Synthesis and antiviral activity of phosphonoacetic and phosphonoformic acid esters of 5-bromo-2'-deoxyuridine and related pyrimidine nucleosides and acyclonucleosides

Phosphonoacetic acid (PAA, 1) was coupled with various acyclonucleosides, 2'-deoxyuridines, cytidines, and arabinosyluracils, with 2,4,6-triisopropylbenzenesulfonyl chloride (TPS) or dicyclohexylcarbodiimide (DCCI) as condensing agents, to give a range of phosphonate esters. The carboxylic ester linkage of PAA to the 5'-position of 5-bromo-2'-deoxyuridine (BUdR, 3) was achieved via the mixed anhydride formed from (diethylphosphono)acetic acid and trifluoroacetic anhydride. Phosphonoformic acid (PFA, 2) was coupled with BUdR by using the DCCI method to give the phosphonate ester. Of these compounds only phosphonate esters in the 2'-deoxyuridine series showed significant activity against herpes simplex virus types 1 and 2. The BUdR-PAA derivative and the BUdR-PFA derivative were highly active, especially the latter, which was more active than the parent nucleoside BUdR against the type 2 virus. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agents, but an intrinsic component of antiviral activity may also be involved.     

Analog language teaching versus natural language teaching: Generalization and retention of language learning for adults with autism and mental retardation

Examined the effects of two instructional methods on language generalization and longterm retention in 23 adults with autism and severe to profound mental retardation. Analog language teaching employed discrete trials in a controlled setting concentrating on discrimination and identification of materials. Natural language teaching emphasized instruction through interactions that occurred incidentally to training students in the use of materials to perform functional tasks. Assessments were conducted under conditions favoring analog teaching to assure against partiality toward natural language teaching. Under such disadvantageous conditions, the methods of natural language teaching would be supported by results showing either no difference or an advantage in their favor. Both techniques increased initial and long-term generalization though the results suggest no relative superiority for either method under these assessment conditions. A significant interaction was found between prior functioning level and sequence of instruction. Because natural language teaching has many strengths, few drawbacks, and produces equal generalization and retention under disadvantageous conditions, it is strongly supported as preferable for people with autism and mental retardation.The authors acknowledge the important assistance provided by the following people: the staff and management of the Behavior Development and Learning Center at CSH/DC directed by Israel Perel, Lisa Kramer, Steve Hafferkamp, James Lowdermilk, and, finally, and especially, to the participants themselves.     

Recovery from coma that results as a complication of cardiac arrest followed by cardiopulmonary bypass

Many possible complications are associated with cardiopulmonary bypass. They are similar to the risks accompanying most surgical procedures and include stroke, renal failure, and death. This potential for complication increases when bypass exceeds 2 hours and rises sharply when pump time is prolonged more than 3 to 4 hours. One group of serious complications is major neurologic disorders. The risk of significant cerebral dysfunction, that is, severe focal stroke or coma, is about 1%, and this risk increases with age and coexistent cardiovascular disease. This article focuses on the complication of coma and the possible role cardiopulmonary bypass plays in improving survival rates. A case study is presented illustrating the potential role of cardiopulmonary bypass in the unexpected neurologic recovery from coma.     

Cytokines in anaesthesia

The scope of cytokine biology is fascinating with widespread applications anticipated in many areas of medical science. We have emphasized the fundamental roles that cytokines play in the control of normal immunological functions, defence mechanisms and normal cell growth, and how major surgery and trauma can affect these processes. It remains to be determined if morbidity and mortality may be improved after major illness and surgery by altering cytokine production and function.      

Fentanyl and the interleukin-6 response to surgery

It has been suggested that large doses of opioids may suppress the interleukin-6 response to surgery. We examined the effects of the supplementation of inhalational anaesthesia with either 3 or 15 μg.kg⁻¹ fentanyl on the circulating interleukin-6, interleukin-8, C-reactive protein, cortisol and glucose concentrations in 16 patients undergoing pelvic surgery. In both groups, surgery evoked the expected glucose, cortisol and interleukin-6 response but no increase in interleukin-8 was detected. There were no significant differences between the two groups. We conclude that the supplementation of inhalational anaesthesia with conventional doses of opioids does not modify the cytokine response to surgery.     

Modulation of human T cell functions by surface sulphydryl groups: differential effects on IL-2 production and responsiveness.

An impermeable thiol blocker has been used to investigate the role of sulphydryl (SH) groups in the production of and responsiveness to IL-2 by normal human T lymphocytes. Surface SH blockade of mononuclear cells prior to incubation with mitogen (phytohaemagglutinin, concanavalin A, CD3 MoAb) had no effect on production of IL-2 but markedly impaired cellular responsiveness to exogenous IL-2. Studies using MoAbs indicated that this effect was accompanied by decreased expression of both the CD25 and p75 subunits of the IL-2 receptor. Blocking surface SH groups did not affect binding of IL-2 to p75 on unstimulated mononuclear cells, but inhibited binding to high-affinity receptors on a T lymphoma cell line. The data are consistent with the hypothesis that sulphydryl groups on the IL-2 receptor are required for its function and may be involved in the interaction of the CD25 and p75 subunits leading to generation of the high-affinity binding site. The surface thiol identified on the IL-2 receptor may be a candidate for oxidation on cells from patients with chronic inflammatory diseases such as rheumatoid arthritis and thus contribute to the aberrant function of T cells in these patients.     

Epidemiology and laboratory diagnosis of infection with viral and bacterial pathogens in infants hospitalized for suspected sepsis

A prospective study was conducted to determine the frequency and distribution of bacterial and viral pathogens in infants hospitalized with suspected sepsis and to evaluate the potential of virus detection for improving patient management. A causative organism was detected in 157 (67%) of 233 previously healthy infants less than 3 months of age, who had been hospitalized for suspected sepsis: 19 (8%) had bacterial infections, 135 (58%) had viral infections, and 3 (1%) had mixed viral-bacterial infections. Viral infections occurred in a seasonal pattern: enteroviruses were responsible for most of the hospitalizations during summer and fall (65/110; 63%) and respiratory syncytial and influenza A viruses were responsible for most of the infections during winter (44/81; 55%). In contrast, bacterial infections were not seasonally distributed. Virus was detected in 33% of the 138 infected infants within 24 hours, and in 64% within 3 days. We conclude that viral infections are prevalent among infants hospitalized for suspected sepsis, and most can be detected early enough to influence patient management.     

Neuro-otologic evaluation of the patient with acute, severe head injuries: correlations among physical findings, auditory evoked responses, and computerized tomography

Long-term clinical neurologic and otologic sequelae of traumatic head injury are well recognized. In this article, we describe the relationship among neurophysiologic, neuro-otologic, and neuroradiologic findings in a series of fifty patients with acute, severe head injury. Seventy percent of the patients had one or more otologic abnormalities, of which hemotympanum was most common. Outcome of computerized tomography (CT), auditory brainstem response (ABR), and otologic examination findings were not mutually dependent. For example, otologic disease was found in 50% of the patients with normal ABR. All but one patient in the series showed brain damage by CT; yet only 14% of the series had evidence of temporal bone fracture and, unexpectedly, one third of this group yielded normal otologic findings and a normal ABR. We conclude that combined application of otologic examination, CT scanning, and auditory evoked response assessment provides complementary information on structural and functional neuro-otologic status in persons with acute, severe head injury.