Differential inhibition of human neutrophil functions. Role of cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase.

Multiple molecular forms of cyclic nucleotide phosphodiesterase have been characterized in various tissues and cells according to their substrate specificity, intracellular location, and calmodulin dependence. The purpose of this study was to evaluate the possible involvement of different molecular forms of phosphodiesterase in regulating the respiratory burst and lysosomal enzyme release responses of human neutrophils. Treatment with the selective cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase inhibitors Ro 20-1724 or rolipram, or the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), resulted in inhibition of respiratory burst stimulated by the chemoattractants formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) (IC50 values: 0.71-17 microM) and complement fragment C5a (IC50 values: 61-93 microM), but did not inhibit phagocytosis-stimulated respiratory burst (less than 10% inhibition at 100 microM). Selective inhibitors of calmodulin-dependent phosphodiesterase (ICI 74,917), calmodulin-insensitive, cyclic GMP-specific phosphodiesterase (M & B 22,948), cyclic GMP-stimulated phosphodiesterase (AR-L 57), or cyclic AMP-specific, cyclic GMP-inhibited phosphodiesterase (amrinone and cilostamide) exhibited little or no inhibitory effect on FMLP- or phagocytosis-stimulated respiratory burst (0-42% inhibition at 100 microM). Regulation of neutrophil activation by phosphodiesterase was also response specific, as Ro 20-1724, rolipram and IBMX were less potent inhibitors of FMLP-induced lysosomal enzyme release (0-14% inhibition at 100 microM). Analysis of human neutrophil preparations confirmed the existence of a cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase, which was associated with the particulate fraction of the cell. These results demonstrate a role for the cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase in the regulation of human neutrophil functions, which appears to be both stimulus specific and response specific.     

Unusual presentation of culture positive brucellosis

We have reviewed the clinical presentation of 100 consecutive culture positive cases of brucellosis which came under our care during the last two years. Of these, six had atypical presentations and but for the routine practice of sending blood for brucella culture, the diagnosis would have been missed. The unusual presentations included a 19 year old boy presenting as an acute abdomen ending in laparotomy, a 52 year old man presenting with a psoas abscess, a 29 year old woman presenting with a transient perinephric mass, a 75 year old man with an acute flare up of his osteoarthritis, a 65 year old diabetic man presenting in an insulin-resistant diabetic state and a 35 year old man presenting with a cauda equina syndrome.     

Synthesis, chemical, and biological properties of vinylogous hydroxamic acids: dual inhibitors of 5-lipoxygenase and IL-1 biosynthesis.

Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.     

Vigabatrin in adults with poorly-controlled epilepsy and learning disabilities.

Twenty-two adult patients with uncontrolled epilepsy and severe learning difficulties were included in an open study of vigabatrin. Patients were all in residential care and had experienced at least 12 seizures during the previous 12 months despite all attempts to optimize antiepileptic drug (AED) treatment. Following a 4 month baseline period, vigabatrin 500 mg twice daily was added to the current AED treatment and the dose increased according to response, up to a maximum of 4 g/day. Ten patients achieved a reduction in seizure frequency of more than 50% during this 4 month dose titration phase. Two patients had no seizures during the baseline period. For the 30 patients with seizures during the baseline period the median improvement in seizure frequency with the addition of vigabatrin was 49% (P = 0.014). The response rate was higher for patients with partial seizures than for those with generalized seizures. Ten patients continued with vigabatrin while the dose of one of their other AEDs was gradually reduced and successfully withdrawn in three patients. Adverse events were reported in 20 patients during the 64 week study period. The most frequently reported events were sedation (8 patients), aggression (4 patients), agitation (3 patients) and ataxia (3 patients). No patients were withdrawn from the study as a consequence of adverse events. Vigabatrin was therefore an effective add-on therapy in 45% of these difficult-to-treat patients and allowed reduction of other AED treatment in a small number.     

Self-expanding endovascular graft: an experimental study in dogs

An arterial endovascular graft was constructed by wrapping an expandable nylon mesh around a framework of Gianturco self-expanding metallic stents. The devices were passed through a 12-French Teflon catheter and positioned in the normal abdominal aorta of five dogs, two of which also had a device placed in an external iliac artery. At follow-up (1-6 months), all grafts remained patent, even though slight luminal narrowing due to neointimal encasement was noted. Histologically, all grafts were covered by neointimal proliferation at the time of removal. The graft material expanded with the stents, resulting in a tight fit between the graft and the vessel wall. Side branches narrowed but remained open because of the size of the nylon mesh. No migration of the grafts equipped with a barbed lead stent was noted. Expandable nylon mesh can be used as an endovascular graft material when wrapped around a framework of self-expanding stents. The resulting device can be easily delivered via transcatheter techniques, and once placed in a vessel, the nylon acts as a support for neointimal encasement, which forms a new vascular lumen.     

Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease.

The pathogenesis of hypertension in autosomal-dominant polycystic kidney disease (ADPKD) is unclear, but increased activity of the renin-angiotension system may contribute. The renal and systemic hemodynamic response to lisinopril, an angiotension converting enzyme (ACE) inhibitor, in patients with ADPKD without renal failure was compared with the response in matched unaffected family members. Mean blood pressure and renal vascular resistance decreased in the affected group after lisinopril, with no significant change in the unaffected group. Glomerular filtration rate (GFR) was unchanged and therefore filtration fraction fell significantly. Changes in urinary excretion of 6-keto-PGF1 alpha and kallikrein suggested that increased renal synthesis of PGI2 or activation of the renal kallikrein-kinin system were not likely to be responsible for the hemodynamic effects. The acute decrease in renal vascular resistance without change in GFR suggests that ACE inhibition may have a particular value in the treatment of hypertension associated with ADPKD which should be assessed by further long-term studies.     

Incidence of otitis media in vitamin A-deficient guinea pigs.

After observing an association between vitamin A deficiency and otitis media among children in Micronesia, we sought to develop an animal model for vitamin A-deficiency-induced otitis media. Thirty juvenile guinea pigs were screened for absence for otitis and then divided into two groups. The experimental group was placed on a vitamin A-free diet, whereas control animals were fed a standard formula. The animals were followed by means of otologic examination and serum retinol determinations. When experimental animals demonstrated vitamin A deficiency, they were killed along with one control and temporal bones were harvested and prepared for histologic examination. None of the 15 controls demonstrated middle ear abnormalities. In the experimental group, 77% of temporal bones showed middle ear pathology consisting of either of subepithelial edema (27%) or frank otitis media (50%). These results indicate that the guinea pig is a suitable species for study of otitis media in association with vitamin A deficiency. We postulate that eustachian tube dysfunction is the primary mechanism for inducing middle ear inflammation in this animal model.     

Hearing loss in myotonic dystrophy

Seventeen of 25 patients with myotonic dystrophy had moderate to severe hearing loss, usually sensorineural, that was identified by routine audiometric screening and was treatable in some patients. Further testing failed to reveal a single pathophysiological process.     

The neglect of data-gathering instruments in behavior therapy practice

Although the Willoughby Personality Questionnaire and the Fear Survey Schedule are demonstrably valuable aids to the practice of behavior therapy of neurosis, it is evident that many behavior therapists do not use them. In order to determine the extent of their neglect, we sent a questionnaire to all Clinical Fellows of the Behavior Therapy and Research Society. The 134 replies we received revealed that the Willoughby was routinely used by only 19% and the Fear Survey Schedule by only 42%. This seems to be manifestation of a wide-spread but indefensible homogenized view of neuroses. It is a sad reflection on the quality of behavior therapy training programs.