Deficiency of lubricating surfactant lining the articular surfaces of replaced hips and knees

While preceding papers have demonstrated that the active load-bearing agent in the boundary mode of joint lubrication is surface-active phospholipid (SAPL)--probably adsorbed as the outermost layer of articular cartilage--this study is designed to determine whether that layer is deficient in osteoarthritis (OA). This layer has been studied on 12 hips and 31 knees obtained from surgically replaced joints afflicted with OA. Measurement of the contact angle (theta) subtended by a droplet of saline clearly demonstrated a highly significant decrease in hydrophobicity, theta falling from 100 degrees for 13 bovine controls (78 degrees for five human controls) to 56 degrees for arthritic hips and 63 degrees and 68 degrees for the 'worn' and 'unworn' areas of arthritic knees, respectively. These changes were reflected in the quantities of SAPL (and proteolipid) recovered from the same articular surfaces by solvent rinsing, yields of SAPL being 36% lower in hips and 25% lower in 'worn' areas of knees, but not significantly different in 'unworn' areas. These results indicate that the outermost lubricating layer of SAPL deposited onto articular cartilage from SF is deficient in OA.      

The effects of uncontrolled hyperglycemia on thrombosis and formation of neointima after coronary stent placement in a novel diabetic porcine model of restenosis

BACKGROUND: Results of recent clinical studies suggest that patients with diabetes mellitus have a higher than normal rate of restenosis after percutaneous transluminal coronary angioplasty or coronary stenting. The mechanism for this exaggerated neointimal response is not known. OBJECTIVES: To determine the technical feasibility of a model of in-stent restenosis in swine with streptozotocin-induced hyperglycemia and to compare the late arterial responses to injury induced by placement of oversized coronary stents in diabetic and nondiabetic animals. METHODS: Eighteen 25-40 kg castrated male or intact female Yucatan miniature swine aged 6 months were obtained from a commercial supplier. Twelve of the miniature swine were randomly selected for intravenous treatment with 125 mg/kg streptozotocin to induce a hyperglycemic state. Twelve weeks after treatment, all animals underwent placement of oversized balloon-expandable stainless steel stents in the coronary arteries. After 28 days, histomorphometric analysis of the stented coronary arteries to determine the neointimal responses for the diabetic and nondiabetic animals was completed. RESULTS: Sudden death due to stent thrombosis occurred for five of 11 (45%) of the diabetic animals and none of the age-matched nondiabetic control animals (P=0.05). For histology after 28 days, the neointimal response was correlated to the extent of arterial injury for the diabetic (r=0.79, P < 0.0001) and nondiabetic (r=0.86, P < 0.0001) animals. The surviving diabetic animals had areas of neointimal (1.67 +/- 0.74 mm2) and percentages of in-stent stenosis (28 +/- 14) similar to those of the nondiabetic swine (1.36 +/- 0.40 mm2, P=0.26; 22 +/- 6, P=0.17). Multiple regression analysis also demonstrated that arterial injury (P < 0.0001) alone, not hyperglycemia (P=0.237), was independently correlated to formation of neointima. CONCLUSIONS: Uncontrolled hyperglycemia results in greater than normal thrombosis after coronary-stent placement in swine with streptozotocin-induced diabetes. These data suggest that greater than normal early formation of thrombus rather than proliferation of smooth muscle cells contributes to restenosis after coronary stenting in patients with diabetes mellitus.     

Evidence that several high-frequency human blood group antigens reside on phosphatidylinositol-linked erythrocyte membrane proteins

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder associated with absence of expression of phosphatidylinositol (PI)- linked membrane proteins from circulating hematopoietic cells of multiple lineages. Recent work demonstrated that decay accelerating factor, one such PI-linked protein, bears the Cromer-related blood group antigens. This study demonstrated that other high incidence antigens, including Cartwright (Yta/Ytb), Holley-Gregory (Hy/Gya), John Milton Hagen (JMH), and Dombrock (Doa/Dob), are absent from the complement-sensitive (PNH III) erythrocytes of patients with PNH. The relatively normal, complement-insensitive erythrocytes from the same patients express these antigens normally. Therefore, these antigens most likely reside on PI-linked proteins absent from PNH III, but not PNH I, erythrocytes.     

Predictive factors of resistance to antihypertensive treatment

Results of antihypertensive treatment were analyzed in a group of 5,209 hypertensive patients referred in two hypertension Clinics in Paris from 1976 to 1985. Patients were included in the study if they fulfilled the following criteria: 1) at least four visits in the clinic, 2) follow-up period greater than 6 months, 3) initial diastolic blood pressure greater than or equal to 90 mmHg and/or presence of an antihypertensive treatment. After a mean follow-up period of 43 months, blood pressure was reduced from 177/105 mmHg to 148/89 mmHg. However, in spite of at least two antihypertensive drugs, 16.7 p. 100 of these patients had a diastolic blood pressure above 95 mmHg at the end of the follow-up period and were defined as uncontrolled hypertensives (UH). By comparison with controlled hypertensives (CH), UH patients were more frequently males (67.9 vs 56.6 p. 100, p less than 0.001), had a greater known duration of hypertension (11.6 vs 8.7 years, p less than 0.001), and presented at the first visit with higher blood pressures (188/113 vs 174/103 mmHg, p less than 0.001/p less than 0.001), despite a higher rate of antihypertensive treatment (66.6 vs 53.8 p. cent, p less than 0.001), a higher ponderal index (26.3 vs 25.3/kg/m2, p less than 0.01) and a higher prevalence of end-organ damage (23.2 vs 16.3 p. 100, p less than 0.001). Sokolov index, serum creatinine and uric acid levels were higher among UH than among CH patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnostic and prognostic significance of Sezary cells in peripheral blood smears from patients with cutaneous T cell lymphoma

Blood smears stained with Wright-Giemsa were obtained from 124 patients with pathologically confirmed cutaneous T cell lymphoma (CTCL), 70 patients with various other cutaneous disorders, and ten healthy adult volunteers. These were examined in a blinded fashion for atypical lymphocytes with cerebriform nuclei (CLs), which were characterized further according to cell diameter. CLs, comprising up to 15% of lymphocytes in smears, were observed in 20% of the patients with benign dermatitis. CLs, comprising up to 89% of lymphocytes in smears, were found in 22%, 30%, 50%, and 96% of patients with patch, plaque, tumor, and erythrodermic CTCL, respectively. Large-diameter CLs (15 to 20 micron) were observed only in smears from patients with CTCL. Total CL counts above 15 per 100 lymphocytes and/or the presence of large CLs occurred in 33 of 49 (67%) patients with erythrodermic disease and in only two patients with other skin manifestations. Blood smears obtained at the time of cytogenetic studies indicated that a total CL count above 15% was the smear criterion that correlated best with the demonstration of a chromosomally abnormal malignant clone in the blood. The presence of large CLs per se, although also predictive of a malignant clone, was less useful. Multivariate survival analysis showed that the duration of disease before the blood smear and the proportion of large CLs within the total CL population were the covariates that correlated most significantly with survival. We speculate that the reduced survival of patients with increased proportions of large CLs in smears reflects the presence of polyploid malignant lymphocytes in the blood.     

Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation

Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony- stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady- state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = - .86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = - .70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.     

p22-phox-deficient chronic granulomatous disease: reconstitution by retrovirus-mediated expression and identification of a biosynthetic intermediate of gp91-phox

Chronic granulomatous disease (CGD) results from defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, central to which is the membrane-bound cytochrome b-245. The cytochrome is composed of two protein subunits, the larger (gp91-phox) being deficient in X-linked CGD. In this study, we have analyzed expression of the cytochrome subunits in B-cell lines from two autosomal CGD patients for whom the disease is caused by deficiency of p22-phox, the smaller subunit. We report the presence of a 65-kD precursor of gp91- phox in the membrane fraction of both p22-phox-deficient cell lines, corresponding to the core protein with N-linked carbohydrate side chains in the high mannose form. Expression of p22-phox in these cells resulted in functional correction of NADPH oxidase. In addition, gp91- phox in the reconstituted cells was processed to its terminally glycosylated form. These data suggest that the association of the 65-kD gp91-phox precursor with p22-phox is a prerequisite for processing of the carbohydrate side chains to the complex form in the Golgi. The detection of this precursor will enable characterization of mutations disrupting the subunit interaction (either naturally occurring or derived by in vitro mutagenesis) and so aid in structure-function analysis of cytochrome b-245. Reconstitution of p22-phox-deficient cells shows the potential of gene therapy for this autosomal form of CGD.     

Rearrangement of the breakpoint cluster region and expression of P210 BCR-ABL in a "masked" Philadelphia chromosome-positive acute myeloid leukemia

The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a "masked" Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.