Renal transplant function after ten years of cyclosporine.

Although the nephrotoxic side effects of cyclosporine are well known, the impact of long-term CsA on renal transplant function is uncertain. We studied 5-10-year renal function in 347 CsA-treated patients, and in 64 randomly selected non-CsA-treated patients who had a minimum of 55 months of graft function. Non-CsA patients had a lower creatinine (Cr) level at one year than CsA patients (P = .001), with no change in renal function over time (P = .6). In CsA-treated patients there was also no suggestion of progressive renal damage, as evidenced by no change in Cr or 1/Cr. Simple linear regression models of 1/Cr vs. time for the first 10 years posttransplant were fit to the data for each patient. Analysis of the Y-intercept estimates from these regressions showed that age (P = .001), sex (P = .001), cyclosporine toxicity (P = .024), and initial cyclosporine dosage (P = .016) significantly affected the one-year serum Cr. Variables not affecting one-year Cr included donor source, early rejection episodes, late rejection episodes, ATN, diabetes, transplant number, HLA ABDR mismatch (for cadaver transplants), maximum PRA, and PRA at transplant. Analysis of the slope estimates from the regressions revealed that only age (P = .001) and late rejection episodes (P = .001) significantly affected the rate of change in 1/Cr over time. We conclude that, in long-term renal transplant patients, there is no evidence of progressive deterioration in renal function due to CsA nephrotoxicity.     

Protective capacity of polyclonal and monoclonal antibodies directed against endotoxin during experimental sepsis

Both monoclonal antibody (MAb) and polyclonal antibody (PAb) directed against the shared core/lipid A region of lipopolysaccharide (LPS) (endotoxin) provide protection during experimental gram-negative bacterial sepsis. Although these preparations have not been compared, clinical trials administering either preparation to septic patients have been instituted. The core/lipid A region of LPS represents an antigenic domain common to many, if not all, gram-negative microbes, and thus represents an ideal target site for antibody binding. We sought to determine (1) the protective capacity of similarly reactive IgG anti-core LPS/lipid A MAbs and PAbs, (2) whether the timing of administration was important, and (3) whether either would act additively with antimicrobial agents. Antibody was administered intravenously to outbred mice, and Escherichia coli 0111:B4 was then administered intravenously or intraperitoneally with hemoglobin. Monoclonal antibodies and PAbs were equally protective, and protection was maximized by pretreatment, although the effect extended to four hours after bacterial challenge. Both MAbs and PAbs acted in concert with gentamicin hydrochloride to further reduce lethality. We concluded that MAbs and PAbs were equally protective and that clinical utility may eventually be dictated by ease and cost of antibody production.     

Status epilepticus in children: etiology, clinical features, and outcome

Between August 1984 and September 1986, data were gathered prospectively on 114 episodes of convulsive status epilepticus, defined as seizure duration longer than 30 minutes, affecting 97 children. Status epilepticus was symptomatic in 72% (chronic 59%, acute 13%) and idiopathic or febrile in 28%. We identified precipitating factors in 63% of episodes. The most common factors were inadequate blood levels of anticonvulsants (32 of 60 episodes in children with prior seizures) and febrile illnesses, excluding meningitis or encephalitis (38 of 114 episodes). There was an elevated peripheral white blood cell count in 60%, acidosis with a pH of less than 7.0 in 12.5%, and cerebrospinal fluid pleocytosis not due to meningitis or encephalitis in 8 of 64 episodes. Eight children died, three with severe pre-existing brain damage, two with meningitis, and two with a poorly defined encephalopathy. Eighteen children developed a new neurologic deficit. Outcome was associated with the etiology and duration of status epilepticus, with age at the time of status a minor factor. A permanent deficit occurred in only five children with idiopathic or febrile status epilepticus.     

Endotoxin promotes synergistic lethality during concurrent Escherichia coli and Candida albicans infection.

Previous studies have suggested that the lipopolysaccharide (LPS, endotoxin) component of the gram-negative bacterial cell wall is a key virulence factor that serves to enhance mortality during infections in which fungi and gram-negative bacteria are copathogens. To test this hypothesis, mice were challenged ip with Escherichia coli 0111:B4, Candida albicans, or both, and the effect of administration of anti-E. coli 0111:B4 LPS monoclonal antibody (mAb) 8G9 on endotoxemia, bacteremia, and mortality was assessed. E. coli (2 x 10(7) colony-forming units (CFU)) plus C. albicans (6 x 10(7) CFU) infection produced 100% mortality at 7 days, compared to the relatively low mortality caused by infection with either E. coli or C. albicans alone (20 and 3%, respectively, P less than 0.01). Administration of mAb 8G9 to animals receiving both pathogens reduced mortality (100% versus 14%, P less than 0.05), endotoxemia (3653 +/- 3187 versus 2 +/- 2 endotoxin units (EU), P less than 0.01), and bacteremia (4.2 +/- 2.3 versus 1.1 +/- 2.1 log(CFU/ml), P less than 0.01) compared to animals receiving saline alone. In a separate series of experiments, purified E. coli 0111:B4 LPS was administered in place of viable E. coli. The simultaneous injection of 200 micrograms E. coli LPS and C. albicans (6 x 10(7) CFU) produced 93% mortality at 7 days, compared to the low mortality that occurred following injection with either E. coli 0111:B4 LPS or C. albicans alone (21 and 3% respectively, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of atrial fibrillation in a district general hospital.

OBJECTIVE--To assess current strategies used to investigate and manage acute atrial fibrillation in hospital. DESIGN--Prospective survey of all acute admissions over 6 months. SETTING--District general hospital serving a population of 230,000 in north east Glasgow. SUBJECTS--2686 patients admitted as emergency cases over 6 months. RESULTS--Of the 2686 patients, 170 (age range 38-95, mean (SD) 73.5 (10.6) years; 70 men (41%) and 100 women (59%)) were admitted with atrial fibrillation. The principal underlying medical conditions were ischaemic heart disease in 79 (46.5%), rheumatic heart disease in 26 (15.3%), and thyroid disease in six (3.5%). Cardiac failure was present on admission in 61 (36%), cerebrovascular events in 23 (14%), and myocardial infarction in 17 (10%). Of those with a history of atrial fibrillation (102 (60%) including 10 with paroxysmal atrial fibrillation) treatment on admission included digoxin in 71 (70%), warfarin in 20 (20%), and aspirin in 17 (17%); the aspirin was predominantly given for concomitant vascular disease. The mean (SD) inpatient stay was 16 days (19.7) (range 1-154) largely due to the patients with stroke. Thyroid function tests were performed in only 63% and echocardiography in 33%. Overall, the rate of introduction of anticoagulation (seven patients) and attempted cardioversion (21 patient: 19 pharmacological and two electrical) was surprisingly low. Only 49 patients (34% of those not on warfarin) had contraindications to anticoagulation: these included peptic ulcer or gastrointestinal bleeding in 18 (12%), dementia in eight (6%), chronic renal failure or dialysis in eight (6%), and alcohol excess in four (3%). CONCLUSION--Standard investigations were inadequately used in patients with atrial fibrillation and there was a reluctance to perform cardioversion or to start anticoagulant treatment.     

HP 818: A centrally acting analgesic with neuroleptic properties

HP 818 (1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED₅₀ values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self-stimulation assays (ED₅₀ values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine- and apomorphine-induced stereotypy, indicative of D₂-dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.