Major life event stress and dyspepsia of unknown cause: a case control study

Stress is purported to be a major cause of non-ulcer dyspepsia, defined here as dyspepsia where peptic ulcer, oesophagitis, and cancer are excluded by endoscopy. There is a subgroup of non-ulcer dyspepsia patients who have no definite cause for their dyspepsia, provisionally termed essential dyspepsia. The aim of the present study was to determine if stress, as measured by major life events, was associated with essential dyspepsia. The frequency of life events during the year before the diagnosis of essential dyspepsia in 68 consecutive patients was compared with the frequency of these events over the same time period in 68 randomly selected age and sex-matched community controls. The mean number of events and the associated life change and distress scores were similar for both groups. Concerning individual events, patients reported more minor personal illness (p = 0.008). When events were broadly categorised, only one difference was found - more controls reported bereavements (p = 0.008). Age, sex, social class, and the duration of dyspepsia did not influence the number and nature of events. Although the study suggests that stress, as measured by major life events, is not associated with dyspepsia of unknown cause, it does not exclude the fact that other forms of stress, especially that associated with chronic difficulties, may be relevant.     

Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction

A significant proportion of hemophilia A patients receiving transfusions of factor VIII (FVIII) develop a specific antibody response towards FVIII. These antibodies are usually detected by assays in which they inhibit the function of the molecule, such as the Bethesda clotting test. We have prepared anti-FVIII antibodies by specific immunoadsorption from the plasma of four hemophiliacs with stable inhibitor levels. The isotypic distribution of such antibodies was determined and their capacity to bind to insolubilized FVIII was compared with their inhibitory activity in two functional assays, namely, the Bethesda assay and a chromogenic assay. In addition, the FVIII epitope specificity was determined by competition with monoclonal antibodies for the binding to insolubilized FVIII. We show here that (1) anti-FVIII antibodies are not isotypically restricted; thus, a significant proportion of specific IgG2 was found; (2) antibodies are frequently directed towards epitopes of FVIII that are not directly involved in the function of the molecule and therefore escape detection in the Bethesda method or chromogenic assay; and (3) each patient shows a unique pattern of FVIII epitope recognition. We conclude that evaluation of anti-FVIII antibodies by a functional method does not provide an accurate evaluation of the specific antibody response. These findings have important implications for the comparison of the immunogenicity of FVIII molecules produced by different technologies and for the development of methods to control anti-FVIII antibody production.     

Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene

Fanconi anemia (FA) is a genetically heterogeneous, inherited blood disorder characterized by bone marrow failure, congenital malformations, and a predisposition to leukemias. Because FA cells are hypersensitive to DNA cross-linking agents and have chromosomal instability, FA has been viewed as a disorder of DNA repair. However, the exact cellular defect in FA cells has not been identified. Sequence analysis of the gene defective in group C patients (FAC) has shown no significant homologies to other known genes. The FAC protein has been localized to the cytoplasm, indicating that FAC may either play an indirect role in DNA repair or is involved in a different cellular pathway. Recent evidence has indicated that FA cells may be predisposed to apoptosis, especially after treatment with DNA cross-linking agents. The demonstration that genes can suppress apoptosis has been accomplished by overexpression of such genes in growth factor-dependent cell lines that die by apoptosis after factor withdrawal. Using retroviral-mediated gene transfer, we present evidence that expression of FAC in the hematopoietic factor-dependent progenitor cell lines 32D and MO7e can suppress apoptosis induced by growth factor withdrawal. Flow cytometry and morphologic analysis of propidium iodide stained cells showed significantly lower levels of apoptosis in FAC-retroviral transduced cells after growth factor deprivation. Expression of FAC in both cell lines promoted increased viability rather than proliferation, which is consistent with other apoptosis-inhibiting genes such as Bcl- 2. These findings imply that FAC may act as a mediator of an apoptotic pathway initiated by growth factor withdrawal. Furthermore, the congenital malformations and hematologic abnormalities characterizing FA may be related to an increased predisposition of FA progenitor cells to undergo apoptosis, particularly in the absence of extracellular signals.     

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.     

Clonal dysregulation of the antibody response to tetanus-toxoid after bone marrow transplantation

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell- depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B- cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.     

Factors influencing mortality from bleeding peptic ulcers

The mortality, causes of death, and the factors that are influencing deaths from bleeding acute and chronic peptic ulcers were evaluated retrospectively. During a 2-year period (1986-87) 272 patients were endoscoped for acute gastrointestinal hemorrhage and were found to have bled from a peptic ulcer (chronic gastric ulcers, 90; chronic duodenal ulcers, 114; acute gastroduodenal ulcers, 66; stomal ulcers, 2). The overall mortality was 9.6% (n = 26) (gastric ulcers, 6.7%; duodenal ulcers, 11.4%; acute ulcers, 10.6%). Statistically significant factors adversely affecting prognosis for gastric ulcer were re-bleeding, need for operation and serious intercurrent illness; for duodenal ulcer were units of transfused blood, re-bleeding, signs of recent hemorrhage at endoscopy, need for operation, and serious intercurrent illness; and for acute ulcer were increasing age, shock, units of transfused blood, re-bleeding, and serious intercurrent illness. Multivariate analysis was only attempted for duodenal ulcers because of sample sizes; it suggested that active bleeding or visible vessel at endoscopy, re-bleeding, and serious intercurrent illness were independent factors for mortality. From this study it is apparent that the major determinants of a fatal outcome in bleeding peptic ulcer diseases were serious intercurrent illness and rebleeding. As it must be anticipated that patients with these particular problems are at high risk of a poor outcome, it follows that it is important they have access to skilled treatment as provided by a specialist team in an intensive care ward. It also follows that every effort should be made to keep ulcers in remission to free the ulcer patient of potentially lethal complications.     

Assessing the delivery of neutrophils to tissues in neutropenia

Studies of neutrophil kinetics in neutropenic individuals, as well as clinical observations of variability in the occurrence of infection among patients with neutropenia, have suggested that blood neutrophil counts may not uniformly reflect the effective delivery of neutrophils to extravascular tissues where the cells perform their principal host defense functions. To evaluate this possibility we developed a sensitive, reproducible method of measuring the extravascular delivery of neutrophils to a normal mucosal site of neutrophil turnover. This method is based upon the quantification of neutrophils recoverable from saline mouth wash specimens. Twenty-five mL specimens, obtained in a controlled manner from neutropenic patients and normal subjects, were centrifuged and the sediments resuspended in 1.0 mL Hank's buffer with 2 micrograms acridine orange, incubated at 37 degrees C for 15 minutes, and then examined in a hemocytometer chamber by fluorescence microscopy. Neutrophils could be clearly distinguished by their characteristic fluorescence and were counted. With this method as few as 1,500 neutrophils were detected reliably in mouth wash specimens. Mucosal neutrophil counts varied less than 10% with repeated sampling of individual subjects over 5-day periods and were consistently greater than 1.3 X 10(5)/specimen in non-neutropenic individuals. Although profound neutropenia was generally reflected by lower than normal oral mucosal neutrophil counts, these counts were significantly higher in individuals with chronic severe neutropenia (blood neutrophils less than 300/mm3) than in patients with acute neutropenia of comparable severity that had developed following chemotherapy. Also, in individuals recovering from profound neutropenia, neutrophils usually reappeared earlier in mouth wash specimens than in blood, and oral mucosal neutrophil counts attained recovery levels more rapidly than did blood counts. This phenomenon was particularly evident in an individual with cyclic neutropenia. Moreover, mucosal neutrophils could occasionally be detected in profoundly neutropenic patients when neutrophils were not present in blood samples. These findings indicate that mucosal neutrophil counts in individuals with neutropenia provide information about the delivery of neutrophils to tissues that may not be apparent from blood neutrophil counts alone.     

Acceptability of a Dapivirine/Placebo Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-026)

AIDS and Behavior - This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand)...     

Ventilatory function in chronic peptic ulcer. A controlled study of ventilatory function in patients with gastric and duodenal ulcer

The aim of this study was to determine if a defect in ventilatory function is present in patients with chronic peptic ulcer and if so, is it present in both gastric and duodenal ulcer and is it related to smoking. Fifty-six patients with peptic ulceration (27 gastric ulcer, 29 duodenal ulcer), together with 56 healthy controls matched for age, sex, and smoking status, were studied. Ventilatory function was measured and the ABH blood group antigen secretor status was determined. Vital capacity and forced expiratory volume in 1 s were significantly reduced in both smokers and nonsmokers with gastric ulcer when compared with controls; total lung capacity was lower than controls only in smokers with gastric ulcer. In duodenal ulcer patients, a trend similar to that observed in gastric ulcer patients was present. It is concluded that a defect in ventilatory function is present in patients with chronic gastric ulcer; a lesser defect is present in patients with duodenal ulcer.     

Release of adenosine and cyclic AMP from coronary endothelium in isolated guinea pig hearts: relation to coronary flow

The coronary efflux of radioactive 3',5'-cyclic adenosine monophosphate (cAMP) and adenosine from isolated guinea pig hearts was measured following selective prelabelling of coronary endothelial adenine nucleotides with 10 nM [2,8,5'-3H] adenosine. Intracoronary infusion of adenosine and its derivatives 5'-N-ethyl-carboxamide-adenosine (NECA), (-)-N6-(R-phenyl-isopropyl)-adenosine (R-PIA), and (+)-N6-(S-phenyl-isopropyl)-adenosine (S-PIA) caused dose-dependent parallel increases in both coronary flow and the coronary efflux of radioactive cAMP with a rank order of potency: NECA greater than R-PIA greater than adenosine greater than S-PIA. In contrast, adenosine receptor stimulation of isolated cardiomyocytes in primary culture decreased the cellular release of cAMP below control levels with a rank order of potency: R-PIA greater than NECA. Under control conditions, coronary efflux of adenosine and cAMP was 34.3 +/- 2.3 and 3.9 +/- 0.8 pmol/min (mean +/- SEM, n = 6), respectively. NECA (12 microM) caused an increase in cardiac cAMP release of 3.8 times and elevated the specific radioactivity of cAMP 5 times to 63.7 +/- 6.0 Ci/mol, a value 11 times greater than the specific radioactivity of tissue ATP. Based on these findings, it was concluded that the coronary endothelium possesses adenosine A2 receptors linked to adenylate cyclase, which are activated in parallel with increases in coronary flow and that cardiomyocyte adenosine receptors are predominantly of the A1 subtype. In addition, the contribution of the coronary endothelium to total cardiac adenosine release was calculated to be 14% using the specific radioactivities of adenosine and cAMP released into the effluent perfusate.