Elevated alpha-fetoprotein and a normal fetal sonogram: association with placental abnormalities

This report documents the outcome of 25 pregnancies with elevated serum alpha-fetoprotein levels on two separate samplings despite normal anatomic appearance of the fetus on a detailed "consultative" sonographic examination. Six of these also had elevated amniotic fluid alpha-fetoprotein. All fetuses in this series were anatomically normal at time of delivery; one aborted fetus was triploid. Of the 25 pregnancies, 16 had sonographically demonstrable placental hemorrhage, eight retroplacental and eight subchorionic. One had hydropic changes in the placenta associated with triploidy. Of the subgroup of six pregnancies in which both serum and amniotic fluid values were elevated, one had a retroplacental hemorrhage, one had a subchorionic hemorrhage, and one had diffuse hydropic changes in the placenta. A control group of 112 patients with normal alpha-fetoprotein levels yielded four with small (less than 2 cm3) subchorionic hemorrhage. The occurrence rate of placental hemorrhage in women with elevated alpha-fetoprotein and normal fetus was 64%, whereas the control group of patients with normal alpha-fetoprotein had a 3.6% occurrence rate of placental hemorrhage. Sonographically detectable placental abnormalities may be associated with elevated alpha-fetoprotein in serum and/or amniotic fluid samples. Such abnormalities may occur because of fetomaternal admixture associated with placental hemorrhage and/or intraamniotic bleeding resulting from subchorionic hemorrhage.     

The poor quality of early evaluations of magnetic resonance imaging

To study the quality of early research on the clinical efficacy of diagnostic imaging with magnetic resonance, we assessed 54 evaluations published in the first four years after introduction of this modality using ten commonly accepted criteria of research methodology. The terms sensitivity, specificity, false-positive or false-negative, accuracy, and predictive values were used infrequently. Nineteen percent of the evaluations used three terms appropriately, 48% used one or two terms, and 33% used none. Data were presented appropriately for one or more of the five terms in 59% of evaluations. A "gold standard" comparison with the results of an independent procedure, such as surgical or autopsy findings, was presented in 22% of evaluations. Results of another imaging procedure were described in 63% of evaluations. Only one evaluation clearly described a prospective study design, although 11 evaluations apparently were planned in advance. Not one evaluation contained an appropriate statistical analysis of the distributions of quantitative readings, "blinded" image readers to diagnosis or other test results, measured observer error, or randomized the order of magnetic resonance imaging and other imaging procedures. We conclude that health care professionals paying for expensive innovative diagnostic technology should demand better research on diagnostic efficacy.     

Natural killer cells and reproductive failure--theory, practice and prejudice

The relationship between peripheral blood natural killer (NK) cells and reproductive failure is one of the most controversial areas in reproductive medicine. Amidst much publicity, peripheral blood NK cell testing is being promoted as a useful diagnostic test to guide the initiation of a variety of immunosuppressive therapies amongst patients with either recurrent miscarriage or infertility. We contend (i) that at present there is no scientific basis for the introduction of NK cell testing into routine clinical practice, and (ii) that the use of immunosuppressant agents based on the results of such testing may potentially be harmful.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Protection and injury: the differing roles of complement in the development of glomerular injury

The role of complement in autoimmune glomerulonephritis (as in other autoimmune diseases) is paradoxical, in that complement activation mediates acute inflammatory injury, yet inherited deficiency of complement may predispose to immune complex disease in particular immune complex glomerulonephritis. We have investigated the role of complement in experimentally induced glomerulonephritis in C3-deficient mice, using antibodies against the mouse glomerular basement membrane (GBM). In the acute phase of the disease, which is initiated by binding of heterologous antibody to the GBM, we confirmed that the inflammatory injury was positively complement dependent, with C3-deficient mice developing less severe injury. In contrast, in the autologous phase of the disease, mediated by the immune response against the heterologous antibody fixed in the GBM, the disease was negatively complement dependent. That is, by 14 days after disease induction the C3-deficient mice had heavier proteinuria and more severe uremia (p < 0.001) compared to the complement sufficient mice. The C3-deficient mice also showed a greater accumulation of electron-dense deposits in the GBM. These findings were reproduced in an accelerated model of this disease in which C3-deficient mice also develop more severe functional disturbance and demonstrate a higher rate of immune complex deposition. These data illustrate the potential for the net effect of complement to switch from a detrimental to a protective mode at different stages of autoimmune injury.     

Effects of complement inhibition with soluble complement receptor-1 on vascular injury and inflammation during renal allograft rejection in the rat.

Complement is both an effector of the humoral immune response and a stimulator of leukocyte activation. To examine the influence of complement on the allograft response, we inhibited complement using recombinant human soluble complement receptor-1 (sCR1; TP10), in an unsensitized model of rat renal allograft rejection. Lewis to DA renal transplant recipients were treated daily with 25 mg/kg sCR1 or saline and sacrificed on days 1 to 5 after transplant. Transplanted organs were examined histologically and immunohistochemically for leukocyte subset markers and for the third component of complement, C3, and membrane attack complex deposition. A second set of recipients was followed from day 5 to day 9 to assess graft survival. sCR1-treated recipients displayed > 90% inhibition of plasma complement activity and a marked reduction in tissue C3 and membrane attack complex deposition. Inactivation of complement reduced the vascular injury such that there was almost complete sparing of vascular damage in day 5 sCR1-treated rats. There was a significant reduction in infiltrating leukocytes by day 5 after transplant, and complement inhibition delayed the time to reach a histologically defined end point of graft survival from 5 days in controls to 9 days in the sCR1-treated group. These results imply that the vascular and cell-mediated injury arises, in part, from complement activation. The partial inhibition of these injuries by sCR1 may have functional implications for strategies to inhibit allograft rejection.     

Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease

There is increasing evidence that immunological mechanisms play a role in the pathogenesis and pathophysiology of endometriosis. It was therefore of interest to study interleukin-8 (IL-8), a chemokine, in the peritoneal fluid and peripheral blood of women undergoing laparoscopic procedures. The presence and concentrations of IL-8 in relation to endometriosis, infertility and abdominal pain were evaluated. Samples of peritoneal fluid (n = 49) and peripheral blood (n = 50) were obtained from 50 consecutive patients undergoing laparoscopic surgery for various gynaecological indications (abdominal pain, infertility, sterilization). IL-8 was present in the peritoneal fluid of most women (87%). The concentration of IL-8 in the peritoneal fluid was higher in women with endometriosis compared to women without (P = 0.02). This difference was more pronounced in early (stage 1) endometriosis (P = 0.001). IL-8 concentrations in the peritoneal fluid were also higher in women with early endometriosis compared to women with later stages of the disease (P = 0.003). Peripheral blood concentrations did not correlate with peritoneal fluid concentrations of IL-8 and/or the presence of endometriosis. We conclude that IL-8 is an important factor that may contribute to the pathogenesis of endometriosis possibly by promoting neovascularization. This information can be a guide in the development of new therapeutic approaches for the treatment of endometriosis.