Studies on uterine tract infections and the IUCD with special reference to actinomycetes

Summary. Since the advent of the plastic IUCD, an increasing number of patients with clinical pelvic actinomycosis have been reported in the literature and in a very much larger number of women, actinomycetes have been identified in cervical smears, either by Papanicolaou stain or specific immunofluorescence. After a 3-year study, we have concluded that actinomycetes can readily be cultured when the growth of more rapidly growing anaerobes is inhibited by metronidazole and anaerobic culture is continued for up to 14 days. We consider that actinomycetes form part of a polymicrobial anaerobic infestation developing in the presence of a foreign body. The organisms are found almost exclusively in women who have used all-plastic IUCDs for a long term and, from a continuing study, it is apparent that most disappear rapidly when the plastic device is removed or replaced by a copper device. Significant symptomatic evidence of infection is found in a small proportion of patients who are actinomycete-positive.     

Alternans of the ST Segment and T Wave. A Sign of Electrical Instability in Prinzmetal''s Angina

In an effort to determine the incidence of ventricular arrhythmias associated with ST segments alternans, the patterns of ST segment and T-wave electrical alternans (STEA) were analyzed in 93 patients during spontaneous Prinzmetal's angina. Twenty-eight of 93 patients, or 30% (Group I), showed STEA during episodes of ST segment elevation. SIxty-five of 93 patients, or 70% (Group II), showed no alternans during episodes of ST segment elevation. In Group I, ventricular arrhythmias, defined as all ventricular ectopic activity greater than 5 beats per minute and complex Lown grades III to V, occurred during 52 of 55 episodes, or 95%; whereas in Group II, ventricular arrhythmias occurred in only 51 of 125 episodes, or 41% (p less than 0.01). The difference in the incidence of ventricular fibrillation (VF) or ventricular tachycardia (VT) in the two groups was more striking. VT or VF occurred in 20 of 55 in Group I (36%) versus 5 of 125 in Group II (4%). Although there were no significant differences in age or sex between Group I and II patients, there was a significant difference in the magnitude of the maximum ST segment elevation (5 mm in Group I versus 3 mm in Group II, p less than 0.01). This study demonstrates that the occurrence of STEA and T wave alternans frequently heralds the onset of ventricular arrhythmias in Prinzmetal's angina. Both the arrhythmias and the alternans occur during the time of maximal ST segment elevation.     

Long-Term Pacing in Heart Transplant Recipients is Usually Unnecessary

The indications for and timing of permanent pacing were reviewed in all 17 of 154 adult heart transplant recipients at this center who have had permanent pacemakers implanted. Resting 12-lead ECGs recorded during routine follow-up were examined. A prospective study of pacing requirement was then undertaken. Holter monitoring was performed before and after reprogramming the pacemakers to VVI mode at 50 beats/min. Exercise responses in various pacing modes were then assessed in seven patients with rate responsive pacemakers using a standard Bruce protocol treadmill test. The indication for pacing was sinus node dysfunction in 59% (10/17) and atrioventricular (AV) block in 41% (7/17). The majority of pacemakers were implanted between seven and 21 days after transplantation. There was a progressive reduction in the frequency of pacing on 12-Jead ECGs with time after transplantation. Eight of 14 patients with empirically selected programming paced during Holter monitoring. After reprogramming to 50 beats/ min VVI mode only three of 14 patients, all with sinus node dysfunction, paced. Rate responsive pacing made no difference to exercise time. The requirement for long-term pacing in cardiac transplant recipients is small (3/154) and is limited lo patients with sinus node dysfunction. Rate responsive pacing did not increase exercise tolerance.     

Fmoc/solid-phase synthesis of Tyr(P)-containing peptides through t-butyl phosphate protection

The synthesis is of Tyr(P)-containing peptides by the use of Fmoc-Tyr(PO₃Me₂)-OH in Fmoc/solid phase synthesis is complicated since, firstly, piperidine causes cleavage of the methyl group from the -Tyr(PO₃ Me₂)-residue during peptide synthesis and, secondly, harsh conditions are needed for its final cleavage. A very simple method for the synthesis of Tyr(P)-containing peptides using t-butyl phosphate protection is described. The protected phosphotyrosine derivative, Fmoc-Tyr(PO₃^tBu₂)-OH was prepared in high yield from Fmoc-Tyr-OH by a one-step procedure which employed di-t-butyl N,N-diethyl-phosphoramidite as the phosphorylation reagent. The use of this derivative in Fmoc/solid phase peptide synthesis is demonstrated by the preparation of the Tyr(P)-containing peptides, Ala-Glu-Tyr(P)-Ser-Ala and Ser-Ser-Ser-Tyr(P)-Tyr(P).     

Post-orchidectomy radiation therapy for patients with stage I seminoma of the testis

The outcome of radiotherapy in patients with stage I testicular seminoma was evaluated. During the period 1960–89 (inclusive) 270 patients with stage I seminoma of the testis received radiotherapy to the para-aortic nodes and ipsilateral hemipelvis following radical orchidectomy. Two hundred and fifty seven patients (95.2%) received a minimum tumour dose of 30Gy in 20 daily fractions using 4–6 MV photons. The 5 year overall and recurrence-free survival rates were 97 and 95%, respectively. Only eight of the 270 patients relapsed and three were cured with ‘salvage’therapies. Of the 11 patients who died, four deaths (36%) were the result of uncontrolled testicular cancer, six (55%) intercurrent illness and one (9%) the result of attempted salvage. Patients staged and treated prior to 1979 had a significantly worse disease-free survival compared to patients treated during and after 1979. As side effects were negligible, it was concluded that radiotherapy for stage I seminoma provides excellent cure rates. The difficulties arranging a ‘surveillance’programme in so large a State as Queensland are discussed.     

Developmental Toxicity Evaluation of Ethylene Glycol by Gavage in New Zealand White Rabbits

Artificially inseminated New Zealand white (NZW) rabbits wereadministered ethylene glycol (EG) by gavage on Gestational Days(GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day,with 23–24 inseminated animals per group. Clinical signswere recorded and water consumption was measured daily; doeswere weighed on GD 0, 6–19, 25, and 30. At necropsy (GD30), maternal liver, kidney, and gravid uterine weights wererecorded. Histopathologic examination was performed on kidneysfrom 10 does/dose and for all unscheduled deaths. Ovarian corporalutea were counted and uterine implantation sites (total sites,resorptions, dead and live fetuses) were recorded. All livefetuses were weighed, sexed, and examined for external, visceral,and skeletal malformations and variations. EG resulted in profoundmaternal toxicity at 2000 mg/kg/day (42% mortality; three earlydeliveries and one spontaneous abortion) associated with renalpathology and unaccompanied by any other indicators of maternaltoxicity. Renal lesions at 2000 mg/kg/day involved the corticalrenal tubules and included intraluminal oxalate crystals, epithelialnecrosis, and tubular dilatation and degeneration. No dose-relatedmaternal toxicity occurred at 100–1000 mg/kg/day. Therewas no indication of developmental toxicity at any dose tested,including no effects on pre- or postimplantation loss, numberof fetuses, fetal body weight, or sex ratio (% male fetuses)per litter, and no evidence of teratogenicity. The "no observableadverse effect level" (NOAEL) for maternal toxicity was therefore1000 mg/kg/day and the NOAEL for developmental toxicity wasat least 2000 mg/kg/day in this study. The sensitivity of NZWrabbits relative to that of Sprague—Dawley rats and Swissmice for maternal and developmental toxicity from gavage administrationof EG during organogenesis can be determined for maternal toxicity:rabbits>mice>rats, and for developmental toxicity, mice>>rats >> rabbits.     

A 90-Day Inhalation Toxicity Study of Raw Shale Oil in Fischer 344 Rats

A 90-Day Inhalation Toxicity Study of Raw Shale Oil in Fischer344 Rats. GORDON T., STROTHER, D. E., CRAMER, D. V., AND GOODE,J. W. (1987). Fundam. Appl. Pharmacol. 9, 287–296. Thepotential health effects of a raw shale oil were evaluated ina 90-day inhalation study in Fischer 344 rats. Groups of 15male and 15 female rats were exposed 6 hr/day, 5 days/week for13 weeks to aerosol concentrations of 0, 56, 120, or 492 mg/m³.In the high-dose group, 10 males and 7 females died prior tothe termination of the study, most within the first 5 weeksof the experiment. A dose-dependent suppression in weight gainwas seen in all of the shale oil-exposed groups. The failureto gain weight was associated with a variety of clinicopathologicabnormalities, including a dose-related decrease in red andwhite blood cells, with lowered plasma protein levels and increasedserum alkaline phosphatase, and with total bilirubin levelsin males. The exposure of the test animals to aerosolized rawshale oil was also associated with inflammatory and hyperplasticlesions in the lungs and upper respiratory tract, atrophy ofthe thyrnus and thymic-dependent portions of the peripherallymphoid system, and bone marrow. These changes demonstratethat inhalation of raw shale oil aerosol can produce major organtoxicity similar to that found after exposure to other unrefinedoil products.     

Limited value of the urinary phenytoin metabolic ratio for the assessment of cytochrome P4502C9 activity in vivo

Relationships between the ratio of p -hydroxyphenytoin (p-HPPH), the major metabolite of phenytoin, to unchanged phenytoin excreted in urine (the urinary metabolic ratio or MR) were compared with a number of indices of the metabolic clearances of phenytoin and tolbutamide published previously for seventeen subjects separately administered these known cytochrome P4502C9 (CYP2C9) substrates. Significant correlations ( r _s=0.50–0.60, P <0.05) were observed between the phenytoin MR, derived from either 0–24 or 24–48  h urine collections, and inverse areas under the plasma unbound concentration-time curves (measured over various time intervals) of phenytoin and with plasma unbound tolbutamide clearance. Significant correlations ( r _s =0.59–0.74) were also observed between the phenytoin MRs and metabolic unbound clearances for p -hydroxyphenytoin formation. Despite the significant correlations, variability in tolbutamide and phenytoin metabolic clearance parameters tended to account for <50% of the variability in phenytoin MR. Correlations between the renal clearance of phenytoin and the phenytoin MRs suggest that variability in the renal clearance of unchanged drug limits the usefulness of the phenytoin MR for the investigation of factors influencing CYP2C9 activity in vivo .     

TOPICAL UNDECYLENIC ACID IN TINEA PEDIS: A NEW LOOK

ABSTRACT: One hundred and four patients with mycologically confirmed tinea pedis took part in a controlled clinical trial to determine the efficacy of undecylenic acid powder preparations in the treatment of their fungal infections. Clinical and mycological cures were obtained in 53% of those subjects treated with undecylenic acid powders as compared with 7% of those treated with the talc vehicle or left untreated. Undecylenic acid in a powder vehicle appears to be a safe and effective agent in the treatment of tinea pedis.     

Efficacy of Mono- and Bis-Pyridinium Oximes Versus Soman, Sarin and Tabun Poisoning in Mice

Efficacy of Mono- and Bis-Pyridinium Oximes Versus Soman, Sarinand Tabun Poisoning in Mice. Clement, J.G. (1983). Fundam. Appl.Toxicol. 3:533–535. Various oximes (PAM, toxogonin, TMB-4,HS-6, HI-6, HGG-12, HGG-42) combined with atropine were comparedas antidotes of soman, sarin and tabun poisoning in non-fastedCD-1^® male mice. TMB-4 was the most toxic oxime with ani.p. LD₅₀ value of 80 mg/kg and HI-6 was the least toxic oximewith an i.p. LD₅₀ of 588 mg/kg. Upon comparing ED₅₀ values,HGG-42 was the most effective oxime versus soman and tabun poisoningwhereas, HI-6 was the most effective oxime versus sarin poisoning.Further research needs to be done to explain the distinct differencesin efficacy of the oximes versus poisoning by soman, sarin ortabun.