Comparative evaluation of clindamycin/gentamicin and cefoxitin/doxycycline for treatment of pelvic inflammatory disease: a multi-center trial. The European Study Group. The clinical efficacy and safety of clindamycin-gentamicin versus doxycycline-cefoxitin in the treatment of acute pelvic inflammatory disease was evaluated in a comparative, randomized, prospective, multicenter study. Ten investigators enrolled 170 patients. Those judged to be eligible for efficacy were 60/88 (68%) who received the clindamycin-gentamicin regimen and 55/82 (67%) of those treated with cefoxitin-doxycycline. A successful clinical outcome was attained for 52/60 (87%) and 46/55 (84%) for patients treated with clindamycin-gentamicin and cefoxitin-doxycycline, respectively, a difference that was not statistically significant. In the clindamycin-gentamicin series, 8/8 (100%) of patients with positive C. trachomatis culture at baseline were culture negative at the late follow-up 21-35 days after treatment. For those given cefoxitin-doxycycline, 9/11 (82%) who had C. trachomatis at pretreatment showed eradication at follow-up. Neisseria gonorrhoeae was present at baseline in 8/60 (13%) of the clindamycin-gentamicin patients and in 9/55 (16%) of those treated with cefoxitin-doxycycline. Of those who had appropriate follow-up cultures performed, 6 in the clindamycin-gentamicin group and 8 in the cefoxitin-doxycycline series, all showed eradication of the organism. It is concluded that clindamycin-gentamicin and cefoxitin-doxycycline have similar clinical cure rates for acute pelvic inflammatory disease, and based on this limited experience, it is suggested that the clindamycin-gentamicin combination will satisfactorily eradicate Chlamydia trachomatis and Neisseria gonorrhoeae when either or both of these pathogens are present.


Lymphoid cell distribution as prognostic factor in carcinoma of the uterine cervix. Pretreatment assessment of blood lymphoid cells was performed in 44 patients with carcinoma of the cervix and in 19 healthy controls. White blood cells were determined by routine differential counting, and T-lymphocyte subsets and monocytes were quantitated using monoclonal antibodies. Increase in monocyte numbers, as determined by the 1D5 antibody, was seen in the cancer patients, especially in the group with advanced disease. No change in T-lymphocyte subpopulations could be found. During the 5-year follow-up period, 17 patients had a recurrence or died of cancer. The best prognostic information was obtained from conventional clinical parameters, e.g. stage, tumor size and lymph node status. Increased numbers of granulocytes and monocytes were found in advanced stage disease but had no independent prognostic influence. In pelvic lymph node biopsies taken from patients undergoing Wertheim-Meigs operation the T-helper/T-suppressor ratio was higher and the monocyte number lower than in peripheral blood. No correlation could be detected between node cell distribution and the prognosis. It is concluded that immunological testing, as performed in this study, elicits very little new prognostic information.


Torsion of a mucocele of the appendix in a pregnant woman. A case of torsion of a large appendicular mucocele presenting as acute abdomen in a 38-week pregnant woman is reported. Ultrasound showed a localized cystic lesion with internal echoes on the right side of the abdomen. It was diagnosed preoperatively as twisted ovarian cyst. The patient was treated surgically with cesarean section and curative appendectomy.


Pregnancy complicating irradiation-induced constrictive pericarditis. A case is reported of a 24-year-old primigravida who had severe effusive constrictive pericarditis secondary to mediastinal irradiation following chemotherapy for Hodgkin's disease. Pregnancy was threatened by serious maternal cardiovascular complications, and a non-viable fetus was born spontaneously and prematurely. Patient was completely asymptomatic before pregnancy.


Fetal death following labetalol administration in pre-eclampsia. Labetalol (Trandate) 50 mg i.v. was administered to a pre-eclamptic primigravida with an asphytic fetus prior to cesarean section, in order to reduce the risk of excessive increase in blood pressure during induction of anesthesia. Blood pressure fell rapidly from 170/110 to 115/85 mmHg. A dead infant was born. Oral labetalol is arguably a suitable remedy for pre-eclampsia, but if i.v. administration is necessary, an initial dose of 5-10 mg is recommended.


Pseudotumors of the umbilical cord and fetal membranes. Antenatally diagnosed pseudotumors, i.e. non-neoplastic tumors, of the umbilical cord and fetal membranes may when scanned by ultrasound have an appearance leading to misdiagnosis. In the present cases, a hematoma in the fetal membranes was interpreted as a chorioangioma, and a cystic mass inside the umbilical cord caused by degeneration of Wharton's jelly was regarded as an omphalomesenteric or allantoic cyst. The two cases are presented. Color Doppler evaluation seems advisable.


Hemodynamic collapse following labetalol administration in preeclampsia. On the 3rd day after a cesarean section, because of pre-eclampsia, blood pressure was still high, oral labetalol 100 mg with an 8-hour interval was given, followed by 50 mg i.v. administered over 10 min, twice with a 5-hour interval. The last injection was immediately followed by an atrio-ventricular tachycardia with massive decrease in blood pressure. The reason for this is discussed.


Steroid hormones and gonadotropins in a case of ovarian endometriosis associated with virilization. The clinical course, the hormone secretion, the testosterone receptors and the enzymatic activities related to androgen metabolism in a 56-year-old postmenopausal woman with a history of virilization and ovarian endometrioma are reported. Unexpectedly, at the time of examination, no evidence of biochemical hyperandrogenism was obtained. The uncommon association of virilization and ovarian endometrioma simulating a functioning tumor of the ovary is discussed.


Combined anomalies of the müllerian and wolffian systems. Combined congenital anomalies of the Müllerian and Wolffian duct systems are a rare phenomenon. We report a case of bicornuate uterus and infected right Gartner duct cyst, associated with agenesis of the left kidney and a left ovarian cyst. The case is discussed in view of its unknown occurrence.


Polymerase chain reaction and direct DNA tests in detection of human papillomavirus (HPV) DNA in cytologically normal and abnormal cervical smears. Scandinavian Multicenter Study Group. The detectability of human papillomavirus DNA from cervical smears was studied by DNA tests of varying sensitivity. The results were correlated with cervical cytologic abnormalities. A total of 326 women examined at the gynecological outpatient clinics of five Scandinavian hospitals were enrolled in the study on the basis of previous pathological cervical smear or clinically suspected human papillomavirus (HPV) infection. The cervical smears were examined for HPV-DNA of types 6/11, 16 or 18 by two direct DNA tests, the AffiProbe HPV test and the ViraType test. The proportion of HPV-DNA-positive women with normal cytology, benign atypia (mild nuclear and cytoplasmic changes without signs of dysplasia) and dyskaryosis were 16% (12/77), 27% (42/156) and 37% (30/81), respectively. The smears negative for HPV types 6/11, 16 or 18 and those yielding discrepant results in the two commercial tests were also analysed by the polymerase chain reaction (PCR) method. By PCR analysis, the HPV 6/11, 16 or 18 DNA positivity increased from 27% to 41%. The increase was particularly pronounced among the women with dyskaryosis in cytology.


Supraspinal fiber outgrowth and apparent synaptic remodelling across transected-reconstructed feline spinal cord. Following complete transection of the spinal cord at T9, 12 cats were separated into two groups: Group 1 received a collagen matrix (CM) treated with a neuroactive agent or with saline to bridge the spinal cord stumps and an omental transposition which was placed on the dorsal surface of the matrix; Group 2 received spinal cord transection only. Two cats received no spinal cord transection. After 90 days, all animals were killed and their brains and spinal cords were removed for immunohistochemical examination. Two weeks prior to sacrifice, spinal cord blood flows (SCBF) were measured and the retrograde axonal tracer Fluoro-Gold was injected below the transection site. Results show that omental transposition to the CM bridge in Group 1 animals increased SCBF an average 59% (assessed by clamping the omental blood supply to the cord). Examination of the brain 90 days after cord transection revealed Fluoro-Gold accumulation in the cytoplasm and processes of neurons located in the brainstem, midbrain, and diencephalic region which are known to contribute pathways to the spinal cord. Immunohistochemical staining with antibodies against the catecholamine synthesizing enzymes tyrosine hydroxylase and dopamine-B-hydroxylase, indicated that only Group I treated cats developed dense bundles of dopaminergic and noradrenergic fibers within the CM bridge and distal spinal cord tissue. These fibers were seen to extend 90 mm below the transection site. In addition, the synaptogenic marker synaptophysin (SYN) was observed in association with dopaminergic and noradrenergic fibers distal to the collagen matrix bridge, an indication that synaptic remodelling (regeneration) by previously denervated supraspinal axons may have occurred. Immunostaining for glial fibrillary acidic protein (GFAP) showed little to none reactive astrocytosis near the transection site of cats treated with the CM and omentum transposition (Group 1). No catecholaminergic fibers or SYN expression below the transection site were observed in Group 2 treated cats. Group 2 treated cats also showed dense immunostaining of GFAP near the transection site indicating significant astrocytic proliferation. These findings indicate that following complete spinal cord transection in cats and reconstruction with a treated collagen matrix and omental transposition, disconnected supraspinal fibers have the ability to regenerate for long anatomic distances and seemingly engage in synaptic remodelling with distal target tissue.


Lomefloxacin versus amoxicillin in the treatment of acute exacerbations of chronic bronchitis: an Italian multicenter study. Nine centers in Italy participated in a worldwide, multicenter study comparing the effectiveness and safety of lomefloxacin and amoxicillin in patients with acute exacerbations of chronic bronchitis caused mainly by gram-negative pathogens. The 157 enrolled patients received either 400 mg lomefloxacin once daily (n = 78) or 500 mg amoxicillin every 8 hours (n = 79) for 7-10 days. A total of 131 patients were evaluable for bacteriologic efficacy and 154 for clinical efficacy. At 2-4 days after the conclusion of treatment, the bacterial eradication rate was 84.8% for lomefloxacin-treated patients and 64.6% for amoxicillin-treated patients (p = 0.0065); the clinical success rate (cure plus improvement) for lomefloxacin was 94.7% and for amoxicillin was 83.3% (p = 0.0212). The reinfection rate was lower in the lomefloxacin group than in the amoxicillin group (3.0% vs 13.8%, p = 0.0382). Both drug regimens were well tolerated. Once-a-day treatment with 400 mg lomefloxacin was more effective than 500 mg amoxicillin three times daily for the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.


Compliance with universal precautions in a medical practice with a high rate of HIV infection. Universal precautions have been recommended to limit occupational exposure to the human immunodeficiency virus (HIV) and other infectious agents, but whether these recommendations have been incorporated into routine practice has not been demonstrated. Using a one-group, before-after design, we assessed the knowledge and attitudes concerning universal precautions and the level of compliance with these recommendations. The health care professionals had various levels of training and worked in an ambulatory practice with a high rate of HIV. A total of 195 procedures involving potential exposure to various body fluids were observed. No improvement in compliance with recommended precautions was observed following a didactic educational program for either latex glove use (44 percent versus 49 percent, chi 2 less than 1, P greater than 0.2) or appropriate use of hand washing (34 percent versus 47 percent, chi 2 = 3.38, P = 0.07). Faculty demonstrated the lowest levels of adherence to universal precautions. While knowledge of precautions was high, staff members at all levels overestimated their own compliance with these recommendations. Although the number of observations limits the conclusions, the results suggest that the basic protective measures included in universal precautions are not being routinely applied in ambulatory medical practice. Furthermore, didactic educational programs might not be sufficient to improve compliance. Finally, faculty in training programs should monitor their own compliance with universal precautions because of their responsibilities as role models for physicians in training.


Safety and efficacy of lomefloxacin versus cefaclor in the treatment of acute exacerbations of chronic bronchitis. In two multicenter trials, lomefloxacin and cefaclor were compared as treatments for acute bacterial exacerbations of chronic bronchitis. In total, 522 adult outpatients were enrolled at 50 centers in the United States. Patients were randomized to treatment groups receiving either 400 mg lomefloxacin orally once daily (n = 259) or 250 mg cefaclor every 8 hours (n = 263) for 7-10 days. Both groups were comparable in terms of age, severity of exacerbation, smoking history, theophylline use, and baseline pathogens. The most common baseline pathogens were Haemophilus influenzae, found in 32% of patients in the lomefloxacin group and in 29% in the cefaclor group, Pseudomonas aeruginosa (13% and 16%, respectively), Moraxella (Branhamella) catarrhalis (12% and 13%), and Streptococcus pneumoniae (10% in both groups). Bacterial eradication rates 1-4 days after the completion of treatment for all patients with baseline pathogens were 81.8% in the lomefloxacin group and 62.7% in the cefaclor group (p less than 0.001). Clinical success (disappearance or improvement of presenting signs and symptoms) was noted in 80.0% of patients in the lomefloxacin group and 64.7% in the cefaclor group (p = 0.002). Eradication rates for the subgroup of patients who had pathogens susceptible in vitro to both study drugs and who completed treatment were 97.1% for lomefloxacin and 84.6% for cefaclor (p = 0.002). Clinical success rates in this subgroup were 92.4% for lomefloxacin and 90.1 for cefaclor (p = 0.585). Treatment-related adverse events were reported for 7% of patients in the lomefloxacin group and 5% in the cefaclor group. The most common adverse events in both groups were nausea and diarrhea. Six patients were withdrawn from treatment with lomefloxacin and four from the cefaclor group because of adverse events. There was no clinical or laboratory evidence of theophylline interaction with either treatment. Once-daily oral administration of 400 mg lomefloxacin was an effective, well-tolerated alternative to 250 mg of cefaclor three times daily in the treatment of acute exacerbations of chronic bronchitis.


Urinary tract infection prophylaxis in transurethral surgery: oral lomefloxacin versus parenteral cefuroxime. The purpose of this study was to compare the efficacy and safety of single-dose oral lomefloxacin and single-dose parenteral cefuroxime for the prevention of urinary tract infection following transurethral surgery. A total of 63 patients were enrolled in this prospective, randomized open-label study, which was conducted at two medical centers in France. Patients were randomized to receive either 400 mg of oral lomefloxacin 2-6 hours before surgery or 1.5 g parenteral cefuroxime 30-90 minutes before surgery. Postoperative clinical evaluation was performed daily, and bacteriologic evaluation included urine cultures performed 24 hours after surgery, just before and 1 day after removal of the indwelling catheter, and 3-5 days after surgery. Another urine culture was optionally performed 1-3 months after surgery. Infection was defined as a urinary bacteria count greater than or equal to 10(5) colony-forming units (CFU)/mL of urine. Of the 63 patients enrolled, 54 were evaluable for efficacy, 27 in each group. The success rate of prophylaxis was 88.9% in the lomefloxacin group and 88.5% in the cefuroxime group (p = nonsignificant). None of the 16 lomefloxacin-treated patients who were re-cultured at 1-3 months was found to be infected. Adverse events were minor in both groups. A single oral dose of lomefloxacin was as efficacious and as safe as a single intravenous dose of cefuroxime for prevention of postoperative urinary tract infection in patients undergoing transurethral surgery.


A multicenter comparison of oral lomefloxacin versus parenteral cefotaxime as prophylactic agents in transurethral surgery. This report presents the pooled results from two randomized trials of lomefloxacin and cefotaxime used as prophylaxis in patients undergoing transurethral surgical procedures. A total of 499 patients were enrolled at seven centers in the United States. Patients received either 400 mg of lomefloxacin orally 2-6 hours prior to surgery, or 1 g of cefotaxime intravenously or intramuscularly 30-90 minutes preoperatively. Patients undergoing simple cystoscopy or retrograde pyelograms were not eligible for inclusion. Urine cultures were obtained prior to surgery, 24 hours post-surgery, prior to catheter removal, and 3-5 days post operatively. Treatment failure was defined as isolation of greater than or equal to 10(5) colony-forming units (CFU)/mL of pathogenic bacteria from any post-surgical urine culture. Lomefloxacin was successful in preventing post operative infections in 204 of 207 evaluable patients (98.6%); there were three prophylactic failures. Cefotaxime was successful in 196 of 206 (95.1%) evaluable patients; 10 were prophylactic failures. Lomefloxacin concentrations were measured simultaneously in serum and in samples of prostate tissue from 29 patients undergoing transurethral resection of the prostate. Lomefloxacin prostate concentrations were 1.0-22.3 micrograms/g, with a mean of 5.0 micrograms/g. The average tissue:plasma ratio was 2.0. The safety profile of the two study drugs was excellent, and both were well tolerated. Adverse events were reported by 12.7% of the patients treated with lomefloxacin and 13.8% of those treated with cefotaxime. The majority of events were mild and required no treatment.


Infection in the elderly: studies with lomefloxacin. Results of trials of lomefloxacin (400 mg once daily) in elderly patients with uncomplicated urinary tract infections, complicated urinary tract infections, acute bacterial exacerbations of chronic bronchitis, and as prophylaxis for transurethral surgical procedures (400 mg single dose) have been analyzed. In patients greater than or equal to 65 years of age with uncomplicated urinary tract infections, the bacterial eradication rate for lomefloxacin was 100%. In patients with complicated urinary tract infections, the bacterial eradication rate for lomefloxacin (92.2%) was statistically superior to comparator agents (84.9%, p = 0.012). In elderly patients with acute exacerbations of chronic bronchitis caused predominantly by gram-negative pathogens, lomefloxacin eradicated 85.2% of pathogens versus 73.8% for amoxicillin (p = 0.004). Lomefloxacin was 98% effective as a prophylactic agent in transurethral surgery. The bacteriologic and clinical efficacy of lomefloxacin was similar in young and elderly groups of patients. Lomefloxacin appears to be as effective as the comparator drugs in both young and elderly patients.


The U.S. clinical experience with lomefloxacin, a new once-daily fluoroquinolone. Lomefloxacin is a new fluoroquinolone antimicrobial agent that has undergone extensive worldwide clinical evaluation. This report summarizes the safety and efficacy of lomefloxacin in the treatment of uncomplicated urinary tract infections, complicated urinary tract infections, acute exacerbations of chronic bronchitis, and for prophylaxis during urinary tract surgery. The clinical data presented are an overview of all clinical studies conducted in the United States to date. The results have been derived from multiple studies in which patients received lomefloxacin or a comparative agent in either blinded or open-label studies. During the course of the clinical program in the United States, lomefloxacin has been compared with oral norfloxacin, ciprofloxacin, and cefaclor, as well as parenteral cefotaxime. In all instances, the once-daily oral administration of lomefloxacin was either equally effective or statistically significantly superior in clinical and/or bacteriologic efficacy to these comparative agents. In addition, the comparators were administered either two or three times per day, except in the surgical prophylaxis studies, in which single doses of each antibiotic were administered preoperatively. These results attest to the value of the convenience and simplicity of the oral dosing regimen for lomefloxacin. During the course of the clinical program, lomefloxacin was well tolerated, with most adverse events of mild to moderate severity. In general, the incidence of adverse events for patients and subjects receiving lomefloxacin was comparable to that observed in patients treated with comparator drugs. The most common adverse events were related to the gastrointestinal tract (nausea and diarrhea), the skin and appendages (photosensitivity), and the central nervous system (dizziness and headache). A sub-analysis of adverse events in the respiratory studies demonstrated that concomitant administration of lomefloxacin and theophylline does not increase the incidence of adverse events when compared to lomefloxacin alone. An additional sub-analysis also showed that the incidence of adverse events in elderly patients was similar to that in younger patients. The results of the U.S. clinical program indicate that lomefloxacin administered orally once daily is effective and well tolerated in a variety of infections of bacterial origin.


Lomefloxacin concentrations in bone after a single oral dose. We studied the penetration characteristics of lomefloxacin in bone in 30 patients with osteoarthritis undergoing total hip replacement. Patients were given a single oral 400 mg dose at various times from 1 to 12 hours prior to removal of bone samples. The peak plasma and bone (subchondral bone from femoral head) concentrations reached approximately 4.0 micrograms/mL at 2 hours post-dose and 3.0 micrograms/mL at 3 hours post-dose, respectively. At 12 hours post-dose both plasma and bone concentrations were still greater than 1.0 microgram/mL. Two hours after dosing the average bone-to-plasma ratio was greater than 0.6. These data indicate that a single 400 mg oral dose of lomefloxacin attains bone concentrations that are above its usual minimum inhibitory concentrations for susceptible organisms.


Influence of renal function on the pharmacokinetics of lomefloxacin compared with other fluoroquinolones. Fluoroquinolones have similar chemical structures but wide differences in their pharmacokinetic profiles. Disparity in fluoroquinolone elimination is most evident in patients with various degrees of renal insufficiency. Ofloxacin is almost exclusively eliminated by the kidney, whereas pefloxacin is predominantly cleared by the liver. The fluoroquinolones eliminated by both renal and nonrenal routes (hepatic and transintestinal) include norfloxacin, ciprofloxacin, enoxacin, fleroxacin, temafloxacin, and lomefloxacin. The primary renal mechanism of elimination for norfloxacin, ciprofloxacin, enoxacin, fleroxacin, temafloxacin, and lomefloxacin is glomerular filtration and tubular secretion. Both total clearance and renal clearance significantly correlate with creatinine clearance for these fluoroquinolones, and creatinine clearance is a useful clinical marker on which to base dosage adjustments. For some fluoroquinolones, dosage adjustments are recommended when creatinine clearances fall below 30-40 mL/min. This is especially evident for lomefloxacin, temafloxacin, norfloxacin, ciprofloxacin, enoxacin, and fleroxacin. There is very little removal of fluoroquinolones from the plasma during hemodialysis due to their extensive tissue distribution.


Multiple-dose pharmacokinetics of lomefloxacin: rationale for once-a-day dosing. Six dosage regimens of oral lomefloxacin, a new difluorinated quinolone, were given to healthy volunteer subjects for 7 days in a randomized, placebo-controlled trial to evaluate pharmacokinetics and tolerability and to determine the optimum dosage schedule. Single daily doses of lomefloxacin up to 800 mg and multiple doses up to 600 mg twice daily (1,200 mg/day) were well tolerated. At all dose levels and schedules, lomefloxacin was well absorbed and achieved peak plasma concentrations approximately 1 hour after administration. Urine concentrations were approximately 100 times the plasma concentrations. Elimination half-lives of 7-8 hours were found for all dosage regimens. Steady-state was achieved on the second day of dosing. Little accumulation was observed. A 400 mg oral dose provided a mean peak plasma concentration of 3.43 micrograms/mL, and trough concentrations at steady state that were above the minimum inhibitory concentration for 90% (MIC90) of most common Enterobacteriaceae. The 400 mg dose produced a urine concentration of greater than 80 micrograms/mL during the 12- to 24-hour period after the dose, thus exceeding the MIC90 for clinical isolates such as Pseudomonas aeruginosa, Serratia marcescens, and methicillin-susceptible and -resistant Staphylococcus aureus. There was good agreement between the results of this study and previously reported single-dose data. In summary, lomefloxacin's rapid absorption, long half-life, and high sustained plasma and urine concentrations should permit effective once-daily administration in many clinical situations.


Quinolone pharmacokinetics in the elderly. As a class, quinolones undergo both renal excretion and hepatic metabolism. The dominant elimination pathway is usually renal, where secretion by the proximal tubule results in renal clearances 1.5-4 times greater than creatinine clearance. The benefit of this two-pathway elimination is protection from excessive accumulation in patients with single-organ dysfunction. A number of investigations have been performed to assess how the changes in renal and hepatic function that occur in the elderly influence quinolone pharmacokinetics. For example, lomefloxacin serum concentrations are slightly higher in elderly subjects, whereas total clearance, renal clearance, and nonrenal clearance are reduced, in comparison with younger subjects. The decline in renal clearance can be explained, in part, by the parallel decline in creatinine clearance in the elderly. Dosage adjustments should not be necessary in elderly patients with only minor changes in renal function caused by age-related changes in physiology. Although the relationship between nonrenal clearance of lomefloxacin and age is slightly less precise than the relationship between total clearance and age, this may be explained by the age-related decline in hepatic function and perhaps by changes in metabolic function. Quinolones show little evidence of altered absorption or altered pharmacodynamics in the elderly. These age-related alterations in drug elimination due to normal physiologic changes are generally not significant enough to warrant changes in dosage regimens; however, disease effects, particularly alterations of renal function, appear to be more important than gradual changes in physiology characteristic of the aging population.


Single-dose pharmacokinetics of lomefloxacin in patients with normal and impaired renal function. The quinolone antibiotic lomefloxacin was administered as a 400 mg single oral dose to 12 subjects with renal impairment (creatinine clearance 5-65 mL/min/1.73 m2) and to 13 healthy subjects (creatinine clearance 80-135 mL/min/1.73 m2). The concentrations of lomefloxacin in plasma and urine were determined by high-pressure liquid chromatography up to 48 hours post-administration. Linear correlations were found between lomefloxacin plasma and renal clearances and creatinine clearance. The mean nonrenal clearance of lomefloxacin (approximately 32 mL/min/1.72 m2) was not influenced by renal function. The mean plasma clearances of lomefloxacin in healthy subjects and in a subgroup of patients with severe renal impairment (creatinine clearance 5-15 mL/min/1.73 m2) were 209 and 43 mL/min/1.73 m2, respectively. The decrease in plasma clearance of lomefloxacin was explained fully by the decrease in renal clearance. The elimination half-life of lomefloxacin increased significantly with the degree of renal impairment, from 7.5 hours in normal subjects to 26.9 hours in subjects with severe renal impairment. The maximum serum concentration and the time to maximum serum concentration were not significantly affected by renal function. The pharmacokinetics of lomefloxacin are dependent on renal function, and appropriate dosage adjustment is necessary when creatinine clearance is less than 30 mL/min/1.73 m2.


Pharmacokinetics of lomefloxacin in patients with cirrhosis. The effect of liver failure on the pharmacokinetics of lomefloxacin was studied in 12 patients with cirrhosis. Patients received a single oral dose of 400 mg lomefloxacin, and blood and urine samples were collected at intervals over the next 48 hours. The concentrations of lomefloxacin in all samples were measured using high-pressure liquid chromatography (HPLC). The mean (+/- standard deviation) maximum plasma concentration (Cmax) in these patients was 3.9 +/- 1.20 micrograms/mL. The mean time to maximum serum concentration (Tmax) was 2.1 +/- 2.6 hours, and the mean elimination half-life (t1/2) was 9.16 +/- 1.93 hours. Mean renal clearance was 88.9 +/- 38.0 mL/min/1.73 m2, and the mean nonrenal clearance was 61.6 +/- 19.0 mL/min/1.73 m2, which corresponded to 41% of the total body clearance. No correlations were observed between nonrenal clearance and hepatic insufficiency (Pugh score) or nonrenal clearance and plasma bilirubin. These results show that liver failure does not per se affect lomefloxacin kinetics. Thus, no adjustments in lomefloxacin dosages appear to be necessary for patients with impaired liver function tests.


In vitro assessment of the postantibiotic effect of lomefloxacin against gram-positive and gram-negative pathogens. We evaluated the postantibiotic effect (PAE) of lomefloxacin, a new difluorinated quinolone, on multiply drug-resistant gram-positive and gram-negative clinical pathogens. Lomefloxacin induced a PAE of about 2 hours in gram-negative and gram-positive bacteria exposed for 1 hour to concentrations corresponding to four times their minimum inhibitory concentrations (MIC). PAE values (hours) ranged from 1.8 with Serratia marcescens to 2.5 with Staphylococcus aureus. No significant differences in PAE values were found for ciprofloxacin or ofloxacin against the same pathogens. The PAE was increased when the time of drug exposure was increased to 2 hours. These results indicate that lomefloxacin has a PAE equivalent to that of other fluoroquinolones.


Comparative penetration of lomefloxacin and other quinolones into human phagocytes. The penetration of lomefloxacin into human polymorphonuclear leukocytes (PMNs) and peritoneal macrophages (PMphis) was evaluated using a fluorometric assay. Lomefloxacin reached high intracellular concentrations into PMNs at extracellular concentrations of 2 and 5 mg/L (cellular to extracellular concentration ratio [C/E] greater than 4). At the same conditions (20 minutes incubation; extracellular concentrations: 2 mg/L) lomefloxacin uptake by human PMNs (C/E: 7.9 +/- 2.6) was slightly higher than those of norfloxacin (C/E 5.1 +/- 1.8), ciprofloxacin (C/E: 6.2 +/- 2.0), and ofloxacin (C/E 7.1 +/- 2.6). Lomefloxacin penetration into human PMphis was significantly lower than PMNs but still with C/E ratios greater than 4. Entry of lomefloxacin into phagocytes was not affected by cell viability but was environmental-temperature dependent. It is concluded that lomefloxacin and the other quinolones evaluated reach high intracellular concentrations in human phagocytic cells.


Fluoroquinolone (Lomefloxacin) International Surveillance Trial: a report of 30 months of monitoring in vitro activity. The antimicrobial activity and spectrum of lomefloxacin were assessed by standardized disk diffusion methods in 36 countries. More than 500,000 facultative organisms were tested during the first 30 months of a 3-year monitoring interval. Lomefloxacin demonstrated inhibition (zones greater than or equal to 19 mm) of greater than 90% of Enterobacteriaceae, greater than 99% of Moraxella (Branhamella) catarrhalis, greater than 98% of Haemophilus spp., and 91% of Staphylococcus aureus strains. Pseudomonas spp., especially Pseudomonas aeruginosa (18% resistance), were considered moderately susceptible, as were most strains of streptococci and enterococci. Some variation of national/regional fluoroquinolone resistance rates was observed, using lomefloxacin as an index or indicator drug, with the highest numbers of resistant strains being isolated in France. However, these data demonstrated a wide spectrum of lomefloxacin activity in all nations monitored.


Lomefloxacin: microbiologic assessment and unique properties. In comparative studies, lomefloxacin, a new difluorinated quinolone, exhibits broad antibacterial activity in vitro, similar or superior to that of other quinolones (enoxacin, ofloxacin, pipemidic acid, nalidixic acid, and norfloxacin) but less than that of ciprofloxacin. Lomefloxacin inhibited Neisseria gonorrhoeae, Moraxella (Branhamella) catarrhalis, Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, and the majority of aerobic gram-negative rods, including nosocomial isolates, at concentrations readily achievable in biologic fluids and tissues. Lomefloxacin was less active against obligate anaerobes and streptococci. Organisms resistant to methicillin, penicillin, or the aminoglycosides were susceptible to lomefloxacin. No significant lomefloxacin resistance was identified in 18 countries in which in vitro studies were conducted, with the exception of a small number of strains tested in France. The frequency with which spontaneous single-step resistance to lomefloxacin develops in vitro is low.


Comparison of the safety and efficacy of lomefloxacin and trimethoprim/sulfamethoxazole in the treatment of uncomplicated urinary tract infections: results from a multicenter study. Lomefloxacin, a new difluorinated quinolone, and trimethoprim/sulfamethoxazole (TMP/SMX) were compared in the treatment of adults with uncomplicated urinary tract infections. The study was conducted as a multicenter, controlled, prospectively randomized, single-blind study in five countries (Argentina, Belgium, Brazil, Mexico, and Venezuela). A total of 254 patients were enrolled: 129 in the lomefloxacin group and 125 in the TMP/SMX group. Patients received either 400 mg lomefloxacin orally once daily or 160 mg/800 mg TMP/SMX orally twice daily for 7-10 days. Escherichia coli and Proteus mirabilis were the pathogens most frequently isolated. At 5-9 days post-therapy, satisfactory bacteriologic results were noted in 98.4% of patients treated with lomefloxacin and in 95.8% of patients in the TMP/SMX group (p = 0.2153). Clinical success 5-9 days post-therapy was noted in 99.2% of patients in the lomefloxacin group and in 98.3% of patients in the TMP/SMX group (p = 0.5138). Adverse events probably related to treatment occurred in 6% of those treated with lomefloxacin and in 7% of patients treated with TMP/SMX. Once-daily oral lomefloxacin is a well-tolerated and effective treatment of uncomplicated urinary tract infections caused by susceptible pathogens.


Efficacy of lomefloxacin as compared to norfloxacin in the treatment of uncomplicated urinary tract infections in adults. The efficacy and safety of 7-10-day courses of lomefloxacin (single daily dose of 400 mg) or norfloxacin (twice-daily doses of 400 mg) for the treatment of uncomplicated urinary tract infections were compared in two large, multicenter, randomized trials. This article presents the combined results of these trials, which were conducted in a total of 27 centers throughout the United States. A total of 727 adults, mostly women, with symptoms of acute urinary tract infection were enrolled; 370 patients were randomized to lomefloxacin treatment, and 357 received norfloxacin. The bacteriologic cure rate at 5-9 days post-therapy was 98.2% in the lomefloxacin group and 96.3% in the norfloxacin group (p = nonsignificant). The clinical success rate of 99.1% in the lomefloxacin group was significantly higher than the success rate of 93.5% in the norfloxacin group (p = 0.002). Adverse events were reported by 157 lomefloxacin-treated patients and 129 patients receiving norfloxacin. Adverse events attributable to drug treatment occurred in 41 patients (11.1%) in the lomefloxacin group and 27 (7.6%) in the norfloxacin group. Eight lomefloxacin (2.2%) and three norfloxacin patients (0.8%) were withdrawn from treatment because of adverse events probably attributable to the drug. The incidence of dizziness, tremor, and photosensitivity rash was higher in the lomefloxacin group than in the norfloxacin group, while the incidence of nausea was higher in the norfloxacin group. The results of these trials demonstrate that once-daily administration of 400 mg lomefloxacin is as safe and effective clinically as, and superior bacteriologically to, twice-daily administration of 400 mg norfloxacin in the treatment of acute uncomplicated urinary tract infections in adult patients.


Penetration of lomefloxacin into bronchial secretions following single and multiple oral administration. The bronchial penetration of lomefloxacin, a new difluorinated quinolone, was evaluated in 36 patients who underwent bronchoscopies for diagnostic purposes. Patients were randomized into two groups, with 18 patients (Group I) receiving a single oral dose of 400 mg lomefloxacin and 18 patients (Group II) receiving 400 mg twice daily. Samples of serum and bronchial secretions were collected simultaneously in both groups at 1, 2, or 4 hours after lomefloxacin administration. The results of this study showed that bronchial penetration of lomefloxacin was rapid and yielded high concentrations; the mean bronchial levels of the drug reached 2.78 +/- 3.64 micrograms/mL in Group I 1 hour after the dose, and 2.84 +/- 1.73 micrograms/mL in Group II at the fourth hour. The ratio between bronchial and simultaneous serum concentrations was 89% at the first and second hours after the dose for Group I, and it was 77% 4 hours after oral administration in Group II. In comparing these results to previous reports of lomefloxacin penetration into bronchial mucosa or of concentrations of other new fluoroquinolones into bronchial secretions, it is to be noted that the local concentrations of the newer quinolones are of very similar values, ranging from 2.7 micrograms/mL (ofloxacin) to 4.46 micrograms/mL (pefloxacin). This study confirms that lomefloxacin achieves high tissue concentrations in the respiratory tree; this characteristic, together with lomefloxacin's antibacterial spectrum, indicates promise in the treatment of many respiratory infections.


A comparison of the safety and efficacy of lomefloxacin and ciprofloxacin in the treatment of complicated or recurrent urinary tract infections. The efficacy and safety of two fluoroquinolone antimicrobial agents, lomefloxacin and ciprofloxacin, were compared in a randomized, investigator-blinded, multiple-dose study that enrolled 150 adult outpatients with complicated or recurrent urinary tract infections. A total of 75 patients were treated with 400 mg of lomefloxacin once daily for 10-14 days; an equal number of patients received 500 mg of ciprofloxacin every 12 hours for 10-14 days. Both groups of patients were comparable in terms of demographics and distribution of underlying conditions. The most frequently occurring pathogens in both groups were Escherichia coli and Klebsiella pneumoniae. A total of 142 patients met the criteria for efficacy evaluation, 72 in the lomefloxacin group and 70 in the ciprofloxacin group. Eradication of the initial pathogen (post-treatment culture of less than or equal to 10(4) colony-forming units (CFU)/mL) was noted in 97.2% of patients treated with lomefloxacin and in 95.7% of ciprofloxacin-treated patients. Clinical success (disappearance or amelioration of presenting signs and symptoms) occurred in 98.6% of lomefloxacin-treated patients and in 95.7% of patients treated with ciprofloxacin. The differences in outcome between the two treatment groups were not statistically significant. Both drug regimens were well tolerated. There were no clinically significant changes in clinical laboratory values during treatment. In the lomefloxacin group three patients reported nausea, one nervousness, and one pruritus; in the ciprofloxacin group, two patients reported nausea and three pruritus. Two lomefloxacin-treated patients (3%) and four patients treated with ciprofloxacin (5%) withdrew from treatment because of adverse events. A single daily dose of 400 mg lomefloxacin was comparable to 500 mg ciprofloxacin every 12 hours for the treatment of complicated or recurrent urinary tract infections.


A multicenter study of lomefloxacin and trimethoprim/sulfamethoxazole in the treatment of uncomplicated acute pyelonephritis. A total of 63 adult patients with uncomplicated acute pyelonephritis were enrolled in a multicenter, randomized comparison of lomefloxacin (400 mg orally once daily for 14 days) and trimethoprim/sulfamethoxazole (TMP/SMX, 160/800 mg orally twice daily for 14 days). Study participants were predominantly female (70% in the lomefloxacin group and 80% in the TMP/SMX group). Escherichia coli was isolated from pretreatment urine cultures in 87.5% of the lomefloxacin group and 80.0% of the TMP/SMX group. Baseline pathogens were eradicated in 100% of evaluable patients in the lomefloxacin group 5-9 days after the end of therapy and in 88.9% of patients in the TMP/SMX group (p = 0.05). The clinical cure rate 5-9 days after therapy with lomefloxacin was 65.0% and for TMP/SMX was 68.4%. At the 4-6 week follow-up in the lomefloxacin group, nine pathogens remained eradicated, one E. coli was isolated, and the results for 14 pathogens were unknown or unevaluable. In the TMP/SMX group, 12 pathogens remained eradicated, three E. coli and one Group D Streptococcus were isolated, and the results for nine pathogens were unknown or unevaluable. Both treatment regimens were well tolerated; adverse events occurred in 12% of patients in the lomefloxacin group and in 17% in the TMP/SMX group. Events considered by the investigators to be probably related to treatment occurred in three patients in each group. In conclusion, once-daily lomefloxacin (400 mg) was a well tolerated and effective alternative to twice-daily TMP/SMX (160/800 mg) for the treatment of adults with uncomplicated acute pyelonephritis.


A double-blind study of two dosage regimens of lomefloxacin in bacteriologically proven exacerbations of chronic bronchitis of gram-negative etiology. Lomefloxacin has been shown to produce high and sustained concentrations in serum and bronchial mucosa after once-daily administration. This study was designed to assess whether a dose response exists for 400 mg lomefloxacin given once daily or twice daily for 10 days in the treatment of acute bacterial exacerbations of chronic bronchitis of gram-negative etiology. A total of 100 adult patients with acute exacerbations of chronic bronchitis were enrolled at 10 study sites in Germany. Patients with confirmed bacterial pathogens in the baseline sputum culture (once-daily group n = 49, twice-daily group n = 47) were eligible for analysis of bacteriologic and clinical efficacy. The eradication rates for the most frequently isolated baseline pathogens, Haemophilus influenzae, Pseudomonas aeruginosa, and Klebsiella pneumoniae, were at least 75% for both treatment regimens. Overall, once-daily treatment eradicated baseline pathogens in 42 of 49 (85.7%) patients, while twice-daily treatment eradicated pathogens in 43 of 47 (91.5%). This difference was not statistically significant (p = 0.226). Clinically, 47 of 49 (95.9%) patients in the once-daily group and 46 of 47 (97.9%) in the twice-daily group were cured or improved (p = 0.307). Both regimens were well tolerated; there were no differences in the incidence (six patients in each group), types, or severity of adverse events, nor was there clinical evidence of theophylline interaction. The results of this study demonstrate that once-daily treatment with 400 mg lomefloxacin is as effective as twice-daily dosing with 400 mg in patients with acute bacterial exacerbations of chronic bronchitis.


Expression of the 11p13 Wilms' tumor gene, WT1, correlates with histologic category of Wilms' tumor. Homozygous inactivation of WT1, a Wilms' tumor gene located on chromosome 11 at p13, is believed to predispose to Wilms' tumor and therefore may be a common occurrence in this cancer. The expression of this gene in primary Wilms' tumors was examined by northern and quantitative RNA slot blot analysis and compared with clinical, histologic, and molecular features of each case. The characteristic 3.2 kb RNA was readily detected in most primary tumors although there was marked variation in the level of WT1-specific transcripts. No abnormal-sized RNA products were detected and expression of WT1 was not coordinated with that of several other oncofetal genes: N-myc, insulinlike growth factor 2 (IGF-2), and c-myc. The relative abundance of WT1-specific RNA did correlate with the histologic category of Wilms' tumor such that those tumors with heterologous differentiation have, in general, lower relative levels of WT1 transcripts than those tumors without heterologous differentiation. These results further establish the heterogeneity of Wilms' tumor with respect to the expression of tumor-associated oncofetal genes and suggest a relationship between WT1 expression and cellular differentiation.


Transgenic mice that develop pituitary tumors. A model for Cushing's disease. Transgenic mice that developed adrenocorticotropic hormone (ACTH)-producing pituitary tumors were generated with the polyoma early region promotor linked to a cDNA encoding polyoma large T antigen (PyLT). Light microscopic examination of the pituitaries showed normal morphology at 4 months of age, either unremarkable morphology or microadenoma formation at 9 months of age, and up to 5 mm large adenomas in clinically ill transgenic mice at 13-16 months of age. At age 9 months, transgenic mice weighed significantly more than corresponding control mice, but they began wasting at approximately 1 year of age. The adrenal glands of these older PyLT-1 mice showed a weight increase and exhibited a medullary hyperplasia. Subcutaneous transplants of transgenic pituitary tumors to nontransgenic, immunocompetent mice resulted in tumors with a morphology and ACTH immunoreactivity similar to the primary tumor. The effects of hypercorticotropism were more enhanced and occurred with a shorter latency in the mice carrying transgene pituitary transplants than in the PyLT-1 transgenic mice themselves. Moreover, these transplanted mice showed a weight increase with an axial deposition pattern and hypertrophy of the adrenal cortex that resembled the findings in human Cushing's disease. Plasma ACTH levels were significantly increased in clinically ill transgenic mice and even higher levels were found in the transplant mice. Thus, both murine models should be useful for studying Cushing's disease.


Phagocytic activation of human neutrophils by the detergent component of fluosol. Fluosol (Alpha Therapeutic Corporation, Los Angeles, CA) an emulsion of perfluorocarbons with a high oxygen-carrying capacity, was approved as an adjunct to alleviate myocardial ischemia during coronary angioplasty. This drug also significantly enhances myocardial salvage presumably related to an action on the neutrophil. The mechanism by which fluosol and its individual components, including the detergent Pluronic F-68, affected neutrophil function was examined. During the incubation of neutrophils with fluosol, a rapid stimulation of superoxide anion production and degranulation which progressively increased over a 30-minute period was detected. Neutrophils incubated with only Pluronic F-68 produced similar amounts of superoxide anion. Cytochalasin B, an inhibitor of phagocytosis, significantly inhibited this superoxide anion generation. As shown previously, neutrophils incubated with fluosol for 30 minutes and then subsequently stimulated manifested a reduction in lysozyme release as compared with untreated cells. Results of an electron microscopic examination confirmed the cellular uptake of the fluosol within phagocytic vacuoles. Neutrophil viability determined by trypan blue was unaffected after fluosol treatment. These observations show that the fluosol emulsion, primarily through micelles formed by the detergent Pluronic F-68, activates human neutrophils by serving as a phagocytic stimulus, which produces a cell refractory to subsequent stimulation.


Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha. Characterization of mammary gland and skin proliferations. Eight lines of transgenic mice expressing a mouse mammary tumor virus (MMTV) human transforming growth factor-alpha (TGF alpha) fusion gene were established. Three lines with distinctive phenotypes are presented. All have proliferative changes of the mammary gland. One line has sebaceous gland hyperplasia of the skin. Five histologic patterns of mammary gland hyperplasia based on two of these lines were identified: cystic hyperplasia, solid hyperplasia, dysplasia, adenoma, and adenocarcinoma. Human TGF alpha mRNA and protein were produced in all patterns but appeared reduced in solid hyperplasia, dysplasia, and adenocarcinoma. TGF alpha immunoreactivity in the mammary tissue, cystic fluid, and serum did not show significant differences; hyperplasia developed in 65% of multiparous mice and 45% of virgin mice by 12 months of age. Adenocarcinoma developed in 40% of multiparous mice and 30% of virgin mice by 16 months of age. These transgenic lines may provide useful models of mammary and sebaceous gland hyperplasia analogous to human disease.


Alterations in the expression of uvomorulin and Na+,K(+)-adenosine triphosphatase during mouse skin tumor progression. Uvomorulin (E-cadherin), a cell adhesion molecule, and Na+,K(+)-adenosine triphosphatase (ATPase), a marker protein of the basal-lateral cell membrane domains of polarized epithelial cells, were investigated in a group of mouse skin tumors induced by a two-stage chemical carcinogenesis protocol and in cell lines derived from mouse skin papillomas and squamous cell carcinomas (SCC). Although these two markers were present in benign tumors and in nontumorigenic cell lines, the Na+,K(+)-ATPase showed an altered pattern of distribution that included the presence of enzyme not only in the basolateral domain but also on the apical domain of the cell membrane of basal and spinous cells in well-differentiated squamous cell carcinomas (SCC). In higher grade SCC, a loss of Na+,K(+)-ATPase immunoreactivity was simultaneously detected with a marginal or absent expression of uvomorulin. The more differentiated SCC and papillomas expressed less uvomorulin immunoreactivity than normal epidermal cells. Both markers were seen in tumor cell lines that produced well-differentiated SCC after subcutaneous inoculation into nude mice. Neither Na+,K(+)-ATPase nor uvomorulin could be detected in cell lines that produced high grade, poorly differentiated SCC. Northern blots confirmed the absence of uvomorulin mRNA in these highly malignant cell lines. These data indicate that progression from premalignant papilloma to low-grade SCC and subsequently to high-grade SCC is accompanied by loss of epithelial cell polarity as detected by changes in Na+,K(+)-ATPase and by decreased or absent expression of uvomorulin in tumors and cell lines characterized by an advanced malignant phenotype.


Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors. Carcinomas of the pancreas that developed in Tg(Ela-1, SV40E)Bri18 and Tg(Ela-1, SV40E+Ela-1, neo)Bri19 strains of transgenic mice were classified into eight histologic patterns. Most were variants of acinar cell carcinoma, but cystic and undifferentiated carcinomas were found. The spectrum of phenotypes was similar in small and large carcinomas, but the small group included a higher fraction of well-differentiated tumors and fewer poorly differentiated and anaplastic tumors. The incidence of islet cell tumors was far higher in the Bri18 strain (77%) than in the Bri19 strain (1.6%). Islet cell hyperplasia was much more prevalent in Bri18 than Bri19 mice. In both strains, the nontumorous pancreas showed acinar cell dysplasia with a more abnormal and distinctive pattern in the Bri19 strain. While the spectrum of exocrine tumor phenotypes is similar, significant differences occurred between these two transgenic mouse strains as models for pancreatic carcinogenesis.


Presence of the diffuse early antigen of Epstein-Barr virus in lymphomas and lymphoproliferative disorders. The authors recently demonstrated that 40% of Epstein-Barr virus (EBV) associated lymphoproliferative lesions contained lytic as well as latent EBV DNA. To examine more fully the replicative state of EBV in these disorders, the authors studied protein extracts of EBV-associated lymphoid lesions from 13 patients, most of whom were immunosuppressed, for expression of the diffuse early antigen (EA-D) of EBV, by immunoblotting techniques. The reagent used was a mouse monoclonal antibody. Seven of thirteen samples (54%) contained EA-D. These data indicate that in EBV-associated lymphoproliferative lesions, lytic viral replication occurs frequently, manifested by the presence of EBV diffuse early antigen as well as by the presence of lytic EBV DNA replication.


Potentiometric and voltammetric investigations of H2/H+ catalysis by periplasmic hydrogenase from Desulfovibrio gigas immobilized at the electrode surface in an amphiphilic bilayer assembly. Interactions of an enzyme with an organized amphipilic bilayer are explored as a general means of enzyme immobilization in electroenzymatic systems. Immobilization of Desulfovibrio gigas hydrogenase at the electrode surface involves hydrophobic interactions of the enzyme with the bilayer assembly consisting of octadecyltrichlorosilane and octadecylviologen (C18MV2+) molecules. Due to a hydrophobic character of the enzyme, these interactions direct the enzyme to occupy a central position in the bilayer's hydrocarbon region and lead to immobilization of 3 pmol/cm2 of the enzyme in the plane of the bilayer. This corresponds to 50% surface coverage. The immobilized enzyme catalyzes H2 oxidation mediated by the C18MW2+/.+ couple. This electroenzymatic scheme functions under steady-state voltammetric as well as potentiometric conditions in the pH range 3.5-10. Coupling of enzymatic activity to the electrode surface is accomplished via lateral diffusion of the octadecylviologen molecules along the bilayer assembly.


[Etiology of splenomegaly in children in the tropics. 178 cases reviewed at the university hospital center of Abidjan-Cocody (Ivory Coast)]. Discovery of an enlarged spleen in a child requires steps to identify the etiology. One hundred and seventy-eight patients seen over a four-year period (1985-1988) at the Cocody Teaching Hospital were reviewed. The incidence of splenic enlargement among pediatric inpatients was 1.6%. Males (n = 106) were more often affected than females (n = 72). Slightly over half the children (54.49%) were 0 to 5 years of age. The main clinical presenting features were fever (90%), anemia (72%), a decline in general health (36.50%), enlargement of the liver (33.50%), jaundice (26.50%), and enlarged lymph nodes (7%). Type II of Hackett's classification accounted for most cases (61.80%), followed by Type III (14%). Main etiologies included malaria (53%), salmonella infections (15%), sickle cell anemia (14%), schistosomiasis (9%), AIDS (3%), and thalassemia (2%). Malignancies (leukemia, lymphoma) were relatively infrequent. More than one etiology was found in 13 cases. The distribution of etiologies by age group was determined and a strategy for investigating children with splenic enlargement in tropical countries was developed.


Chronic granulomatous disease.

Chronic granulomatous disease. Chronic granulomatous disease (CGD) encompasses a group of rare inherited disorders characterized by defects in a phagocyte-specific NADPH-oxidase complex that forms the superoxide radical during the respiratory burst. In this chapter, the protein components and cellular biochemistry of the oxidase are reviewed in light of recent genetic and biochemical studies of CGD. The classification and molecular genetic analysis of CGD is discussed. Finally, the use of recombinant human interferon-gamma as a new therapeutic agent for management of the disorder is reviewed.


Acute progressive Epstein-Barr virus infections. A few Epstein-Barr virus (EBV) infections result in progressive, potentially fatal disease. Nearly all of these progressive EBV infections occur in individuals known or suspected to be immunodeficient. Diagnosis and treatment are difficult.


Lipid peroxidation in human breast cancer cells in response to gamma-linolenic acid and iron. Lipid peroxidation in human breast cancer (ZR-75-1) cells and cancer cell killing were confirmed by using ultraviolet (UV)-spectrophotometry and mass spectrometry (MS). ZR-75-1 cells and human normal fibroblast CCD-41-SK (41Sk) cells were cultured with gamma-linolenic acid (GLA) and ferrous iron Fe (II) combinations. Formation of lipid peroxide and cytotoxic effect were highest in ZR-75-1 cells treated with GLA + Fe (II), though 41Sk cells showed little evidence of either lipid peroxidation or cytotoxity. These results indicate a cancer-cell-specific lipid peroxidation mechanism in association with the selective cancer cell killing effect in response to GLA.


Cell interactions and motility in human lung tumor cell lines HS-24 and SB-3 under the influence of extracellular matrix components and proteinase inhibitors. The human NSCLC cell lines HS-24 (squamous cell carcinoma) and SB-3 (metastasis derived from an adenocarcinoma) were investigated in respect to cell interactions, motility and invasive properties. HS-24 revealed high self adhesion capacity. Testing the interactions with collagens type I/III or IV, laminin and fibronectin by adhesion, non directional motility and haptotaxis assays, tight interactions and stimulation, particularly with collagen type I/III, was detected. Proteinase inhibitors (E64, Stefin A or leupeptin) revealed a slightly negative influence. Invasion in vitro of lung explants was reduced by leupeptin in a dose dependent manner and slightly increased by plasmin. SB-3 cells revealed low self adhesion. As judged from interaction with fibronectin, these cells have low integrin receptor concentrations and thus reduced adhesiveness to extracellular matrix. Collagen type I/III was inhibitory for undirectional motility and not permissive for haptotaxis. Therefore, it may play a restrictive role during the spread in vivo of these cells. Colonization of lung explants was low and was not influenced by cathepsin B proteinase inhibitors. The results emphasize a particular role of collagens for primary site tumor and metastasis development.


Increase in proto-oncogene raf expression precedes differentiation induction in different clonal rhabdomyosarcoma subpopulations. Three clonal rat rhabdomyosarcoma subpopulations (A, B, C) with a block of differentiation at different levels of rhabdomyogenesis were exposed to the differentiation inducers retinoic acid (RA), N-methylformamide (NMF) and sodium butyrate (NaBut). Since an increased expression of c-raf and c-fos had recently been demonstrated for subpopulation C after exposure to RA and NMF (1), the mRNA expression of c-raf, c-fos and retinoic acid receptor (RAR) alpha, beta and gamma was compared in all three subpopulations. After exposure to RA, NMF or NaBut, subpopulation C exhibited a significant (p = 0.0001) increase in creatine kinase (CK) activity and in morphological differentiation. In subpopulation B, the response was confined to a significant (p = 0.0001) increase in creatine kinase activity, whereas subpopulation A proved to be differentiation-refractory. On the molecular level, a uniform increase in c-raf expression became evident in all three subpopulations after 6 to 12 hours, persisting at an elevated level throughout the observation period of 120 hours. In contrast, the pattern of c-fos expression observed after exposure to RA, NMF or NaBut was heterogeneous. Expression of RAR alpha and gamma was detected in all subpopulations, whereas RAR beta mRNA was not expressed. Summarizing our results, the uniform pattern of c-raf expression might suggest a participation of c-raf in differentiation signal transduction. Since the three subpopulations differ markedly in their degree of differentiation, the block of differentiation characteristic for each subpopulation supposedly becomes effective only after the action of the c-raf gene product.


[Growth rate of hepatocellular carcinoma and nutritional state]. To clarify the relationship between the growth rate of hepatocellular carcinoma (HCC) and nutritional state or liver function 32 HCC patients with a tumor volume less than 100 ml at the beginning of the study were investigated. These patients all had been treated by serial transcatheter arterial embolization (TAE). Tumor volume was measured by integrating the CT images of the liver before each TAE. The tumor at the TAE just before significant enlargement occurred was defined as the stage I tumor and it was designated stage II at the next TAE. The growth rate of the HCC was then calculated from the tumor volume at stage II minus that at stage I. Caloric intake, protein intake, liver function, and serum amino acid were determined in the patients at each stage. The results were as follows: 1) The tumor growth rate was greater in patients whose caloric intake and protein intake were more than 35 kcal/kg/day and 1.5 g/kg/day, respectively. 2) In patients with the greater tumor growth rate, the plasma BCAA/AAA ratio was the lower. However, after tumor growth, the ratio became higher, indicating that the growth of HCC decreased the requirement of BCAA. 3) The tumor growth rate correlated to the change of plasma arginine level (r = -0.76, p less than 0.05).


[Randomized trial-comparing UFT and FT in the treatment of advanced hepatocellular carcinoma (second report: well controlled study on patients with transcatheter arterial embolization) Osaka Research Society for Liver, Gallbladder and Pancreas]. In a randomized trial Tegafur (FT) or Tegafur.Uracil (UFT) was administrated to 90 patients with advanced hepatocellular carcinoma for whom transcatheter arterial embolization was applied. Efficacy in the reduction of tumor size, subjective symptoms and clinical laboratory findings was comparable in both groups. However, survival rate in the UFT group was significantly higher than in the FT group in only 2 limited subgroups of patients without prior chemotherapy and with tumors found in both lobes of the liver. With respect to adverse effects, complaints about gastrointestinal tract were often noted in the UFT group, but no significant difference was found between the two groups.


[Effects of cepharanthin on leukopenia and thrombocytopenia induced by chemotherapy in lung cancer patients]. We studied the effects of Cepharanthin (CEP) on bone marrow suppression induced by chemotherapy in 18 primary lung cancer patients (14 NSCLC, 4 SCLC). NSCLC patients received IP (IFM+CDDP) therapy and SCLC patients received ION (IFM+VCR+ACNU) therapy. For the control, we chose the first course and we administered CEP (1 mg/kg) during the second course. The rate of leukopenia and neutropenia was significantly lower during the CEP course than during the control (p less than 0.01). The recovery rate (at 3 weeks) of leukopenia and neutropenia was significantly higher during the CEP course than during the control (p less than 0.05). But, obvious effects of CEP for lymphopenia and thrombocytopenia were not obtained. Side effects by CEP were not observed in this study. These data suggest that the large dose of CEP contributes to the prevention of leukopenia, especially neutropenia, in patients who receive a sufficient amount of anticancer drugs.


A morphologic, pathologic, and virologic study of anogenital warts in men. Infection with human papillomavirus (HPV) in the anogenital region is associated with benign papillomas (condyloma acuminatum), subtle verrucous changes, subclinical infection, and malignant lesions. Although both men and women are affected, much of the investigation has been directed toward women in the study of cervical and vulvar carcinoma. The current investigation focuses on HPV infection in men. This study was undertaken to correlate the clinical spectrum of disease in our population of male patients with histopathologic features, immunoperoxidase staining for viral capsid antigen, and viral typing. Genital lesions from 26 patients were examined and tested prospectively over a 1-year period. The 26 lesions examined demonstrated variable morphologic features with regard to location, size, surface characteristics, and color. Histopathologic features were consistent with the diagnosis of venereal warts, but not necessarily diagnostic. Three of five standard histopathologic criteria were present in only 71% of the specimens. Despite the morphologic variability and the indeterminant histopathologic findings, 20 of 23 lesions positive for the genital tract HPV types tested contained HPV types 6 and/or 11. We conclude that the morphologic appearance of anogenital warts does not necessarily correlate with HPV type. Histopathologic study is helpful in excluding other diagnoses but may be indeterminant in the diagnosis of venereal warts. All men with anogenital warts should be counseled, treated, and undergo follow-up regardless of HPV type.


A case of Woringer-Kolopp disease with Ki-1 (CD30) + cytotoxic/suppressor cells. Woringer-Kolopp (W-K) disease is a rare, localized, histologically malignant, but clinically indolent lymphoproliferative disorder. Most authors have regarded W-K disease as a variant of mycosis fungoides. However, a recent case suggests that W-K disease may represent a spectrum of lymphoproliferative disorders that may not be related to mycosis fungoides. A patient with a 40-year history of localized cutaneous eruption characterized by markedly atypical epidermotropic lymphocytes was seen at Stanford (Calif) University Hospital. The lymphocytes were predominantly CD30+ cytotoxic/suppressor T cells, an immunophenotype not previously described in W-K disease. Genotype analysis revealed a clonal rearrangement. The findings in our patient, along with a review of all cases previously reported in the literature, suggest that W-K disease may be an entity with a uniform clinical and histologic presentation, but one with marked immunophenotypic heterogeneity of the malignant-appearing atypical cells. Some cases showed immunophenotypic similarities to mycosis fungoides. However, in almost half of the reviewed cases, including the one presented here, the immunophenotypic differences exceeded the similarities.


Angiotensin-converting enzyme inhibitors and glycosuria. Renal glycosuria associated with the use of angiotensin-converting enzyme inhibitors has been previously reported in two patients. A third patient was studied who developed isolated glycosuria associated with lisinopril therapy. As in the two previously described patients, this patient had a normal serum glucose level, underlying hypertension, and onset of glycosuria between 2 and 16 weeks after initiation of therapy with an angiotensin-converting enzyme inhibitor. The patient had renal artery stenosis with elevated renin levels. Age, time until resolution of glycosuria, and a rise in serum creatinine level did not have a consistent relationship with glycosuria associated with angiotensin-converting enzyme inhibitor therapy. Since glycosuria was the only defect noted, without evidence of any other urinary solutes, angiotensin-converting enzyme inhibitors may exert an effect on the glucose-specific proximal tubule transport system.


[Pneumoblastoma].

[Pneumoblastoma]. Pneumoblastoma is a rare malignant pulmonary tumor. A new case is reported in a 2 years 5 month-old girl. Because the lack of locoregional extension an isolated surgical excision was performed. However, 6 months later, a local relapse occurred, with inframediastinal extension and cerebral metastases. On the occasion of this case, the authors review the problems set by the histogenesis of this tumor, its therapeutic indications, poorly codified due to its rarity and, overall, its often unfavourable outcome.


Human T-lymphotropic virus type I/II. Status of enzyme immunoassay and western blot testing in the United States in 1989 and 1990. In three performance evaluation surveys, panels that consisted of human T-lymphotropic virus type I or type II (HTLV-I/II) antibody-positive and -negative plasma samples were mailed to laboratories that voluntarily participated in the Centers for Disease Control Model Performance Evaluation Program. Donor samples were identical among surveys. In each survey, more than 98% of the laboratories reported enzyme immunoassay (EIA) test results; about 11% also reported results of Western blot (WB) testing. Variation in analytic sensitivity (96.7% to 99.4%) and specificity (98.3% to 99.5%) of EIA tests was noted in the three surveys. For WB testing, no nonreactive interpretations were reported for HTLV-I/II antibody-positive samples in any survey; however, indeterminate interpretations were reported for 35.2% to 40.7% of the WB tests that were performed on HTLV-I/II antibody-positive samples. More than 95% of these indeterminate WB test interpretations were reported for HTLV-II antibody-positive samples. Although HTLV-I/II antibody tests are generally sensitive and specific, their accuracy could be further improved by increasing the specificity of EIA tests and the sensitivity of WB tests.


Detection of human cytomegalovirus antigen and DNA in lymph nodes and peripheral blood mononuclear cells of patients with angioimmunoblastic lymphadenopathy with dysproteinemia. The cause of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) remains unknown. It is characterized by acute onset, severe constitutional symptoms, cervical or generalized lymphadenopathy, lymphopenia, and polyclonal hypergammaglobulinemia, all of which are highly suggestive of a viral origin. Using immunohistochemical methods, employing murine monoclonal antibody as the primary antibody, we detected human cytomegalovirus antigen in the lymph nodes of eight of 11 patients with AILD. Cytomegalovirus DNA was also detected in the peripheral blood mononuclear cells by DNA dot hybridization in all five of the patients with AILD who were tested using this technique. None of the lymph nodes from the 11 patients stained positive for the rubella virus antigen. Based on the above evidence and the similarity of the immunologic abnormalities found in both AILD and cytomegalovirus infection, the possible role of cytomegalovirus as one of the causative agents for AILD is proposed.


Multiple cytomegalovirus-related intestinal perforations in patients with acquired immunodeficiency syndrome. Report of two cases and review of the literature. We present two cases of patients with acquired immunodeficiency syndrome who, in the course of their disease, suffered multiple intestinal perforations that were directly related to cytomegalovirus infection. Biopsy and surgical specimens and autopsy findings in both cases revealed extensive lesions of gastroenteritis; the gastroenteritis was characterized by randomly distributed deep ulcers, resulting in multiple perforations. The main characteristic histopathologic finding was the association of intestinal lesions with a severe form of cytomegalovirus-related occlusive vasculitis. This report provides evidence that supports the contention that cytomegalovirus is the primary causal agent of gastrointestinal lesions affecting immunocompromised patients.


Cytomegaloviral laryngitis and probable malignant lymphoma of the larynx in a patient with acquired immunodeficiency syndrome. We describe a case of cytomegaloviral laryngitis and probable primary laryngeal malignant non-Hodgkin's lymphoma in a man with acquired immunodeficiency syndrome who presented to an otolaryngology clinic with odynophagia and hoarseness. While both of these disease processes have a known association with human immunodeficiency virus infection, laryngeal presentation is extremely rare. We stress the need for thorough clinical and pathologic otolaryngologic evaluation of patients with human immunodeficiency virus infection who have upper aerodigestive complaints.


Degradation of methyl and ethyl mercury into inorganic mercury by other reactive oxygen species besides hydroxyl radical. Degradation of methyl mercury (MeHg) and ethyl Hg (EtHg) with reactive oxygens was studied in vitro by using peroxidase-hydrogen peroxide (H2O2)-halide and rose bengal-ultraviolet light A systems. For this purpose, the direct determination method for inorganic Hg was employed. Both systems could effectively degrade EtHg, and MeHg to some extent. Degradation of MeHg and EtHg with the myeloperoxidase (MPO)-H2O2-chloride system was inhibited by MPO inhibitors (cyanide and azide), catalase, hypochlorous acid (HOCI) scavengers (glycine, alanine, serine and taurine), 1,4-diazabicyclo[2,2,2]octane and 2,5-dimethylfuran, but not by hydroxyl radical scavengers (ethanol and mannitol). Iodide was more effective than chloride as the halide component. Lactoperoxidase (LPO) could substitute for MPO in the iodide, but not the chloride system. With MPO-H2O2-chloride, MPO-H2O2-iodide and LPO-H2O2-iodide systems, we observed the increased degradation of EtHg in deuterium oxide (D2O) medium better than that in H2O medium. The D2O effect upon MeHg degradation was extremely weak. These results suggested that HOCl (or HOI) might be also capable of degrading MeHg and EtHg, besides the hydroxyl radical already reported by us. Singlet oxygen could degrade EtHg but not MeHg.


Degradation of methyl and ethyl mercury into inorganic mercury by various phagocytic cells. In connection with the dealkylation of methyl mercury (MeHg) and ethyl Hg (EtHg) with reactive oxygen-producing systems, we examined the ability of phagocytic cells to degrade MeHg or EtHg into inorganic mercury in vitro by collecting them from blood or peritoneal cavity of several species of animal. EtHg was readily degraded by human polymorphonuclear leukocytes (PMN), rat PMN, guinea-pig PMN, rabbit PMN, guinea-pig macrophages (M phi), human monocytes and guinea-pig eosinophils. In contrast, rat hepatocytes and the M phi hybridoma clone 39 cells were weaker in their degrading ability. Degradation of MeHg by these cells was always much weaker than EtHg, under identical conditions; however, by increasing the cell numbers, MeHg was appreciably degraded by human PMN, rat PMN and rabbit PMN. The reactive oxygen species mainly responsible for alkyl Hg degradation seemed to be hydroxyl radicals produced by M phi, and hypochlorous acid produced by PMN, monocytes and eosinophils. It was also suggested that the degradation of alkyl Hg by these cells might be an intraphagosomal event.


Phenylmethanesulfonyl fluoride elicits and intensifies the clinical expression of neuropathic insults. It has been recently reported that phenylmethanesulfonyl fluoride (PMSF) when given to hens after a neuropathic organophosphate (OP) promotes organophosphate-induced delayed polyneuropathy (OPIDP). Chicks are resistant to OPIDP despite high inhibition/aging of neuropathy target esterase (NTE), the putative target of OPIDP initiation. However, when PMSF (300 mg/kg s.c.) is given to chicks after di-butyl 2,2-dichlorovinyl phosphate (DBDCVP, 1 or 5 mg/kg s.c.), OPIDP is promoted. Inhibition/aging of at least 30% of NTE was thought to be an essential prerequisite for promotion to be elicited in adult hens. However, we observed in hens that when NTE is maximally affected (greater than 90%) by phenyl N-methyl N-benzyl carbamate (40 mg/kg i.v.), a non-ageable inhibitor of NTE, and then PMSF is given (120 mg/kg/day s.c. x 3 days) clinical signs of neuropathy become evident. Methamidophos (50 mg/kg p.o. to hens), which produces in vivo a reactivatable form of inhibited NTE, was shown either to protect from or promote OPIDP caused by DBDCVP (0.45 mg/kg s.c.), depending on the sequence of dosing. Because very high doses of methamidophos cause OPIDP, we considered this effect to be a "self-promoted" OPIDP. We concluded that NTE inhibitors might have different intrinsic activities for producing OPIDP once NTE is affected. Aging might differentiate highly neuropathic OPs, like DBDCVP, from less neuropathic OPs, like methamidophos, or from the least neuropathic carbamates, which require promotion in order for neuropathy to be expressed.(ABSTRACT TRUNCATED AT 250 WORDS)


Regional glycine receptor binding in the p,p'-DDT myoclonic rat model. Abnormal glycinergic neurotransmission has been implicated in the pathophysiology of DDT-induced myoclonus. To examine the role of glycine receptors in the DDT model, was measured [3H]strychnine receptor binding in brainstem and spinal cord in the rat after acute administration of DDT. The highest dose of DDT tested significantly increased both Bmax (20%) and Kd (57%) of glycine sites in spinal cord but not brainstem compared to vehicle-treated controls at 4 h. Lower DDT doses, which also induced myoclonus, had no significant effects on [3H]strychnine specific binding. In vitro, 10(-7) DDT did not displace [3H]strychnine binding in naive rat spinal cord, but higher doses could not be studied due to poor solubility of DDT under the assay conditions. These data suggest that only a maximal dose of DDT has significant though mixed effects on parameters of [3H]strychnine binding in spinal cord which are not correlated with the onset of myoclonus.


Evoked potentials in cerebrotendinous xanthomatosis and effect induced by chenodeoxycholic acid. Evoked potentials are reported in 10 patients with cerebrotendinous xanthomatosis, eight of whom had peripheral neuropathy. Four subjects showed delayed N13 to N20 interpeak latencies for arm somatosensory evoked potentials, and five showed moderately prolonged I to III and I to V interpeak latencies of brain-stem auditory evoked potentials. Six of seven patients showed marked delay and desynchronization of visual evoked potentials. All five patients undergoing transcutaneous magnetic stimulation of the motor cortex presented greatly delayed central motor conduction time, especially of the lower limbs. After treatment with chenodiol (750 mg/d for at least 2 years), there was a significant improvement in nerve conduction velocities, N13 to N20 interpeak latencies, and visual evoked potential latencies. Brain-stem auditory evoked potentials remained unchanged.


The effects of chronic administration of ethanol on synaptosomal fatty acid composition: modulation by oil enriched with gamma-linolenic acid. Chronic ethanol administration significantly decreased the percentage of arachidonate and significantly increased the linoleate: arachidonate ratio in the cortical synaptosomal phosphatidylinositol (PI) of rats. However, concomitant administration of evening primrose oil (rich in gamma-linolenic acid) reversed the effects seen with ethanol alone. These results suggest that the decrease of arachidonate, especially in PI, caused by chronic administration of ethanol may be overcome by systemic administration of gamma-linolenic acid.


Evidence that changes in hippocampal excitability in vitro are caused by withdrawal from chronic in vivo ethanol administration. A complex pattern of changes in the field potentials recorded from mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, has previously been demonstrated in this laboratory. In the present study, recordings from slices prepared immediately after 2 weeks of ethanol treatment, showed only an increase in paired pulse potentiation, compared with controls, whereas recordings made immediately after 16 weeks of ethanol administration showed decreases in the thresholds for single and multiple population spikes, increases in paired pulse potentiation and epileptiform activity. In hippocampal slices prepared after 24 hr withdrawal, following 16 weeks of ethanol treatment, there were no signs of hyperexcitability in the field potentials. Ratings of convulsive behaviour were increased in mice during a 12-hr period after withdrawal from 16 weeks of ethanol treatment. Corresponding behaviour ratings for the mice given ethanol for 2 weeks, or those withdrawn for 24 hr after 16 weeks ethanol treatment, were not significantly different from control values. It was concluded that epileptiform activity seen in hippocampal slices after prolonged ethanol administration may contribute to the ethanol withdrawal hyperexcitability seen in vivo.


Temporal patterns of immunoblot-reactive antibodies to cytomegalovirus in transplant recipients. A total of 234 sera from 44 allograft recipients were compared with 12 sera from 9 immunocompetent patients with symptomatic cytomegalovirus (CMV) infection and with 20 sera of 20 healthy individuals with latent CMV infection. The presence of immunoreactive proteins was not associated with a specific transplant group or with different immunosuppressive regimens but rather with the kinetics of the immune response. Acute phase sera demonstrated early antibodies to proteins p38 and p48, followed by high or still rising antibodies to high molecular weight proteins, particularly p150, and their later decline to persistent lower levels. Convalescent phase sera were identified serologically by the transient appearance of IgG antibodies directed to 22-26 kDa polypeptides. Immunoreactive p44 was present in 85% of all patients with mild disease and in 40% of all patients with severe CMV disease. When tested in parallel, the immunoblot analysis was shown to be a more sensitive indicator of early CMV antibodies in allograft recipients than the ELISA technique.


Inquiry of photosensitization mechanism of yangzhou hematoporphyrin derivative (YHPD). By the use of the advanced ESR technique and through comparing with BHPD, the characteristic of YHPD photosensitization is discussed in this paper in the respect of the primary process of photosensitization. The experiment results showed: (i) not only 1O2, but also free radicals (O2-. .OH and YHPD-.) can be formed by the aid of YHPD; and (ii) as to the ability of producing 1O2, YHPD less than BHPD, while for generating O2-. and .OH, YHPD greater than BHPD. Two points are indicated: first, the photosensitized damage of YHPD is interrelated to not only 1O2, but also free radicals (O2-. .OH and YHPD-.); second, although the photosensitized damage of YHPD is stronger than that of BHPD, yet the photosensitized damage is negatively correlated to the yield of 1O2 but positively correlated to those of O2-. and OH. Based on these two points, it is suggested that activated oxygen free radicals (O2-. and .OH) instead of 1O2 play the main role as instantaneously activated material in the photosensitized damage of YHPD.


Retrovirus mediated transfer of antisense human c-myc gene into human esophageal cancer cells suppressed cell proliferation and malignancy. A retroviral vector, called pDAM3, containing the neomycin resistant gene and the antisense human c-myc gene fragment (the third exon and 3' flanking sequence) was constructed. pDAM3 was introduced into amphotropic packaging cells PA317 by the calcium phosphate precipitation method. Several G418-resistant PA317 clones were isolated. The virus titer of these cell lines was determined by infectivity of their culture fluid to NIH/3T3 cells. The highest titer obtained was 8 x 10(5) G418-resistant colony forming units/ml. Clonal and pooled G418-resistant PA317 colonies with high titers were expanded and analyzed by Southern blot for the presence of intact viral sequences. All cell lines were found to harbor the internal sequences of the pDAM3 vector without any rearrangement. Recombinant virus DAM3 infected human esophageal cancer cell line EC8712 efficiently. The DAM3-infected EC8712 (called EC-DAM3) was found to contain the full DAM3 sequence (4.8 kb) by Southern blot analysis. Antisense myc RNA expressed in the EC-DAM3 cell was detected by RNA hybridization. Further studies indicated that [3H]-thymidine incorporation in EC-DAM3 cells was reduced by 45% in average compared to that in untreated EC8712 cells. Growth rate of EC-DAM3 cells also decreased about 50%. DAM3-infected EC8712 cells lost their ability of forming tumor in nude mice. It thus appeared that the antisense myc gene introduced into EC8712 cells via retrovirus vector was capable of inhibiting cell proliferation and malignancy.


Corticotropin effects on blood pressure and fluid and electrolyte homeostasis in five strains of rats. The hemodynamic and metabolic effects of 11 days of sham (saline) and corticotropin injection were examined in five different strains of rats: Sprague-Dawley, spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), Brattleboro, and Long Evans. Corticotropin significantly increased systolic blood pressure (SBP) compared with sham injection in all strains: final SBP in Sprague-Dawley was 108 +/- 5 mm Hg corticotropin, 94 +/- 4 mm Hg sham; SHR 146 +/- 6 mm Hg corticotropin, 141 +/- 3 mm Hg sham; WKY 117 +/- 3 mm Hg corticotropin, 103 +/- 3 mm Hg sham; Brattleboro 108 +/- 5 mm Hg corticotropin, 93 +/- 2 mm Hg sham; and Long Evans 103 +/- 5 mm Hg corticotropin, 90 +/- 4 mm Hg sham (P less than .001). Corticotropin also produced a decrease in body weight and increases in water intake and urine output. Increases in urine electrolyte excretion were seen in some, but not all strains. The rise in pressure in the Brattleboro rats indicated that vasopressin is not essential for the corticotropin-induced rise in pressure. Blood pressure rises in SHR were not exaggerated. Withdrawal of corticotropin in Sprague-Dawley rats led to rapid reversal of the corticotropin-induced hemodynamic and metabolic changes. Thus, strain does not appear to be an important factor in corticotropin hypertension in the rat, in contrast to deoxycorticosterone hypertension.


Regulation of phenobarbital-induced ferrochelatase mRNA activity by dibutyryl cAMP and glucose in normal and diabetic rat hepatocytes. The induction of ferrochelatase activity by phenobarbital and its potentiation by dibutyryl cAMP assayed in normal rat hepatocytes are associated with increased activity of ferrochelatase mRNA. Glucose inhibits this stimulatory effect. This inhibition can be reversed with increasing concentrations of dibutyryl cAMP. The inducing effect exerted by phenobarbital on the activity of ferrochelatase mRNA in diabetic hepatocytes is greater than that observed in normal cells. This enhanced response in diabetic rat hepatocytes is neither potentiated by adding dibutyryl cAMP nor repressed by glucose. The absence of a glucose effect persists even when the endogenous cAMP content is lowered to normal levels. The results obtained in this study are consistent with those reported in other published studies of ferrochelatase activity. This adds more experimental evidence to support the concept that ferrochelatase is inducible. The results obtained suggest that ferrochelatase is more susceptible to induction with phenobarbital in diabetic rat hepatocytes than in normal rat hepatocytes.


Detection of human papillomavirus (HPV) using dot blot and Southern blot, hybridizing with a mixture of seven probes. A previously presented method for the detection and typing of human papillomavirus (HPV) DNA has been modified for the simultaneous analysis of HPV types 6, 11, 16, 18, 31, 33 and 35. The method has two steps, where a dot blot test is used to exclude cases that do not hybridize with HPV-DNA. The remaining cases are then analysed by a Southern blot procedure, using a mixture of subgenomic probes for the simple and accurate analysis of HPV types. When the procedure was used for the analysis of clinical samples, patient groups at varying risk were found to differ with regard to the prevalence of HPV infections. Thus, the virus was detected in only 8.8% of otherwise healthy young women - i.e. women without clinical signs of HPV-related disease - as compared to 48% of women who also had cervical intraepithelial neoplasia (CIN). A similarly high prevalence was found in patients in whom CIN persisted (42%) as compared to those in whom the morphological lesion regressed to normal (8%).


Immunohistochemical characterization of an amphicrine mucinous islet-cell carcinoma of the pancreas. Case report. Immunohistochemical characteristics of a mucinous islet-cell carcinoma of the pancreas are described. The tumour presented with jaundice in a 59-year-old male. It consisted of polygonal atypical cells forming a reticular pattern, and invaded the common bile duct. In DNA flow cytometry, the tumour cells showed a clear-cut aneuploid peak. Intercellular mucin was abundant. A panel of antisera and monoclonal markers was applied in the immunohistochemical analysis. In addition to general epithelial and endocrine markers, the tumour cells showed a focal positive immunoreaction with anti-glucagon, anti-insulin, anti-vasoactive intestinal polypeptide, anti-pancreatic secretory trypsin inhibitor and anti-phospholipase A2 antigen. At the ultrastructural level, mucous and neuroendocrine granules were demonstrated in the same tumour cells.


Extracellular matrix proteins regulate morphologic and biochemical properties of tracheal gland serous cells through integrins. The extracellular matrix has been shown to influence the differentiation of epithelial cells. To identify cues from the extracellular matrix controlling the differentiation of tracheal gland serous cells, we examined the effects of culturing these cells on various extracellular matrix proteins. Bovine tracheal gland (BTG) serous cells attached to Type IV collagen (COL IV), laminin (LM), and fibronectin (FN) in a concentration-dependent manner. Morphologic analysis showed that cells formed confluent monolayers on COL IV or LM, whereas on FN, cells formed birefringent spheres. Metabolic labeling experiments showed that [35S]methionine-labeled protein bands at 68, 105, and 120 kD were prominent when cells were grown on COL IV or LM, but were lost or reduced when the cells were grown on FN. COL IV also enhanced the expression of proteins at 14, 16.5, 18, and 21.5 kD. Attachment to all substrates was inhibited by an antibody directed against beta 1 integrins. This antibody precipitated several integrin heterodimers from a BTG cell membrane extract, caused partial retraction of cells from all substrates, and strongly suppressed the expression of COL IV- and LM-dependent proteins. Control experiments indicated that the latter did not require conspicuous changes in cell shape. These results show that some biochemical properties of serous cells are regulated by integrin-mediated effects of extracellular matrix proteins in vitro and suggest that similar regulation may occur during normal development and remodeling of the glands in vivo.


Potency of antileukoprotease and alpha 1-antitrypsin to inhibit degradation of fibrinogen by adherent polymorphonuclear leukocytes from normal subjects and patients with chronic granulomatous disease. We have studied the relative efficacy of antileukoprotease (ALP) and alpha 1-antitrypsin (alpha 1AT) to inhibit the degradation of substrate by polymorphonuclear leukocytes (PMN) attached onto a fibrinogen matrix. PMN elastase activity was assayed by radioimmunoassay of a specific 21-residue cleavage product from the amino terminus of the A alpha chain, A alpha (1-21), of fibrinogen. The adherence of PMN (1.0 x 10(6)) to a fibrinogen matrix was facilitated by incubation with recombinant tumor necrosis factor-alpha (1 nM). Subsequently, the cells were exposed to inhibitors before stimulation with cytochalasin B and formylmethionyl-leucylphenylalanine. Under these conditions, ALP inhibited A alpha (1-21) formation with an IC50 of 85 +/- 30 nM and alpha 1AT gave an IC50 of 220 +/- 98 nM (mean +/- SD). The effect of oxidant production on A alpha (1-21) formation was evaluated by comparing the effect of PMN from normal subjects with PMN from subjects with X-linked NADPH oxidase deficiency. Stimulation of PMN from the latter subjects in a similar fashion as described above resulted in the formation of 40 +/- 4 pmol/ml A alpha (1-21), or approximately twice the amount seen with cells from normal subjects. Preincubation with ALP or alpha 1AT in a concentration range between 10 to 900 nM resulted in an IC50 of 50 +/- 13 nM for ALP compared with 150 +/- 21 nM for alpha 1AT. Both inhibitors are more effective to prevent fibrinogen degradation caused by chronic granulomatous disease (CGD) PMN than by normal PMN despite the fact that CGD PMN generated more A alpha (1-21) than did normal PMN.(ABSTRACT TRUNCATED AT 250 WORDS)


Diminished arachidonic acid metabolite release by bovine alveolar macrophages exposed to surface-modified silica. Modification of the silica surface has been shown to reduce its cytotoxicity in vitro and its fibrogenic activity in vivo. We have shown silica to be a potent stimulator of arachidonic acid (AA) metabolism in bovine alveolar macrophages (BAM). To determine the effect of surface-modified silica on AA metabolism in BAM, we exposed BAM in vitro to silica treated with aluminum lactate or polyvinylpyridine-N-oxide (PVPNO). BAM were prelabeled with [3H]AA and incubated with 3 and 5 mg of silica. Unmodified silica at these doses elicited maximal AA metabolite release from BAM. AA metabolites were analyzed by high performance liquid chromatography. Lactate dehydrogenase release was quantitated to determine the cytotoxicity of treated and untreated silica on BAM. Treating silica with aluminum lactate or PVPNO significantly (P less than or equal to 0.05) reduced 5-lipoxygenase metabolite release and significantly (P less than or equal to 0.05) increased cyclooxygenase metabolite release. These changes in AA metabolite release were accompanied by a significant (P less than or equal to 0.05) reduction in the cytotoxicities of the treated silicas compared with untreated silica. Our results suggest that the reduced inflammatory and fibrogenic activity of surface-modified silica may in part be due to reduced AA metabolite release from exposed macrophages.


Platelet-activating factor provokes release of mucin-like glycoproteins from guinea pig respiratory epithelial cells via a lipoxygenase-dependent mechanism. Primary cultures of guinea pig tracheal epithelial cells maintained in an air/liquid interface system that maintains differentiated characteristics were grown to near confluence and exposed for 1 h to platelet-activating factor (PAF) on both apical and basal sides. PAF provoked release of high-molecular-weight mucin-like glycoproteins (MLG) from the cells, with maximal stimulation occurring at 10(-8) and 10(-9) M. The inactive form of PAF, lyso-PAF, was without effect. Indomethacin, the cyclooxygenase inhibitor, did not affect secretion stimulated by PAF, but nordihydroguiaretic acid (NDGA), a mixed cyclooxygenase and lipoxygenase inhibitor, attenuated secretion stimulated by PAF in a concentration-dependent manner. High performance liquid chromatography assay of the culture medium after addition of PAF revealed increased production of 15-, 12-, and 5-hydroxyeicosatetraenoic acids (15-, 12-, and 5-HETEs). The stimulatory effect of PAF on both mucin secretion and formation of HETEs was inhibited by the PAF receptor antagonists, CV-3988 and Ro 19 3704, with Ro 19 3704 acting at a concentration 10-fold lower than CV-3988 in inhibiting both effects. When added exogenously to the cell cultures, the combination of 5-, 12-, and 15-HETEs stimulated MLG release in a concentration-dependent manner. The results suggest that PAF stimulates release of MLG by guinea pig airway epithelium in vitro by a mechanism involving binding of PAF to receptors on epithelial cell surfaces, stimulation of lipoxygenase metabolism of arachidonic acid to HETEs within the epithelium, and stimulation of secretion by these epithelial-derived HETEs via an autocrine or paracrine mechanism.