Role of neutrophil-endothelial cell adhesion in inflammatory disorders

Polymorphonuclear leukocytes are armed with an impressive arsenal of bactericidal agents that allow these cells to play a vital role in host defense against invading pathogens. However, these same agents can produce extensive cellular damage in host tissues when leukocytes are activated during inflammatory conditions. Recognition of this fact, when coupled with the observation that leukocyte adhesion to post-capillary venules is a critical first step in the inflammatory process, has led to the development of the concept that inhibition of neutrophil-endothelial cell adhesion (NECA) may represent a novel therapeutic strategy for the prevention of leukocyte-dependent injury in inflammatory conditions. Indeed, pharmacological or immunologic inhibition of NECA reduces cellular injury, dysfunction, and necrosis induced by ischemia/reperfusion, circulatory shock and resuscitation, organ transplantation, cardiopulmonary bypass, frostbite, and thermal trauma. NECA also appears to play an important role in the pathobiology of airway inflammation and asthma, pulmonary oxygen toxicity, arthritis, bacterial meningitis, and cerebral malaria. The aim of this review is to summarize the evidence implicating NECA in the pathogenesis of these inflammatory conditions.     

Doctors who perform operations. A study on in-hospital surgery in four diverse geographic areas (second of two parts)

To facilitate manpower planning in the surgical field, a study was c onducted into the work loads of surgeons in various specialities in 4 different geographical areas. Surgeons in group practice and surgeons who were Board-certified specialists carried a statistically significant larger work load of surgery. The certified surgeons performed more and more complex operations. The mean operative work load increased steeply with age, reaching a maximum at 40-44 years, and fell linearly after that age. Approximately 18 years following medical school graduation were needed for a surgeon to achieve his maximum work load. The geographic factor had no appreciable effect on work loads. Tables which broke down frequencies for each major type of operation for each type of surgical specialist indicated that even commonplace operations were not frequent events on the average for any individual surgeon. It is concluded from the study that work loads are relatively low due to excessive supply of surgeons. This is of concern because there is some doubt about maintenance of surgical skills by those doctors who perform infrequent operations. The widest variation in practice was evident between ophthalmologists and thoracic surgeons, indicating that manpower planning in this field would have to be done on a specialty-by-specialty basis. 3 plans for redistributing the operative work load and reducing the number of specialist surgeons are considered.     

Metabolic clearance and secretion rates of porcine growth hormone in genetically lean and obese swine

The metabolic clearance rate (MCR) and the secretion rate (SR) of porcine growth hormone (pGH) have been examined in swine rendered genetically either lean or obese after 18 generations of selection for or against backfat thickness. At 15 weeks of age (when the muscle:fat ratio was greater than 1) the mean half-life (t1/2), MCR, and SR, for the obese, control, and lean swine were: t1/2 = 7.4, 8.9, and 9.8 min; MCR = 341, 279, and 158 ml/min; SR = 907, 802, and 520 ng/min, respectively. At 90 kg body weight (when muscle:fat ratio was less than 1, and the age was about 30 weeks) the data for obese, control, and lean swine were: t1/2 = 11.3, 12.0, and 11.7 min; MCR =305, 280, and 336 ml/min; SR= 535, 626, and 932 ng/min, respectively. The t1/2, MCR, and SR were not significantly different among the obese, control, and lean swine at either 15 weeks or 90 kg body weight. Comparing the two stages of development, the younger swine (15 weeks of age) had a shorter t1/2 (P less than .01), and secreted and cleared more pGH on a per kg body weight basis (P less than .05) than the older swine (90 kg bodyweight, about 30 weeks of age). However, the results suggest that the selection of swine for either leanness or fatness for 18 generations did not alter the MCR and SR of pGH. In addition, the differences observed between the younger and older swine suggest that GH is cleared at a more rapid rate and more GH is available per unit of mass in the younger animals.     

Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction

Early identification of patients with symptomless left-ventricular dysfunction and early pharmacologic intervention may have an impact on the outlook of patients with heart failure. Atrial natriuretic peptide (ANP) is a cardiac hormone that is released as a C-terminal (C-ANP) and an N-terminal peptide (N-ANP). Since N-ANP has reduced clearance rates compared with C-ANP, N-ANP circulates at higher concentrations. Based on the known increased concentration of C-ANP in symptomatic congestive heart failure, our study was designed to evaluate prospectively N-ANP profile and left-ventricular function in subjects with symptomless and symptomatic heart failure, and the role of plasma N-ANP as a marker for early identification of patients with heart failure. 180 patients who were referred for rest and exercise radionuclide angiography for evaluation of left-ventricular function were studied. Blood was taken for measurement of C-ANP and N-ANP before angiography. Patients were grouped according to New York Heart Association (NYHA) heart failure classification and left-ventricular function. Mean (SD) plasma N-ANP concentration in patients with symptomless left-ventricular dysfunction (NYHA class I, n = 70) was 243 (256) pmol/L (range 27-922 pmol/L), and was higher (p < 0.001) than in 25 control subjects (28 pmol/L). A plasma N-ANP concentration above 54 pmol/L (mean +/- 1.96SD of the control group) had a sensitivity of 90% and a specificity of 92% for detection of patients with symptomless left-ventricular dysfunction. We have shown that plasma N-ANP concentrations are significantly increased in patients with symptomless left-ventricular dysfunction and that this peptide can serve as a marker for diagnosis of such patients.     

Serum- and bradykinin-induced calcium transients in familial Alzheimer's fibroblasts

The calcium-sensitive photoprotein, aequorin, was used to examine serum- and bradykinin-induced transient increases in free cytosolic calcium ions in skin fibroblasts from 10 individuals with early onset familial AD (FAD), including four who were biopsied before their clinical symptoms would allow a diagnosis of AD, 2 individuals with late onset FAD, 8 at-risk but nonsymptomatic individuals, and 13 controls. The data show that (a) among controls, the peaks of the calcium transients increase in height as a function of donor age; (b) transients induced by 10% serum, 10 nM bradykinin (BK) or 100 nM BK were generally lower in FAD fibroblasts, including those from donors in the early stages of the disease, than in age-matched control cells; (c) such transients are reduced in cells from a proportion of the nonsymptomatic, at-risk individuals. Thus, serum- and BK-induced calcium transients are reduced in fibroblasts from both early and more advanced stage FAD donors and perhaps even from donors who are presymptomatic carriers of the defective gene. The data also suggest that changes in calcium transients in FAD fibroblasts neither mimic nor exaggerate the effects of normal aging.     

Mutations in the COL1A2 gene of type I collagen that result in nonlethal forms of osteogenesis imperfecta

Although virtually all mutations that result in osteogenesis imperfecta (OI) affect the genes that encode the chains of type I procollagen, the effects of mutations in the COL1A2 gene have received less attention than those in the COL1A1 gene. We have characterized mutations in 4 families that give rise to different OI phenotypes. In three families substitutions of glycine residues by cysteine in the triple helical domain (a single example at position 259 and 2 families in which substitution of glycine at 646 by cysteine) have been identified, and in the fourth a G for A transition at position +4 in intron 33 led to use of an alternative splice site and inclusion of 6 amino acids (val-gly-arg-ile-leu-phe) between residues 585 and 586 of the normal triple helix. The relation between position of substitution of glycine by cysteine in the COL1A2 gene does not follow the pattern developed in the COL1A1 gene. To determine how COL1A2 mutations produce OI phenotypes, we have produced a full-length mouse cDNA into which we plan to place mutations and examine their effects in stably transfected osteogenic cells and in transgenic animals.