantine (0.1 microM) inhibited the effect of adenosine by 93% (IC50 = 0.14 microM) and 59%, respectively. The inhibition of the Ca2+ current (I(Ca)) was reduced by nisoldipine (an L-type Ca2+ channel antagonist) by nearly 50%, and was unaltered by omega-conotoxin GVIA, a blocker of N-type Ca2+ channels. Adenosine did not affect the voltage-dependent Na+ current (I(Na)) or K+ current (I(K)). We conclude that adenosine A1 receptors are located in chemoreceptor cells and mediate the inhibition of L-type Ca2+ channels and thereby the release of catecholamines produced by hypoxia. The data also indicate that endogenous adenosine acts as a physiological negative modulator of the chemoreceptor cell function. The previously reported excitatory action of adenosine on the activity of the sensory nerve of the CB is discussed in terms of a balance between the inhibition mediated by A1 receptors and the excitation mediated by A2 receptors.     

Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in the pontine reticular formation of the rat

In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase-activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM, respectively), but very low affinity for VIP (IC50 > 1 microM). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long-term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long-term action of PACAP on REM sleep.     

FK506-associated thrombotic microangiopathy: report of two cases and review of the literature

BACKGROUND: FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication. METHODS: We report two cases of FK506-associated TMA and review the 19 previous reported cases. RESULTS: From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported. CONCLUSIONS: TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patient's death.