B-lymphocytes activation by the Fc region of IgG.

Strong stimulation of DNA synthesis (up to 150-fold) and blast transformation can be induced in mouse spleen cells by Fc fragments of human IgG. The mitogenic response is optimal on day 5 of culture and is dependent on the concentration of Fc fragments with a sedimentation rate of 3-5S. Intact IgG is also stimulatory, but only when modified by heat aggregation, and produces only a 10-fold increase in [3H]thymidine uptake. The stimulation by aggregated IgG is dependent on the Fc portion, since aggregated (or soluble) Fab or F(ab')2 fragments are inactive. The results show that the response is T-cell independent and that it is a function of nylon wool adherent, surface Ig-positive, Fc receptor-bearing B lymphocytes. Fc fragments do not induce plaque-forming cells to human IgG in normal mouse spleen cell cultures, but rather trigger polyclonal antibody synthesis (anti-goat erythrocytes, anti-2,4,6-trinitrophenyl). It is postulated that the Fc region of antibodies plays a role in the regulation of the humoral immune response by triggering clonal expansion of B lymphocytes.

Echocardiographic evidence of left ventricular bands in infants and children.

M-mode and two-dimensional echocardiographic studies were carried out on 100 consecutive neonates, infants and children to evaluate the incidence of left ventricular chordae or bands. These fibromuscular structures were noted in 61 subjects and were seen to traverse both the long and short axes of the left ventricle. Although a single left ventricular band was usually noted, several subjects had multiple bands. These bands were seen in normal subjects and in patients with a wide variety of congenital cardiac lesions. Distortion of left ventricular geometry was noted in one subject. Identification of these linear echoes is essential to allow differentiation of left ventricular bands from true anatomic left ventricular outflow tract obstruction or septal thickening.

Rare type of intrapulmonary drainage of one lung by the other with total anomalous pulmonary venous return.

A rare form of obstructed total anomalous pulmonary venous drainage is presented. A neonate with asplenia, pulmonary atresia and complex congenital heart disease also had drainage of the left lung forming a venous confluence that proceeded in an intrapulmonary fashion through the right lung. A hypoplastic pulmonary venous channel then emerged from the right upper lobe leading to the superior vena cava. Pulmonary venous obstruction was suspected on initial plain chest X-ray examination and on angiography, which revealed the pulmonary artery to be larger than anticipated. Administration of prostaglandin E1 may allow augmentation of pulmonary blood flow and angiographic definition of this association in infants with asplenia complex.

Modulation of IL-1 alpha, IL-1 beta, and 25K Mr non-IL-1 activity released by human mononuclear cells.

To determine if the release of IL-1 alpha and IL-1 beta by cultured PBMC could be independently modulated by different exogenous stimuli, we examined the effect of LPS, IFN gamma, latex beads, and indomethacin on the release of IL-1 alpha and IL-1 beta. PBMC culture supernatants were fractionated by Sephacryl-S-200 column chromatography or HPLC (TSK G3000SW), and each fraction was tested for thymocyte mitogenic activity in the presence or absence of preincubation with anti-IL-1 alpha or anti IL-1 beta monoclonal antibody (mAb) and for the presence of IL-1 alpha or IL-1 beta protein by ELISA. In all experiments, thymocyte mitogenic activity not neutralizable by anti-IL-1 alpha or anti-IL-1 beta mAb was detected in the 25K Mr range, which ranged from 12 to 50% of the total thymocyte mitogenic activity released, depending on the stimuli. Cultured PBMC from 95% of individuals release thymocyte mitogenic activity in the absence of exogenous stimuli, which was increased 1.3-to 7-fold by lopopolysaccharide (LPS) (25-50 micrograms/ml). All of this increased activity was due to increased release of IL-1 beta and non-IL-1 thymocyte mitogenic activity, with no change in the total amount of IL-1 alpha released. Indomethacin (0.1 microgram/ml) induced release of increased thymocyte mitogenic activity of 1.3- to 1.4-fold over unstimulated cultures. All of this increased activity was due to increased release of IL-1 alpha and non-IL-1 activity with a concomitant decrease in IL-1 beta release. Interferon gamma (40-100 U/ml) increased the amount of IL-1 alpha and decreased IL-1 beta and non-IL-1 activity released, resulting in no overall change in the total amount of thymocyte mitogenic activity. Molecular weight fractionation of the PBMC culture supernatants revealed that thymocyte mitogenic activity eluting in the 25K Mr range was not due to IL-1 alpha or IL-1 beta. With certain culture conditions, thymocyte mitogenic activity was detected in the 30-40K Mr range. PBMC cultured with LPS and latex beads in the absence of serum released 30-40K Mr IL-1 alpha, as well as 17K Mr IL-1 alpha and 17K Mr IL-1 beta. PBMC cultured in 2% fetal calf serum (FCS) alone from some donors released only 30-40K Mr thymocyte mitogenic activity. Both IL-1 alpha and IL-1 beta protein was detected by ELISA in this Mr range but only the IL-1 alpha was bioactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Red cell cotransport activity and sodium content in black men. Relationship to essential hypertension.

Furosemide-sensitive sodium and potassium cotransport and intracellular sodium content ([Na]i) were measured in erythrocytes (red blood cells, RBCs) from a population of 90 adult black men with and without essential hypertension (EH). The mean values for sodium cotransport activity, expressed as furosemide-sensitive Na efflux (mmol/liter RBC/hr), were not significantly different among the EH patients and two control groups, normotensive subjects with a positive history (N+) and those with a negative family history (N-) for hypertensive disease (EH: 154 +/- 123, n = 53; N+: 167 +/- 93, n = 12; and N-: 207 +/- 142, n = 20; all values are means +/- SD). The mean [Na]i 9.66 +/- 3.02 mmol/liter RBC (n = 56) for the EH group was greater than the mean value for the N- control group (7.96 +/- 1.97, n = 20; p less than 0.05). The N+ group also displayed a higher mean [Na]i (10.38 +/- 3.18, n = 12; N+ vs N- p less than 0.01). Although there was substantial overlapping of [Na]i values between the groups and no clear dividing line, the distribution curve of the [Na]i values in EH was skewed toward higher concentrations than in N-. Nevertheless, we must conclude that erythrocyte cotransport and [Na]i are not clinically useful in the identification of EH in black men.

Red blood cell Na+,K+-ATPase in men with newly diagnosed or previously treated essential hypertension.

Alterations of cellular function of Na+,K+-adenosine triphosphatase (ATPase; Na+-K+ pump) have been implicated in the pathophysiology of essential hypertension. Therefore, this aspect of red blood cell (RBC) Na metabolism was studied in black men with newly diagnosed, untreated essential hypertension (NEH) and a normotensive control group. RBC Na content, Na+-K+ pump number (ouabain binding sites), and pump activity were measured. No statistically significant differences were found between the two groups for any of these three parameters. However, a group of previously treated essential hypertensive subjects (PEH) who had been withdrawn from therapy in the preceding 6 weeks were also studied. This group differed significantly from the NEH subjects in regard to all RBC Na+-K+ pump parameters. Their RBC Na content (10.27 +/- 3.23 vs 7.77 +/- 2.52 mmol Na/LRBC; p = 0.006) was higher, and their Na+-K+ pump activity (166 +/- 50 vs 221 +/- 87 nmol inorganic phosphate/mg membrane protein/hr; p = 0.03) and Na+-K+ pump number (213 +/- 40 vs 284 +/- 85 binding sites/RBC; p = 0.001) were lower compared with those in NEH subjects. Although the PEH subjects were older and somewhat less hypertensive than their NEH counterparts, these factors were not found to influence the Na+-K+ pump parameters. These results indicate that chronic diuretic therapy of patients with essential hypertension is associated with a reduced number of RBC Na+-K+ pumps. Since RBCs are not considered target cells for diuretics, the effects of these drugs on RBC electrolyte metabolism may occur at the time of erythropoiesis by the production of RBCs with fewer Na+-K+ pumps.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-1 and a 7-kDa T-cell inhibitory monokine reflect disease activity in infection with HIV-1.

Previous studies demonstrated that cultured peripheral blood mononuclear cells (PBMC) from patients with AIDS produce high levels of interleukin 1 (IL-1) and a 7-kDa T-cell inhibitory monokine (TCIM). To determine if the increase in the production of these cytokines corresponded with disease activity, we studied the production of IL-1 and TCIM by PBMC from patients with different stages of human immunodeficiency virus (HIV) infection. Eight patients with asymptomatic seropositive infection, three patients with AIDS-related complex (ARC), three patients with persistent generalized lymphadenopathy (PGL), and six patients meeting the full criteria for diagnosis of AIDS were studied. Patients with AIDS produced increased amounts of TCIM (4.1 times control values, p less than 0.003) and IL-1 (2.0 times control values, p less than 0.05). In contrast, asymptomatic seropositive patients produced less TCIM (0.36 times control values, p less than 0.004) and IL-1 (0.61 times control values, p less than 0.05). Different trends in the levels of these factors produced by patients with ARC and PGL were noted, although results were not statistically significant in general. Patients with ARC tended to produce less IL-1 (0.42 times control values, p less than 0.05), whereas patients with PGL tended to produce increased amounts of IL-1 (1.7 times control values, NS). ARC patients produced a wide range of TCIM values (0.05-2.8 times control values, NS), and patients with PGL tended to produce increased TCIM values, (4.0 times control values, p less than 0.02). No correlations between the levels of IL-1 or TCIM and T-cell subpopulation numbers (CD4 or CD8) or CD4/CD8 ratios were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of T cells with proliferating cells in lymphoid follicles.

Frozen sections of lymph nodes from normal mice were examined by immunofluorescence with anti-T lymphocyte and anti-Ig reagents and by autoradiography following [3H]TdR administration. The scattered T lymphocytes present among B lymphocytes of primary follicles were found to be mostly nonproliferating; the few proliferating cells in primary follicles are therefore predominantly B lymphocytes. More than one-half (56%) of these proliferating B lymphocytes were found to be in direct contact with a T lymphocyte; this incidence is 5-fold higher than that expected by random association. In germinal centers, virtually all proliferating cells were found to be non-T lymphocytes as well. The association of proliferating B cells with T cells may be the result of specific cooperation between these two cell types. These data are discussed in the context of what is known of T/B collaboration and of primary follicles as a possible site of this interaction.

Astrocytes express functional chemokine receptors.

Multiple lines of evidence are presented characterizing the functional expression of chemokine receptors CXCR4, CCR1, CCR5, and CX3CR1 on astrocytes. Most of these receptors are expressed at low levels and may only be detectable on a subset of cells during disease or following cytokine induction. The expression of CXCR2, CCR2, CCR3, CCR10, CCR11, and several orphan receptors associated with HIV-1 infection has also been proposed. The appearance of several chemokine receptors implies a wider role for chemokines in the regulation of central nervous system functions. Available evidence indicates that selected chemokines induce further chemokine synthesis in astrocytes providing a mechanism to amplify inflammatory responses in the central nervous system.

Modulation of experimental autoimmune encephalomyelitis: effect of altered peptide ligand on chemokine and chemokine receptor expression.

Experimental autoimmune encephalomyelitis (EAE) is a T helper 1 (Th1) cell mediated demyelinating disease and the principal animal model for multiple sclerosis. Spinal cords from SJL mice primed with proteolipid protein peptide 139-151 (pPLP) expressed the chemokines RANTES, MCP-1, MIP-2, KC, MIP-1alpha, MIP-1beta, Mig, and fractalkine. We also identified IP-10 in these samples and described a sequence polymorphism in this transcript. Chemokine expression was specific for tissues of the central nervous system. MCP-1, IP-10, and MIP-2 RNA expression significantly correlated with clinical score. Chemokine receptor expression generally correlated with ligand expression. pPLP-primed mice expressed the Th1-associated markers CCR5 and CXCR3 on mononuclear cells. In addition, cells expressing CCR1, CCR2, CCR3, CCR4, CCR8, and CXCR2 were detected. Here we demonstrate that altered peptide ligand (APL)-induced protection from EAE was accompanied by modulation of chemokine and chemokine receptor expression. Spinal cord tissue sections from APL-protected mice showed greatly reduced levels of all chemokines and of CCR1, CCR5, CCR8, CXCR2 and CXCR3. The Th2-associated chemokine receptors CCR3 and CCR4 were found in protected mice, supporting the hypothesis that Th1 but not Th2 cells are down-regulated by APL treatment. This report concludes that chemokines and chemokine receptors can be useful tools to follow modulation of autoimmune disease.

Postnatal development of obstruction in coarctation of the aorta: role of the ductus arteriosus.

The sequence of events leading to the development of acute obstruction in two infants with coarctation has been defined by clinical, hemodynamic, and angiographic studies. One infant had normally related great arteries and an isolated coarctation, while the other infant had transposition with a hypoplastic right ventricle, a ventricular septal deffect, narrowing of the aortic isthmus, and a localized site of coarctation. In each instance, a posterior aortic shelf--the basic pathologic lesion in coarctation--could be observed angiographically. Signs of aortic obstruction were absent, however, as long as the ductus arteriosus was widely patent. Following ductal obliteration, femoral pulsations diminished, a peak systolic pressure difference was recorded between the ascending and descending aorta, and a discrete area of juxtaductal coarctation was seen. The basic malformation (posterior aortic curtain) would appear to exist in utero, possibly as an aortic branch point. This lesion is nonobstructive as long as blood can traverse the aortic isthmus through the aortic end of the ductus into the descending aorta. Postnatally, as the ductus arteriosus undergoes constriction at its aortic insertion, signs of acute aortic obstruction may b =ecome apparent. Normal femoral arterial pulsations during the newborn examination do not definitively exclude coarctation. Pediatricians should recheck at 2 weeks of age if the infant is asymptomatic or sooner if there are signs of cardiac failure to establish the presence or absence of this defect.

Effects of acutely increasing systemic vascular resistance on oxygen tension in tetralogy of Fallot.

Effects of phenylephrine hydrochloride on the degree of hypoxia were studied in six cyanotic patients with tetralogy of Fallot. Baseline aortic and right atrial oxygen saturations, blood gas tensions, pH, and indicator-dilution curves were obtained under stable conditions. Phenylephrine was infused while systemic arterial pressure was monitored continuously. Aortic and right atrial blood samples were measured at each 10 mm Hg systolic pressure increment and decrement and analyzed for pH, PO2, PCO2, and oxygen saturation. A 40 mm Hg peak systolic aortic pressure rise was the arbitrary end point for phenylephrine infusion and the indicator-dilution curve repeated. Aortic oxygen tensions rose in all from 4 to 28 mm Hg (mean, 14 mm Hg). The net right-to-left shunt decreased from 10% to 40% (mean, 25%) with phenylephrine infusion as compared to the shunt under basal conditions. The presumed mechanism related to the increase in systemic vascular resistance relative to right ventricular outflow obstruction with resultant augmentation of pulmonary blood flow. It is concluded that acutely raising systemic vascular resistance in patients with tetralogy of Fallot using phenylephrine infusion has a beneficial effect on systemic arterial oxygen level and might be the medical treatment of choice for protracted hypoxic spells.

Echocardiographic assessment of the severity of aortic stenosis in children and adolescents.

The magnitude of ventricular hypertrophy in response to afterloading is determined by wall stress, with wall thickness increasing in proportion to ventricular load until systolic wall stress is normalized. With use of echocardiographic measurements of left ventricular end-systolic wall thickness (Ws) and cavity transverse dimension (Ds), the pressure constant k was calculated in 16 patients without left heart obstruction according to the formula k = P-Ds/Ws. The mean value for k was 225 +/- 6.7 (standard deviation) mm Hg. From this value, left ventricular pressure was estimated in 13 patients with aortic stenosis aged 4 to 17 years using the formula P = k-Ws/Ds. No subject had evidence of cardiac failure. Peak systolic aortic pressure difference (delta P) was calculated by subtracting cuff-measured brachial arterial peak systolic pressure from the estimated left ventricular pressure. Excellent correlation was obtained between the estimated delta P and that found at cardiac catheterization (r = 0.89). In two patients, echocardiographic data predicted significant obstruction in the presence of normal electrocardiographic, vectorcardiographic and vector lead tracings. Echocardiography offers a noninvasive method for estimating the severity of aortic stenosis, in the absence of myocardial failure; it appears to be more sensitive than other currently employed techniques.

HIV type 1 induction of interleukin 1 and 6 production by human thymic cells.

In vitro and in vivo studies have demonstrated that HIV can infect thymocytes at different maturational stages and lead to changes in the thymic microenvironment. To determine the effect of HIV on thymic stromal cells and the production of cytokines important in thymocyte development, three types of adherent thymic cultures were established and studied: thymic epithelial cells (TECs), macrophage-enriched, and mixed cultures of macrophages and TECs (M phi/TEC). Cultures were exposed to HIV-1 strains HIV-1IIIB and HIV-1Ba-L, and studied from day 2 to day 26 for the presence of infection, cytopathology, and cytokine (IL-1 alpha, IL-1 beta, and IL-6) production. M phi/TEC and macrophage-enriched cultures were infected by both HIV strains without cytopathic changes. The TECs grew well in culture for at least 6 weeks and showed no evidence of infection, cytopathology, or changes in cytokine production with HIV. Only cultures containing macrophages (M phi/TEC or macrophage enriched) showed changes in cytokine production with HIV. Sustained production of IL-1 alpha was seen for up to 20 days, with small or no increases in IL-1 beta. M phi/TEC cultures produced high constitutive levels of IL-6 that were not changed by HIV. Unstimulated macrophage-enriched cultures produced small amounts of IL-6 that were increased by HIV 20-fold. This study suggests that HIV infection in vivo can lead to infection of thymic macrophages resulting in cytokine abnormalities and a constant source for HIV to infect maturing thymocytes. These cytokine effects could lead to abnormal maturation and contribute to the lack of regeneration of the mature CD4+ T cell pool.

HIV-1 infection of macrophages promotes long-term survival and sustained release of interleukins 1 alpha and 6.

HIV infection of macrophages in vivo may result in activation of monokine genes and cause persistent release of immunomodulatory and inflammatory cytokines. Studies that have examined cytokine (IL-1, IL-6, and TNF-alpha) activation by in vitro infection of normal peripheral blood mononuclear cells (PBMCs) with HIV-1 have produced conflicting results. The present study shows that for monokine induction by HIV-1-IIIB preparations derived from the H9 tumor cell line, partial purification of virus particles is essential. Infectious HIV-1 induces the release of high levels of IL-1 alpha, IL-1 beta, and IL-6 bioactivity by adherent PBMCs in the first 3 days following in vitro infection, but only IL-1 alpha and IL-6 continue to be released over several weeks of culture. High levels of bioactive IL-1 beta were released only up to 72 hr following infection, although intracellular IL-1 beta was detectable for at least 3 weeks. No TNF-alpha bioactivity or immunoreactive protein was detectable at > 48 hr in HIV-infected cultures. This time course of monokine release was dependent on the number of infectious particles added to PBMC cultures. In long-term cultures (> 1 month) HIV infection was found to promote the viability of macrophages. The finding of sustained release of IL-1 alpha and IL-6 by infected macrophages, without additional stimulation, suggests that these mediators are released by HIV-1-infected macrophages in AIDS patients, where they may interfere with proper immune regulation.

Fibrolamellar carcinoma of the liver: an immunohistochemical study of nineteen cases and a review of the literature.

Hepatocellular carcinoma (HCC) is a rapidly fatal neoplasm of high worldwide prevalence. Fibromellar carcinoma (FLC), a variant of HCC, lacks the dismal prognosis of "ordinary" HCC (O-HCC) and is characterized by a diagnostic histologic appearance. The current study analyzes the clinical characteristics, immunohistochemistry, and treatment of nineteen cases of FLC. These data, together with a detailed review of the literature, further characterize this unique variant. FLC affects younger patients and lacks the male predominance of O-HCC. Also, FLC lacks specific association with cirrhosis, hepatitis B virus infection, use of oral contraceptives, and alcohol abuse, all of which are implicated in other hepatic tumors. This, along with differences in serum tumor marker prevalence (AFP, B12 binding protein) suggests that its pathogenesis differs from that of O-HCC. Despite these differences, FLC shares a common differentiation with O-HCC. The increased amounts in FLC of stainable alpha-1-antitrypsin, fibrinogen, and C-reactive protein, all of which are acute phase reactants and normal hepatocyte products, implies better differentiation of FLC cells. Finally, the better prognosis of FLC is supported by this study, since only two of the 19 patients died because of tumor. This contrasts with the reported survival of patients with O-HCC, usually measured in weeks. Hepatic transplantation may hold promise for future patients with "surgically unresectable" FLC as procedure-related complications are overcome.

Current status of the surgical treatment of truncus arteriosus.

Persistent truncus asteriosus is now correctable surgically in patients with favorable anatomy. Given pulmonary arteries of reasonable size arising from any source, successful correction is possible so long as irreversible pulmonary vascular disease has not occurred. Although the majority of children with this defect demonstrate increased pulmonary blood flow, systemic-pulmonary artery shunts can be used. Also, banding of the pulmonary artery, followed subsequently by successful total correction, has been described. Recent reports of a few successful total corrections in infancy, performed with the aid of deep hypothermia and circulatory arrest, may modify the current approach. Although the majority of the reported corrections have involved aortic homograft reconstruction of the pulmonary artery, we strongly favor a synthetic prosthesis containing a heterograft valve. Based upon our clinical experience and this review of the literature, a suggested management protocol is presented.

d-Transposition of the great arteries and atresia of the mitral and pulmonary valves: association with a normal anatomic left ventricle.

The clinical, angiographic, and pathologic features are presented for a case of d-transposition of the great arteries with atresia of the mitral and pulmonary valves and two well-developed ventricles. The morphologic left ventricle appeared to be functioning as a systemic ventricular aneurysm, and this may have led to the patient's death. A possible explanation for this anomaly is given.

Subclavian flap repair of coarctation of the aorta in neonates. Realization of growth potential?

The subclavian flap repair for coarctation of the aorta allows potential for growth by utilizing autogenous tissue. Although well documented in young children, its promise in the tiny neonate warrants further evaluation. Since August, 1979, 29 patients, including 24 infants, have undergone subclavian flap repair at the University of Maryland Hospital. Weights ranged from 1.4 to 5 kg (mean 3.2 kg). All patients less than 6 months old had associated intracardiac defects and were in severe congestive failure. Fifteen responded to preoperative prostaglandin infusions. The overall early mortality was 14%; among the neonates it was 21%; and among those operated upon within the first week of life, 33%. There was one intraoperative death among the eight patients who underwent simultaneous pulmonary artery banding. There were no deaths among patients older than 5 days at operation. Four of the five neonates who died had some variant of hypoplastic left heart syndrome, with severe stenosis or atresia of the systemic atrioventricular valve, critical aortic stenosis, or hypoplastic left ventricle. Twenty-two survivors continue to do well up to 3.7 years postoperatively (mean follow-up 26 months). At follow-up all patients are normotensive with brisk lower extremity pulses. Patients now weigh 1.3 to 6.9 (mean 2.3) times their operative weight, and only one patient has a measured arm-to-leg gradient greater than 10 mm Hg (mean gradient 3.7 mm Hg). Seven of the neonates have undergone repeat catheterization, and all had satisfactory growth of the subclavian flap segment of repair and no gradient. Two older patients (3 and 4 years old at operation) have undergone exercise testing 3.7 years after repair, with peak exercise gradients of only 7 and 15 mm Hg. We therefore continue to utilize this technique for the treatment of coarctation even in tiny neonates.

Cor triatriatum: masked by complex congenital cardiac anomalies.

The radiographic, angiographic, hemodynamic, and surgical features of 2 cases of cor triatriatum complicated by other cardiac anomalies are presented. In the first case, the patient had tetralogy of Fallot, the scimitar syndrome, and left ventricular obstruction. In the second case the patient had truncus arteriosus. The first case was revealed only after augmentation of pulmonary flow by an aorta-pulmonary artery anastomosis. In the second case, the diagnosis was retrospectively suggested by certain angiographic and hemodynamic clues. The prospective diagnosis was made only after a modified Rastelli procedure for truncus arteriosus. The difficulties encountered in making the diagnosis in both cases are discussed. It is stressed that a high index of suspicion, thorough accumulation and examination of hemodynamic data, and excellent angiograms and plain film radiography are all necessary to an early diagnosis of cor triatriatum when the latter is complicated by other congenital heart anomalies.