Genetic susceptibility to murine collagen II autoimmune arthritis. Proposed relationship to the IgG2 autoantibody subclass response, complement C5, major histocompatibility complex (MHC) and non-MHC loci.

Analysis of the IgG autoantibody subclass response in the collagen II autoimmune arthritis (CII AIA)-susceptible D1 strain mice revealed that the onset of disease was associated with a predominance of IgG2a autoantibody. In a comparative study, resistance in the B6 strain was associated with a deficient IgG2a autoantibody response. B6 IgG1, 2b, and 3 autoantibody responses generally overlapped those of arthritic D1 mice, and estimates of antibody crossreactivity and affinity were similar for both strains. In crosses between D1 and B6, arthritis developed only in those F1 mice with IgG2a autoantibody responses approximating or exceeding those in arthritic D1 mice. Additional studies with B6 and B10 strains suggested an alternate role for the IgG2b autoantibody response. In inbred strains with known genetic backgrounds, a dissociation between the magnitude of the total IgG autoantibody response and the percent of total as IgG2a was demonstrated. The H-2q, Ig-1c D1 strain was a high-total and high-percent IgG2a responder, while the H-2d, Ig-1c D2 strain was a low-total but high-percent IgG2a responder. The H-2b, Ig-1b B6 strain was a low-total and low-percent IgG2a responder, while the H-2b/q, Ig-1b/c (B6D1)F1 hybrid was a low-total but high-percent IgG2a responder. A further dissociation between high-percent IgG2a autoantibody responsiveness and the H-2 haplotype was demonstrated by the H-2 congenic B10.D2/n (H-2d, Ig-1b) strain, in which a low-percent IgG2a response was observed to differ from the D2 strain. High-percent IgG2a autoantibody responsiveness also appeared to be inherited as a dominant trait based upon high responses in all (B6D1)F1 hybrids and backcrosses to D1. These findings suggest that the H-2 haplotype is involved in the total IgG autoantibody response but that the relative fraction of the total response as IgG2a is independent of the H-2 haplotype and possibly related to Igh-C genes. C5-deficient SWR (H-2q, Ig-1c) mice were found to have a high total autoantibody response to mouse CII and IgG2a comparable to arthritic D1 mice, but these mice did not develop arthritis. Based upon these observations, we conclude that susceptibility to CII AIA requires the interaction of multiple genes, both major histocompatibility complex (MHC) and non-MHC, which influence the magnitude (total IgG) and the quality (IgG subclass) of the autoimmune response and the availability of appropriate mediators (C5) to initiate the inflammatory reaction.

Human HLA-DR beta gene hypervariable region homology in the biobreeding BB rat: selection of the diabetic-resistant subline as a rheumatoid arthritis research tool to characterize the immunopathologic response to human type II collagen.

Collagen arthritis (CA), an autoimmune model of rheumatoid arthritis (RA), has been studied in various animals. However, it has not been studied in an animal with a genetic background relevant to RA. We selected rats from a diabetic-resistant (DR) subline of the diabetic BB rat because they have an autoimmune disease-prone background, but not the immunodeficiencies of the diabetic BB rat, and the third hypervariable region (HVRIII) of the BB RT1.D beta gene appeared to encode a nucleotide sequence of the human HLA DR beta gene, which has been reported to be associated with susceptibility to RA. We synthesized oligonucleotide primers flanking the RT1.D beta HVRIII, cloned polymerase chain reaction-amplified DNA into M13mp18, and confirmed the presence of the susceptibility sequence (SS) (RRRAA) by the dideoxy sequencing method in a colony of DR BB/Wor-UTM rats. When immunized with human type II collagen (CII) in incomplete Freunds adjuvant (IFA), arthritis developed rapidly by day 10 with 100% incidence. Light and electron microscopy revealed an unusually severe and aggressive, bidirectional pattern of cartilage resorption by synovial and subchondral mononuclear and multinucleated inflammatory cells. These findings coincided with a predominant humoral response to the cyanogen bromide (CB) 11 fragment of the human CII molecule by the pathogenic IgG2a isotype. This study provides further support to the role of CA as a relevant RA model, the specific roles of the CB11 fragment as a major site of arthritogenic epitopes, and of antibody mechanisms in the pathogenesis of CA. Furthermore, the identification of an RA SS in an immune response gene of the DR BB rat presents a novel opportunity to determine with an animal model the role of other antigens as well as this SS in RA.

Detection and quantitation of tetanus antitoxin in blood donations.

Passive haemagglutination and IEOP have been used both to detect and to measure tetanus antitoxin in human donor sera. Forty percent of blood donors had detectable antitoxin but only 9% had levels suitable for production of human antitetanus immuoglobulin (larger than or equal to 2 IU/ml). The incidence of high titre antitoxin was significantly greater in men and was unrelated to the ABO blood group system. The prevalence of antitoxin in selected donor groups and immunized staff is shown.

Rgulation of intestinal alkaline phosphatase levels in the rat. Role of the adrenal cortex.

Bilateral adrenalectomy produces a reduction in the alkaline phosphatase concentration in rat intestine, which is not prevented by the administration of saline, but is prevented by the administration of cortisone. The administration of A.C.T.H. to normal rats leads to a rise in intestinal alkaline phosphatase levels associated with a small increase in the weight of the adrenals, while the administration of hydrocortisone produces large increases in the enzyme, even with doses which cause significant hypoplasia of the adrenal glands. The significance of these findings in relation to mechanisms of fat absorption and the treatment of steatorrhoea is discussed.

Intra-aortic balloon counterpulsation in patients with severe cardiac dysfunction undergoing abdominal operations.

OBJECTIVE: To assess the effectiveness of intra-aortic balloon counterpulsation (IABC) as adjunctive treatment in patients undergoing abdominal operations. DESIGN: Retrospective review of patient medical records to determine the incidence of mortality following abdominal surgery and the incidence of complications from IABC. SETTING: University-based, tertiary care hospital. PATIENTS: Sixty-eight patients who underwent an abdominal operation and IABC during the same hospitalization were divided into the following groups: Group 1, IABC initiated prior to operation to enhance perioperative cardiac function; group 2, IABC used to treat cardiogenic shock in a patient who subsequently required an operation while undergoing IABC; and group 3, IABC device inserted and removed for treatment of cardiogenic shock in a patient who subsequently required an operation within 30 days of removal of the device. MAIN OUTCOME MEASURES: The incidence of mortality in IABC-supported patients and IABC-related complications. RESULTS: In group 1, excluding 3 patients who died following emergency operation, 26 patients underwent nonemergency procedures and had a 12% mortality rate. In group 2, 5 of 6 patients who underwent emergency operations died, whereas 3 of 4 patients who required only urgent operations survived. In group 3, 18 (62%) of 29 patients who underwent urgent or emergent operations died postoperatively. Thirteen patients experienced complications related to IABC; there were no deaths and no limbs were lost to ischemia. CONCLUSIONS: This is the largest reported series looking at the utility of IABC as adjunctive treatment for patients undergoing abdominal operations. The outcome for those patients requiring emergency operations remains poor, but it is likely that more liberal use of IABC in patients with severe cardiac dysfunction who require nonemergency operations may improve patient outcome.

Acute effects of intermittent pneumatic compression on popliteal artery blood flow.

OBJECTIVES: To investigate the immediate effects of intermittent pneumatic foot and calf compression (IPFCC) on popliteal artery blood flow in symptom-free volunteers and to determine the reproducibility of color flow duplex imaging in the popliteal artery. DESIGN: Cohort study. SETTING: A university associated tertiary care hospital. PATIENTS: Forty lower limbs of 30 volunteers without symptoms or noteworthy risk factors of peripheral vascular disease. INTERVENTIONS: Popliteal artery blood flow was measured in the sitting position before, during, and after the application of IPFCC using color flow duplex imaging. The interobserver, intraobserver, and between occasion within-subject variability of the popliteal artery blood flow were evaluated in 5 symptom-free volunteers who had at least 5 color flow duplex imaging measurements taken at each of the above time points on 3 different days. MAIN OUTCOME MEASURES: The arterial diameter, peak systolic, end diastolic, and reverse-flow velocities were measured, as well as the duration of forward flow during diastole before, during, and after IPFCC. The same variables were measured in 5 separate volunteers by 3 different observers, on 3 separate days, at 3 separate times to determine reproducibility. RESULTS: Including all types of variability, the popliteal artery blood flow varied from 8% to 39% with a mean value of 19%. Since the diameter of the artery was obtained with less than 5% variability, the time average mean velocity was responsible for the high variation in flow. During application of the IPFCC, the popliteal artery blood flow increased significantly in all subjects (P<.001). The mean increase in the flow was 2.4 times the baseline values. The diameter of the arteries remained unchanged while the time average velocity increased significantly (P<.001). This velocity increase was due to marked elevation in the peak systolic and end diastolic velocities and diminution of the reverse-flow component, as well as a prolongation of the forward flow during diastole. After cessation of the pump, flow returned to baseline levels (P=.41) CONCLUSIONS: Ultrasound-derived popliteal artery blood flow measurements show moderate variability. The application of IPFCC greatly enhances popliteal artery blood flow. The flow increase is due to a dramatic drop in the peripheral vascular resistance as the peak systolic and end diastolic flow velocities increase and the reverse-flow component diminishes. Its role in the treatment of lower extremity occlusive arterial disease needs to be determined.

Management of adenocarcinoma in a columnar-lined esophagus.

Of 89 patients diagnosed between 1973 and 1983 as having at least 3 cm of columnar-lined esophagus, 22 were found to have adenocarcinoma. There was no difference in sex ratio, smoking, or the use of alcohol between the benign and adenocarcinoma groups. The patients with adenocarcinoma were older (63 years versus 57 years) and had a higher frequency of dysphagia (64% versus 46%), gastrointestinal bleeding (36% versus 24%), extended columnar-lined esophagus (94% versus 28%), and epithelial dysplasia (68% versus 10%). Heartburn was less frequent in the adenocarcinoma group (59% versus 79%), but when it occurred, it was of longer duration (mean, 18.8 years versus 10.9 years). In 2 patients, progression from benign columnar-lined esophagus to early adenocarcinoma was observed. Of the patients with adenocarcinoma, 2 received palliative treatment without resection and died four and nine months later. Six underwent partial esophagogastrectomy with 1 postoperative death. Four had residual columnar-lined esophagus at the resection margins. In one of them, stricture developed and in one, anastomotic recurrence of adenocarcinoma; 1-year survival was 50%. Fourteen patients underwent total thoracic esophagectomy with no operative deaths, strictures, or anastomotic recurrences; 1-year survival was 5 of 6. Surgical staging revealed that 63% had transmural spread and 55%, lymph node involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

The Xylum Clot Signature Analyzer: a dynamic flow system that simulates vascular injury.

The Xylum Clot Signature Analyzer (CSA) is an automated, user-friendly, benchtop analyzer that assesses platelet function and coagulation in non-anticoagulated whole blood under physiological flow and temperature conditions. From blood drawn in a single venipuncture, the CSA measures: a) the time for platelets to occlude holes "punched" in a blood conduit (platelet hemostasis time or PHT); b) collagen-induced thrombus formation (CITF) as blood flows in a channel containing a collagen fiber; and c) clotting time (CT). Micrographs show platelet-rich thrombi in the punched holes and on the collagen surface after a run. PHT and CITF increased at lower shear rate, suggesting that shear activation of platelets is involved in hole closure and in collagen-induced thrombus formation. In blood mixed with anti-von Willebrand's factor (vWF) antibodies, anti-GPIb antibodies, aurin tricarboxylic acid (ATA), or anti-GPIIb-IIIa, PHT and CITF were prolonged, further supporting the reflection of platelet function by those parameters. At low shear rate (<1000 sec(-1)), native blood and blood treated with anti-vWF did not have significantly different PHTs or CITFs. At high shear rate (>6000 sec(-1)), the PHT and CITF of the anti-vWF-treated sample were significantly greater than those of the untreated sample. This supports the inhibition of shear-induced activation of platelets by anti-vWF in the CSA. Heparin-treated blood showed significantly longer CT, indicating that coagulation of blood under flow is inhibited by heparin. The CSA thus assess multiple aspects of hemostasis under near-physiological conditions.

Evaluation of immunosuppressive potential of cryogenine using developing and established adjuvant arthritis in rats.

Both developing (Days --1-+12 relative to inoculation) and established (Days +18-+29) stages of Mycobacterium butyricum adjuvant-induced polyarthritis in rats were treated orally with cryogenine (100 mg/kg/day), a prototype anti-inflammatory (phenylbutazone, 100 mg/kg/day), or a prototype immunosuppressive (cyclophosphamide, 6 mg/kg/day). During developing adjuvant arthritis, cryogenine and phenylbutazone significantly reduced the nonimmune-mediated inflammation in the inoculated hindpaw. Neither cryogenine nor phenylbutazone provided protection against the development of the delayed-onset, immune-mediated inflammation and the reduction in growth rate seen after Day +12 in unmedicated rats. Cyclophosphamide failed to reduce the nonimmune-mediated inflammation, but it provided significant protection against both the delayed-onset, immune-mediated inflammation and the reduced growth rate. During established adjuvant arthritis, cryogenine and phenylbutazone were effective against the established inflammation, while cyclophosphamide was ineffective. These results confirm the known anti-inflammatory and immunosuppressive activities of phenylbutazone and cyclophosphamide, respectively, and indicate that cryogenine lacks immunosuppressive capability at the effective anti-inflammatory dosage level used.

Hypergastrinemia and gastric acid hypersecretion in uremia.

Twenty-one chronic hemodialysis patients were investigated. While only two had radiologic evidence of peptic ulceration, three had markedly elevated basal acid outputs, thirteen had significantly elevated maximal acid outputs and seven had fasting duodenogastric reflux. Elevated fasting serum gastrin levels and prolonged gastrin circulation following stimulated endogenous release were also demonstrated. The abnormalities in gastric function may be explained by fasting and stimulated hypergastrinemia.

Colonoscopic polypectomy.

Colonoscopic polypectomy is well established as an outpatient procedure. In skilled hands it is essentially safe. The components of a satisfactory therapeutic outcome are good bowel preparation, adequate sedation analgesia, an experienced operator and the proper range of equipment. In this two year series of 71 patients (176 polyps) there were no fatalities, no perforations and only two minor bleeds. Eighty percent of the polyps were of the tubuloadenomatous or tubulovillus type. Carcinoma was present in 6% and their outcome is described in detail. The commonest presentation of colonic polyps was rectal bleeding or occult blood in the stools (56%). Two or more polyps were present in 60% of patients. Seventy percent were located distal to the splenic flexure and the rest proximally. Fifteen percent were over 2 cm in maximum diameter. Policies for the type and frequency of follow-up are a matter for ongoing discussion.

Symposium on diarrhea. 2. Clinical diagnosis of the causes of diarrhea.

Elucidation of the cause of diarrhea is facilitated by considering which of three principal determinants are of relevance in a particular case. These determinants relate to the onset (whether diarrhea is acute or chronic), to infection or an absence ofinfection and to the presence in the stool of blood or mucus, or both. Diagnosis is also facilitated by taking an accurate and full history, conducting a physical examination, performing sigmoidoscopy and, with proper care, attempting a therapeutic diagnosis. Findings from investigations should then enable one to arrive at a diagnosis. The diagnosis can be reached in an orderly fashion by classifying the types of diarrhea into eight categories: with respect to the acute or chronic onset a case of diarrhea may be noninfectious, without blood or mucus in the stool; noninfectious, with blood or mucus, or both; infectious, without blood or mucus; and infectious, with blood or mucus in the stool.

Celiac axis compression: experience with 20 patients and a critical appraisal of the syndrome.

Twenty patients with celiac axis compression were treated surgically during a 5-year period. Fifteen remain asymptomatic, two are partially improved, two are unimproved, and one has been lost to follow-up. The main presenting symptom was upper abdominal pain--constant in some, intermittent in most--and the main diagnostic clue was a loud, localized systolic bruit in the midepigastrium. All had angiographic confirmation of the diagnosis. Ten had previous surgery (appendectomy, cholecystectomy, vagotomy, and pyloroplasty), without relief. The authenticity of celiac axis compression as a symptom-producing entity is difficult to establish objectively because the main treatable symptom is pain. However, eight of these patients gained weight, three have shown improvement in pancreatic function, and one of the unimproved patients still has an occluded celiac axis. A critical review of the literature of this controversial topic is included.

Pulmonary hypertension due to micro-thromboembolism from splenic and portal veins after portacaval anastomosis.

This is a presentation of a unique case of pulmonary hypertension in a 15-year-old girl, due to micro-thromboembolism from splenoportal veins through a portacaval anastomosis.

Serum iron and haemoglobin levels in pregnant East African women of mixed tribal origin.

PIP: To clarify the pattern of hemoglobin and serum iron response during pregnancy, 187 pregnant women from 14 tribal groups in the Nairobi area were studied. None of the women had received iron medication prior to presenting at the antenatal clinic and all were in a good nutritional state. 25 females and 23 males admitted to the Kenya National Hospital for minor surgical procedures were used as controls. The general incidence of anemia among the study subjects was 8.5%, which is lower than that noted in other studies of iron deficiency during pregnancy. The incidence of anemia was higher among primigravidae (11.3%) than among women in the para 3-5 (4%) or para 6+ (1%) groups. This could be due to a high incidence of adolescent pregnancies among primigravidae with a double demand on iron stores. However, further analysis of the data indicated that mean hemoglobin concentrations did not significatnly differ by age. An alternative explanantion is that pregnancy represents the 1st time many women attend a clinic and may therefore be the 1st opportunity for a diagnosis of treatable anemia. Serum iron and total iron binding capacity levels were higher in male controls than in the nonpregnant female controls, who in turn had higher levels than the pregnant cases. Finally, the study subjects demonstrated a rise in total iron binding capacity and a slight fall in serum iron concentration with advancing pregnancy, a pattern that has been noted in other studies. These data suggest that iron deficiency anemia during pregnancy is not a significant problem in Nairobi and the prescription of iron should be based on individual requirements.^ieng

Fat digestion and absorption in the adrenalectomized rat.

Malabsorption of fat in the adrenalectomized rat has been confirmed. The criteria for adrenal hypofunction were more rigorous than in previous studies. The malabsorption is not due to impaired intestinal lipolysis or inadequate intestinal intracellular glyceride synthesis. Delayed gastric emptying is probably secondary to the malabsorption rather than a cause. It is postulated that impaired intestinal fatty acid activation may be the key defect and that in some way this inhibits fatty acid transport across the mucosal membrane.