Low levels of IFN-gamma down-regulate the integrin-dependent adhesion of B cells by activating a pathway that interferes with cytoskeleton rearrangement.

In order to fully mature and participate in the humoral immune response, immature B cells must first migrate into specific areas in the spleen where they differentiate into mature cells. However, before their maturation in the spleen, immature B cells must be excluded from non-splenic secondary lymphoid organs where any antigen encounter would lead to the death of the cells because of the negative selection process. We have recently shown that immature B cells can actively exclude themselves from antigen-enriched sites by down-regulating their integrin-mediated adhesion in a process mediated by interferon-gamma (IFN-gamma). In this study, we followed the pathway by which IFN-gamma regulates the homing of B cells. We show here that the inhibitory signal of IFN-gamma is transmitted through the IFN-gamma receptor whose engagement leads to the activation of PI3K. This PI3K activation subsequently leads to the inhibition of PKCalpha phosphorylation and cytoskeleton rearrangement required for promoting integrin-mediated adhesion and migration of B cells.

[Systemic mastocytosis].

Mastocytosis has a highly variable clinical expression, and systemic mastocytosis is occasionally associated with a myeloproliferative or a myelodysplastic disorder. These patients often present without skin involvement and have a very poor prognosis. We report a 72-year-old man with this condition who had spells of flushing and dyspnea, myelofibrosis, and high serum and urine histamine levels.

Suppressive activity of bronchial macrophages recovered by induced sputum.

BACKGROUND: The immunomodulatory activity of macrophages was shown to be a crucial mechanism in the pathogenesis of asthma. METHODS: Induced sputum (IS) and methacholine challenge (MC) were carried out in 21 atopic subjects. Suppressive activity (SA) of sputum macrophages (SMO) was investigated on autologous peripheral lymphocytes (APL) proliferation in 12 of these patients and compared to the MC. RESULTS: In 10 of the 21 patients, the FEV1 was >80%; five of these had a nonreactive MC. Eosinophils and metachromatic cells correlated well (r=0.6442; P=0.0029), but not with the MC. The SA of SMO correlated (P=0.0152) with the MC: SMO enhanced APL proliferation in five patients with a positive MC, while SMO showed SA in five with a negative MC. Only two patients with suppressive SMO had a positive MC. Cytokine profiles from five patients showed that two patients with a negative MC had interleukin (IL)-1alpha and beta, IL-6, and transforming growth factor (TGF)-beta transcripts, while two patients with a positive MC transcripted IL-4 and IL-5. One patient with a borderline MC transcripted IL-5, but not IL-4. CONCLUSIONS: These data support the theory that patients with reduced suppressive bronchial macrophages display clinical bronchial hyperreactivity.

The effects of sublingual estradiol on left ventricular function at rest and exercise in postmenopausal women: an echocardiographic assessment.

OBJECTIVE: To evaluate the acute hemodynamic effects of 4 mg estradiol given sublingually. DESIGN: Rest and exercise echocardiographies were performed prior to estradiol administration. Then, another set of tests was done post-dose: rest examination at 1 h post-dose, isometric exercise at 65 min post-dose, and dynamic exercise at 100 min post-dose. RESULTS: The administration of 4 mg sublingual estradiol to 24 postmenopausal women (aged 48-58 years) was followed 60 min post-dose by a surge in mean estradiol serum levels (1759 +/- 704 pg/ml). At rest a slight drop in systolic and diastolic blood pressure was measured after estrogen ingestion: 132 +/- 24 mm Hg versus 127 +/- 21 mm Hg, p < 0.05; 83 +/- 11 mm Hg versus 78 +/- 10 mm Hg, p < 0.02. There were no changes in resting heart rate, double product, or vascular resistance. The left heart cavities became smaller: the left atrium diameter decreased from 33.7 +/- 4 mm to 32.3 +/- 4 mm, p < 0.01; the end-systolic diameter decreased from 24.9 +/- 3 mm to 23.6 +/- 4 mm, p < 0.01; the end-diastolic diameter decreased from 44.5 +/- 4 mm to 42.7 +/- 4 mm, p < 0.01. The peak aortic blood flow velocity fell from 120 +/- 19 cm/s to 116 +/- 22 cm/s (p < 0.05), and the flow velocity integral fell from 26.3 +/- 4 cm to 24.9 +/- 5 cm (p < 0.01); the cardiac output underwent a small change, with borderline significance: 7 +/- 2 L/min versus 6.7 +/- 2 L/min, p = 0.06. Only minor changes in the hemodynamic and echocardiographic parameters were recorded after estrogen for both isometric and dynamic exercises. Analyses were also made for two subgroups: 13 normotensive women were compared with 11 hypertensive women. The post-estrogen decreases in resting blood pressure and in peak blood velocity were observed only in the hypertensive subjects, whereas the changes in heart dimensions and in flow velocity integral were the same in both subgroups. CONCLUSIONS: Sublingual estradiol was associated with acute hemodynamic alterations mainly at rest but also after exercise.

Exercise echocardiography in postmenopausal hormone users with mild systemic hypertension.

Rest and exercise echocardiography (at dynamic and isometric exercise) were performed in 30 postmenopausal women (aged 54 +/- 4 years) with borderline to mild hypertension. They were then divided into 2 groups: 17 women who started oral hormone replacement therapy (0.625 mg/day conjugated estrogens or 2 mg/day estradiol) and a control group of 13 nonusers. After 6 to 9 months, a second echocardiography was performed in 26 women (4 withdrew). There were only a few changes in values obtained in the 12 controls at the end of follow-up compared with baseline. Primarily, these changes included a slight decrease in systolic blood pressure at rest and on exercise. Several significant morphologic and hemodynamic alterations appeared in 14 hormone users. Left ventricular cavity dimensions and mass became smaller: mean end-diastolic diameter decreased from 45.9 +/- 3 mm at baseline to 44.4 +/- 3 mm at study termination (p = 0.007). The corresponding values for end-systolic diameter were 25.8 +/- 4 mm and 23.9 +/- 4 mm (p = 0.006); for left atrium diameter, it was 34.5 +/- 4 mm and 32.5 +/- 4 mm (p = 0.001); for left ventricular wall width, it was 19.9 +/- 2 mm and 19.3 +/- 2 mm (p = 0.02); for left ventricular mass, it was 197 +/- 28 g and 179 +/- 32 g (p = 0.006). The resting aortic blood flow velocity and acceleration increased: 119 +/- 18 cm/s before therapy versus 129 +/- 23 cm/s while on hormone substitution (p = 0.04), and 13.6 +/- 3 m/s2 versus 16.5 +/- 4 m/s2 (p = 0.008), respectively. Mean rest to peak exercise systolic blood pressure difference became smaller after hormones: 39 +/- 19 mm Hg versus 28 +/- 13 mm Hg (p = 0.03) during dynamic exercise, and 43 +/- 22 mm Hg versus 25 +/- 13 mm Hg (p = 0.004) during isometric exercise. The above data probably indicate that with hormone replacement therapy, there is an improvement in cardiac function both at rest and during exercise.

Ischemic stroke following an intramuscular injection of diclofenac. Case report.

Nonsteroidal antiinflammatory drugs (NSAIDs) have arterial vasospastic properties. The authors report a stroke that occurred within minutes following an intramuscular injection of diclofenac. A sixty-one-year-old man, a heavy smoker, was admitted for an acute onset of mild hemiparesis thirty minutes after a single intramuscular injection of diclofenac. The neurologic deficit was resolved at one month of follow-up. The authors suggest a temporal causal relationship between the cerebrovascular event and the injection of diclofenac. The mechanism of stroke might be related to a synergistic vasospastic property shared by the use of an NSAID and heavy smoking.

Role of nitric oxide (EDRF) in radiocontrast acute renal failure in rats.

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.

Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus.

OBJECTIVE: To determine the value of measurement of serum soluble tumor necrosis factor receptor (sTNFR), compared with established parameters such as anti-double-stranded DNA, in monitoring systemic lupus erythematosus (SLE) disease activity, and to determine whether serum sTNFR are bioactive and can effectively inhibit TNF bioactivity. METHODS: Fifty-three consecutive ambulatory or hospitalized SLE patients and 140 consecutive healthy subjects were enrolled in a prospective cohort study. Serum levels of sTNFR were measured by a unique 2-sided capture enzyme-linked immunosorbent assay using mouse monoclonal antibodies and rabbit antisera against the sTNFR. RESULTS: The mean +/- SD concentrations of both the p55 (type I) and p75 (type II) soluble receptors were significantly higher in a group of 46 SLE patients than in controls: 1.89 +/- 0.89 ng/ml versus 0.77 +/- 0.19 ng/ml and 7.25 +/- 3.89 ng/ml versus 3.02 +/- 0.57 ng/ml, respectively (P < 0.0001 for both). The incidence and the extent of the increase among the healthy subjects and these patients (as well as in 7 additional patients on whom sequential studies were performed) correlated with disease activity more than did the occurrence of serum anti-DNA antibodies (correlation coefficients with disease activity 0.81 and 0.85 for p55 and p75 sTNFR, respectively, and 0.51 for anti-DNA antibodies). The increase in sTNFR levels seems to reflect, largely, enhanced formation, and only to a minor extent, reduced clearance due to impairment of renal function. Sera of the SLE patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF, and this was shown to result entirely from their higher sTNFR receptor concentration. CONCLUSION: An increase in serum levels of sTNFR may become a useful marker for SLE activity since it shows a stronger correlation than do any other laboratory or clinical parameters employed presently in the daily clinical setting. At the concentrations attained in the serum of SLE patients, sTNFR effectively inhibit the bioactivity of TNF and may thus be a significant determinant of the intensity of the manifestations of SLE.

Anaerobic bacteremia: a retrospective four-year analysis in general medicine and cancer patients.

Anaerobic bacteremia was studied in 32 medical patients (mean age 72 years) in a four-year retrospective analysis. Malignancy was the most common underlying disease and probable portal of entry. The gastrointestinal tract was affected most often, followed by the respiratory and urinary tracts. Bacteremia occurred either following invasive (non surgical) procedures or spontaneously. The clinical course ranged from asymptomatic bacteremia, to mild febrile illness, to sepsis and septic shock (two, 12, 16 and two patients, respectively). The case fatality rate was 25%. The causative organisms were Clostridium and Bacteroides species. All organisms isolated were susceptible to chloramphenicol. Early diagnosis and prompt treatment may reduce mortality in cases of anaerobic sepsis.

Interleukin-6 inhibits the proliferation of B-chronic lymphocytic leukemia cells that is induced by tumor necrosis factor-alpha or -beta.

Tumor necrosis factor (TNF-alpha) acts as a growth stimulatory factor on leukemic B lymphocytes from many patients with chronic lymphocytic leukemia (CLL). Because TNF induces production of interleukin-6 (IL-6), which has been shown to be a growth factor for myeloma and other transformed B cells, we examined the possibility that IL-6 mediates the growth-stimulatory effect of TNF on B-CLL cells. In fact, we found that IL-6 is an inhibitor of B-CLL growth. The addition of recombinant human IL-6 markedly decreased the TNF-induced B-CLL growth, and this decrease was even greater when soluble IL-6 receptor, known to act as IL-6 agonist, was added with recombinant IL-6. Conversely, neutralizing monoclonal antibodies to IL-6 and to the IL-6 receptor potentiated the growth stimulation of TNF on B-CLL cells, in line with the possibility that IL-6 functions as a negative feedback regulator of an autocrine TNF action on these B-leukemic cells. Evidence is presented that production of IL-6 by monocytes and B cells of CLL patients is low, suggesting that administration of IL-6 may be beneficial in CLL to reduce the eventual growth stimulation by TNF and, possibly, also the deficiency in platelets and Ig production in this disease.

Onset of intolerance symptoms during exercise testing is a reproducible threshold for evaluation of cardiac function.

Twenty-one male patients with a history of myocardial infarction underwent bicycle cardiopulmonary exercise testing. The onset of leg pain or dyspnea, which reflects anaerobic metabolism, was termed anaerobic exercise symptom threshold (AEST). Our aims were (1) to evaluate the temporal relationship between AEST and the ventilatory anaerobic threshold (VAT) and (2) to determine whether heart rate, rate-pressure product, exercise time, and the ventilatory parameters at AEST are reproducible and correlate with the same parameters at VAT. AEST overlapped VAT in 4 patients and lagged behind VAT in 15. AEST never preceded VAT. The mean exercise time at VAT was 4.1 +/- 1.2 min and at AEST 5.6 +/- 1.6 min (p < 0.0001); the mean heart rate was 97 +/- 10 and 107 +/- 12, respectively (p < 0.001). The mean values of the rate-pressure product and the oxygen consumption at AEST were significantly higher than at VAT. The correlation coefficient ranged from r = 0.74 to r = 0.93. Fifteen patients were examined twice within 1 month; the above parameters were reproducible at AEST, VAT, and peak exercise. In conclusion, AEST, which is easily recorded during bicycle exercise testing, is useful as a reference point for evaluation and follow-up of the cardiac aerobic function.

Are tiny polyps important when found on sigmoidoscopy in asymptomatic people?

To determine the occurrence of synchronous large bowel polyps located proximal to the sigmoid, in persons undergoing screening flexible sigmoidoscopy, we examined those who had diminutive polyps (less than or equal to 0.5 cm) as the only finding in the distal colon by further colonoscopy. One hundred one asymptomatic persons (mean age 61 +/- 13 years) had 143 diminutive polyps; a single polyp was found in 76%, and 64% of all polyps were located in the rectum. Thirty (21%) were hyperplastic and 86 (60%) were neoplastic, including 14 with moderate and one with severe dysplasia. The others were inflammatory (five) or unclassified (hot biopsy changes or normal mucosa, 14 polyps), and eight were lost before processing. Colonoscopy revealed that 16 (16%) of the 101 patients had 21 additional polyps proximally, mostly less than 1 cm in diameter. These included one hyperplastic and 18 neoplastic polyps, and two specimens showed hot biopsy changes. Age, histological type, number or location of the index diminutive polyps, were not associated with proximal lesions. We question whether immediate colonoscopy is justified in asymptomatic patients with only diminutive polyps at flexible sigmoidoscopy.

Colonoscopy in patients aged 80 years or older and its contribution to the evaluation of rectal bleeding.

Colonoscopies performed in patients aged 80 years or older at the Sheba Medical Center were analysed according to the primary indication for the procedure: 101 colonoscopies were performed because of rectal bleeding of at least 2 months duration, and 335 for all other indications. Carcinoma of the large bowel was found in 29 (28.7%) bleeders, with the rectum being the most frequently involved site (12 patients). Among the non-bleeders, the prevalence of cancer was significantly lower (33 cases, 9.8%; P less than 0.001), and rectal carcinoma was less common (five patients, P = 0.04), but proximal tumours were more frequent. Of patients with cancer who had operations, the majority (72%) had a tumour confined to the bowel wall (Dukes A or B). The rate of adenomas was similar for both groups (34% vs 29%). The non-bleeders complained more frequently of abdominal pain or a change in bowel habits as compared to the bleeders, but both groups had similar rates for anaemia and weight loss. In all, 47% of these octogenarians with cancer, and 26% with adenomas were referred for colonoscopy because of rectal bleeding. This procedure was found to be safe in old age, as we recorded only four (0.9%) non-fatal complications among our series, a similar figure to the overall incidence of complications at our Institute. In conclusion, our data indicate that rectal bleeding in octogenarians warrants a complete colonic investigation, preferably by total colonoscopy.

Disseminated intravascular coagulation with renal and liver damage as the predominant manifestations of recurrent relapses in systemic juvenile rheumatoid arthritis.

Relapses of systemic juvenile rheumatoid arthritis associated with intravascular coagulation are rare. This paper describes a patient who, over a two year period, had two relapses, each accompanied by evidence of liver and renal damage and disseminated intravascular coagulation. The patient was not receiving non-steroidal anti-inflammatory drugs, and all laboratory and clinical manifestations of her disease rapidly resolved after treatment with prednisone. It is therefore believed that the hepatocellular damage, in addition to the disseminated intravascular coagulation, was a direct manifestation of disease activity. A possible pathogenic role for tumour necrosis factor is suggested.

Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients.

Soluble forms of the two molecular species of the cell surface receptors for tumor necrosis factor (TNF) have been detected in normal urine. Using enzyme-linked immunosorbent assays for these soluble receptors, we determined their levels in the sera of 40 healthy subjects and 59 patients with solid tumors. The mean +/- SD concentrations of both the soluble type I (p55) and type II (p75) receptors were significantly higher in the cancer patients than in the healthy controls: 1.96 +/- 1.19 versus 0.79 +/- 0.19 ng/ml (P less than 0.001) and 6.43 +/- 4.8 versus 3.2 +/- 0.6 ng/ml (P less than 0.001), respectively. The incidence and the extent of the increase correlated with the staging of disease. Sera of the cancer patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF. This inhibition was proportional to the content of soluble TNF receptors and could be fully abolished by the addition to the sera of specific antibodies against the receptors. Among the cancer patients, the incidence of increase in the concentrations of soluble TNF receptors (about 70%) greatly exceeded that of the serum carcinoembryonic antigen (about 26%), a commonly used cancer marker. The origin of the serum soluble TNF receptors in cancer patients and the physiological implications of their effect on TNF function remain to be elucidated.

Clustering of colorectal neoplasia: characteristics of coexisting adenomas in patients with severely dysplastic polyps or invasive (malignant) polyps as compared to patients with benign adenomas or carcinomas.

This study compared the size, histology and morphology of coexisting neoplastic polyps found in colonoscopy, and evaluated the clustering of these polyps in patients with either colorectal carcinoma, cancerous polyps or benign adenomas. Patients were divided by their most malignant form of neoplasia: Group A included 58 patients with early invasive cancerous polyps, and Group B included 73 patients with in situ carcinoma within an adenoma. Group C consisted of 335 patients with benign adenomas, and Group D had 289 patients with colorectal carcinoma. There were no significant differences between the four groups regarding sex, age and ethnicity. The cancerous polyps were significantly larger than the benign polyps. There were significantly (P less than 0.01) more patients with multiple (greater than or equal to 5) colonic lesions in Groups A or B than in Groups C or D. Coexisting polyps were much closer to the index growth, and demonstrated more severe dysplastic changes in the case of cancerous polyps than those associated with benign polyps or cancer. Based on our data we speculate that cancerous polyps are not merely a middle link in adenoma-carcinoma sequence, but rather mark a subset of patients who are especially prone to develop neoplastic changes in their colonic mucosa. These patients should be included in a more strict colonoscopic surveillance programme.

Budd-Chiari syndrome in Israel: predisposing factors, prognosis, and early identification of high-risk patients.

In twenty-seven patients with venography-documented Budd-Chiari syndrome (BCS), underlying diseases included polycythemia vera (nine patients), membranous occlusion of the inferior vena cava (three), and cirrhosis (two). In only nine patients did the syndrome occur in the absence of any predisposing factor. All patients with a membranous web were relatively young (mean age 29 years) and were born in Morocco. With regard to prognosis, three groups could be delineated. Eight patients formed a rapidly progressive group, with mean survival from first symptom of only 4.3 weeks, and were characterized mainly by their relatively advanced age and minimal enlargement of the spleen.