Influence of hypothermic cardiopulmonary bypass on atrial natriuretic factor levels

Atrial natriuretic factor (ANF) is a peptide released from the heart in response to atrial distension. This peptide causes diuresis, vasodilatation, decreased blood pressure, and antagonizes the renin-aldosterone and antidiuretic hormone neuraxes. The influence of cardiopulmonary bypass and cardiac surgery on the circulation and release of ANF is unknown. Plasma ANF concentrations were therefore determined in patients undergoing coronary artery revascularization (CABG) and mitral valve replacement (MVR). Peptide levels were unchanged following anaesthetic induction. Plasma ANF concentrations decreased significantly during hypothermic (less than or equal to 28 degrees C) cardiopulmonary bypass in both patient groups. After 60 minutes of cardiac bypass, ANF declined from (mean +/- SEM) 512 +/- 132 to 20 +/- 6 pg.ml-1 (P less than 0.05) during MVR, and from 178 +/- 41 to 110 +/- 48 pg.ml-1 during CABG (P less than 0.05). Rewarming during bypass was associated with an increase in ANF concentration in both groups. Heparin anticoagulation and protamine reversal had no effect on immunoreactive ANF levels. In patients undergoing CABG, there was a linear relationship between plasma ANF concentration (pg.ml-1) and right atrial pressure (mmHg) prior to cardiopulmonary bypass (r = 0.86, P less than 0.005). However, one and three hours after cardiopulmonary bypass there was no significant relationship between right atrial pressure and ANF plasma levels. These results suggest that reduction in plasma ANF concentration occurs during hypothermic cardiopulmonary bypass. Furthermore, the proportional relationship between atrial distension and circulating ANF concentration was altered following cardiac surgery.     

Classical and anaplastic seminoma: difference in survival

Classical and anaplastic seminoma are traditionally treated with radiation therapy and are said to have the same prognosis. A retrospective study was undertaken of 90 seminoma patients treated with radiation therapy between 1961 and 1985. The classical group consisted of 71 patients of whom 50 had stage I and 21 had stage II disease. The anaplastic group consisted of 19 patients of whom ten had stage I and nine had stage II disease. The median follow-up time was 64 months for the entire group. The 10-year relapse-free survival rate for the classical group was 94% and for the anaplastic group was 70% (P less than .05). For patients with classical stage I disease, the relapse-free actuarial survival rate was 98%; for patients with anaplastic stage I disease, it was 64% (P less than .02). For the classical stage II disease group, the relapse-free actuarial survival rate was 84% and for the anaplastic stage II disease group, 75% (P less than .70). Four patients in the classical group (6%) had relapses; of these, one patient had local recurrence of tumor, and three had distant metastases. In the anaplastic group, four patients (21%) had relapses; two patients had local recurrence of tumor, and two had distant metastases. Therefore the data suggest a difference in survival and relapse rates between classical and anaplastic seminoma.     

Spectrum and subcellular determinants of fluorinated anesthetic-mediated proximal tubular injury.

Currently used fluorinated anesthetics are chemically related to methoxyflurane (MF), a drug that caused many cases of clinical acute renal failure during previous widespread use. To determine whether newer fluorinated anesthetics might also have nephrotoxic effects, three currently used agents (isoflurane (IF), sevoflurane (SF), and desflurane) or MF were added to rat proximal tubular segments, followed by assessments of cell integrity (ATP levels and percent lactic dehydrogenase release). Ether served as a negative control. MF, IF, and SF each induced lethal proximal tubular segment injury (up to 92, 71, and 30% lactic dehydrogenase release, respectively) and massive ATP depletion. ATP losses were observed at or near clinically relevant drug levels, they preceded lethal injury, and they correlated with approximately 50% and approximately 100% reductions in total and Na,K-ATPase-driven respiration, respectively. Clinically relevant inorganic fluoride levels simulated fluorinated anesthetic toxicity. However, fluoride release from the anesthetics (a cytochrome P450 process) did not appear to be required for toxicity (no protection with P450 inhibitors and no detectable inorganic fluoride release). As IF was judged to be one-third as toxic as MF, subclinical tubular injury (increased urine N-acetyl-beta-D-glucosaminidase (NAG) levels) after its use was sought in 19 surgical patients. Fifteen patients undergoing comparable operations with SF (approximately one-half as toxic as IF in vitro) and nine patients undergoing regional/ local anesthesia were controls. The IF group doubled its urinary NAG levels by the end of surgery (P < 0.005). Conversely, NAG levels remained stable in both control groups. The conclusions are that 1) currently used fluorinated anesthetics, particularly IF, share (but to a lesser degree) MFs tubulotoxic effects, 2) ATP depletion (probably due to decreased production) and Na,K-ATPase inhibition are likely contributing mechanisms, 3) fluoride is a prime determinant of this toxicity, and 4) tubular injury can be expressed at or near clinically relevant anesthetic/inorganic fluoride levels. That increased enzymuria can develop in patients after IF anesthesia suggests that the above in vitro data could have potential clinical relevance in selected patients.     

Mitoxantrone: Propensity for free radical formation and lipid peroxidation — implications for cardiotoxicity

Summary Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone®; dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofactor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100 M MXN or AM was only 15% and 2% respectively of that produced by 100 M anthracycline.The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50 M inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2-and 2.5-fold at 100 and 200 M, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 M anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 M MXN and AM, whereas 50 M DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4 M (MXN) and 6 M (AM). Moreover, both MXN and AM potently inhibited iron (100 M)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 M anthracenedione.These results are consistent with the diminished cardiotoxicity of mitoxantrone and ametantrone relative to DOX or DNR and may require a reassessment of the role of lipid peroxidation in the mechanism(s) of quinone antineoplastic agent-mediated cardiotoxicity.     

RENAL TRANSPLANTATION – AN EARLY EXPERIENCE

Renal transplant (RT) is now a therapy of choice for end stage renal disease (ESRD). The Nephrology Unit, Asvini started functioning in Dec 90 and to date 1298 sittings of hemodialysis have been given to 45 patients. Of these, 35 were in ESRD and 11 patients underwent renal transplantation at this hospital during the period Jan 91 – Dec 93. One patient expired after 18 months of transplantation due to infection. Early experience in screening patients for RT, use of immunosuppression, management of rejection episodes and protocol are presented with special emphasis on its relevance to the Armed Forces.KEY WORDS: Transplantation, Renal Failure, Immunosuppression, Rejection     

Comparison of in vitro and in vivo inhibition potencies of fluvoxamine toward CYP2C19.

A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (K(i)) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe. K(i) values based on total added fluvoxamine concentration (K(i,total)) and unbound fluvoxamine concentration (K(i,ub)) were calculated, and interindividual variability in K(i) values was examined in six nonfatty livers. K(i,total) values varied with microsomal protein concentration, whereas the corresponding K(i,ub) values were within a narrow range (70-80 nM). In vivo inhibition constants (K(i)iv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (S)-mephenytoin in 12 healthy volunteers receiving fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (S)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with fluvoxamine average steady-state concentration with an intercept of 0.85 (r(2) = 0.88, p < 0.001). The mean (+/-S.D.) values of K(i)iv based on total and unbound plasma concentrations were 13.5 +/- 5.6 and 1.9 +/- 1.1 nM, respectively. Comparison of in vitro and in vivo K(i) values, based on unbound fluvoxamine concentrations, suggests that fluvoxamine inhibition potency is roughly 40 times greater in vivo than in vitro.     

Congenital tuberculosis

Congenital tuberculosis is a rare disease. The non-specific nature of presenting signs and symptoms (because of the lack of host response) and the fatal outcome in the absence of early therapy all underscore the importance of early diagnosis and treatment in infants. Recognition requires awareness that tuberculosis at this age has manifestations not found in older children. Here a case of congenital tuberculosis is presented, where changes were confined only to the thorax. Tuberculosis in the mother could be diagnosed only retrospectively.     

Thyroid dysfunction after mantle irradiation of Hodgkin's disease patients

Thyroid dysfunction can develop in patients with Hodgkin's disease who are treated with mantle irradiation. During the period 1970-89, the records of 320 patients who received mantle irradiation and who had thyroid function tests (TFT) were retrospectively reviewed. The median age was 30 years (range, 7-69 years). The median mantle and thyroid dose was 36 Gy (range, 30-40 Gy) and 39.8 Gy (range, 32-65 Gy), respectively. Overall thyroid dysfunction was present in 39% of the patients. Clinical hypothyroidism was seen in 10% and biochemical hypothyroidism was noted in 25%. Hyperthyroidism was found in 4% of patients. Thyroid nodules had developed in six patients (2%), of which those in four patients were malignant. Age, sex, histological subtype, stage of disease, dose, lymphangiogram and treatment with chemotherapy were not significant factors in the development of thyroid dysfunction. The narrow dose range prevented adequate analysis of dose effect. The results indicate that the incidence of thyroid abnormalities is high enough to warrant regular TFT assessment with pre-irradiation levels and follow-up testing for life because the development of abnormalities can occur many years later. Thyroid examination should form part of the routine follow-up examination and any abnormality should be promptly investigated.