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Antenatal phenotype associated with PAK2 pathogenic variants: bilateral pleural effusion as a warning sign.

Fetal pleural effusions can arise in various contexts with different prognosis. They have been reported in fetuses presenting with hereditary or acquired conditions. One particularly rare genetic disorder, known as Knobloch syndrome, seems to emerge as a potential new cause of fetal pleural effusions, associated with severe outcomes. Knobloch syndrome 1 can be caused by biallelic variants in COL18A1. It is primarily characterized by its ophthalmic features, including severe vitreoretinal degeneration with retinal detachment and macular abnormalities. Neurological defects such as encephalocele and developmental delay, along with skeletal and renal malformations, are also associated with the syndrome. The Knobloch syndrome 2 is caused by monoallelic variants in the kinase domain of PAK2. It is less described and seems to also be associated with cardiac and respiratory damage in addition to the Knobloch syndrome 1 phenotype. PAK2 is a ubiquitous protein with a major implication in regulation and remodeling of the cytoskeleton and numerous other cellular pathways. Knobloch-associated variants seem to cause a loss of the kinase function of the protein. Even if the ophthalmic defects are almost constant, PAK2-associated Knobloch syndrome has slightly different features from Knobloch syndrome 1 in which pulmonary and lymphatic damages are still unseen. In a prenatal trio exome sequencing, we identified a novel de novo PAK2 missense variant, NM_002577.4:c.836 A > C, p.(Gln279Pro), classified as likely pathogenic in a 24 weeks of gestation fetus whose only sign was severe bilateral pleural effusion. From a literature review of patients, we recognize this sign as an important antenatal indicator of Knobloch syndrome 2, as it was the first sign identifiable in 2 out of 5 patients. This adds new evidence for the implication of this gene in fetal pleural effusions, with potentially severe outcomes.

Female

The immune response at the tumor site in lung carcinoma.

The local immune response to lung cancer was investigated by histologic and immunologic means. Distinctive patterns of stromal cellular reaction, characteristic for different histologic types of lung carcinoma, were recognized. The amount of cellular infiltration was highest in squamous cell carcinomas and lowest or nonexistent in oat cell carcinomas. Within the various histologic categories the well-differentiated tumors appeared to be accompanied by more reactive cells than the poorly differentiated ones; there was no relation between tumor necrosis and cellular infiltration. The plasma cells were distinctly associated with squamous cell carcinomas; their number in the stroma was proportionate to the degree of differentiation and the presence of keratin produced by the tumors. Eluates with a high content of immunoglobulins were recovered from pleural effusions and from solid lung carcinomas by dissociation of antigen-antibody complexes. These preparations reacted positively in indirect immunofluorescence tests with tissue cultures and with fresh suspensions of lung carcinoma cells, but not with tissue culture cells of most nonpulmonary tumors or with cell suspensions of normal adult and fetal lung. Similarly prepared fractions of noncarcinomatous pleural effusions did not react with lung cancer cells.

Adenocarcinoma

Characterization of human breast milk macrophages cytostatic for human cell lines.

Approximately 40% of the cells in human early lactation milk possessed the characteristics of macrophages, being adherent, phagocytic, alpha napthyl acetate esterase positive, and possessing C3b and Fc receptors. These cells were also cytostatic for MDA 157, a cell line derived from a pleural effusion of human breast cancer, and HEL 23, a strain of human fetal lung fibroblasts. Investigations into the cytostatic phenomenon indicated that the cytostasis could not be mediated by macrophage-conditioned medium and that very close contact between breast milk macrophages and target cells was required. Cytostasis was not fully effective until 18 hr after the initial interaction between macrophages and target cells.

Breast

The ultrasonic demonstration of fetal abnormalities in utero.

The demonstration of fetal diseases and anomalies in utero can now be performed with a high degree of accuracy with modern ultrasonic equipment. This paper describes the more common and important fetal anomalies which can be demonstrated by ultrasound and indicates the importance of meticulous attention to technique and the significance of the acquistion of skill in real-time sonography by the physician-sonologist. The thoroughness of all obstetric sonographic examinations is emphasized to enable detection of unsuspected fetal anomalies. Specific methods to demonstrate these anomalies in the high-risk patient are also described. Several pitfalls in the diagnosis of fetal disease in utero are included which show the nonspecificity of some of the ultrasonic signs.

Abdominal Muscles

Multiple serous effusions complicating pre-eclampsia. A case report.

A patient with multiple serous effusions and the nephrotic syndrome complicating the middle trimester of pregnancy is described. Rapid resolution of the effusions after delivery and exclusion of other causes of serous effusions and nephrosis make pre-eclamptic toxaemia the most likely cause. Anasarca can be a feature of this disease and there are a few reports of patients in whom clinical ascites has occurred. Our patient was exceptional in that pleural and synovial effusions into the knee joints were also present.

Adult

Establishment of cultured cell lines derived from a human gastric carcinoma.

A human gastric carcinoma cell line, KATO-II, and its subline, KATO-III, have been established in vitro from a pleural effusion of a 55-year-old male patient. Kato-II cells have been maintained using a culture medium containing human cord serum and KATO-III cells have been cultured with a medium containing fetal bovine serum. Both cell lines are morphologically quite similar; they grow in vitro floating free and have cytological features of signet ring cells. Population doubling times for KATO-II and KATO-III were 74 hours and 36 hours, repsectively. The modal chromosomal numbers of these cell lines fell in a tetraploid range. Heterotransplantation of KATO-II and KATO-III cells was successfully done in the cheek pouches of antithymocyte serum-treated hamsters. Microscopical appearance of the resultant tumors was consistent with poorly-differentiated adenocarcinoma comparable to the original tumor.

Adenocarcinoma, Mucinous

Oncofetal antigens. Increasing the specificity of the CEA radioimmunoassay.

The biologic and clinical significance of the oncofetal antigens carcinoembryonic antigen (CEA) and alpha1-fetoprotein (AFP) are discussed. Although the current assays for these molecules are not tumor-specific, measurement of these molecules in the circulation of cancer patients is useful either for tumor diagnosis or for management of the cancer patient in the postoperative or post-chemotherapy state. An approach to increasing the specificity of the CEA radioimmunoassay is described.

Amniotic Fluid

Lung carcinoma-reactive antibodies isolated from tumor tissues and pleural effusions of lung cancer patients.

Low pH elution techniques were used on lung cancer tissues and pleural effusions of lung cancer patients to dissociate antigen-antibody complexes. The immunoglobulins obtained were assayed by indirect immunofluorescence against tissue cultures and fresh cell suspensions of various target cells; they reacted positively, in significant titers, with cells of squamous cell carcinomas and adenocarcinomas of the lung but not with cells of normal adult and fetal lung or of nonpulmonary tumors. Immunoglobulins, similarly dissociated from tumor effusions of other organs, showed no reactivity in indirect immunofluorescence tests against lung carcinoma cells.

Adenocarcinoma

Isolation of two human tumor epithelial cell lines from solid breast carcinomas.

Most of the available human breast tumor cell lines have been derived from pleural effusions. The two cell lines herein described, BT-474 and BT-483, were derived from solid, invasive ductal breast carcinomas. Both are epithelial and neoplastic as judged by their general morphology, their fine structure, and their ability to produce growing nodules in nude mice and colonies in soft agar and methocel. BT-474 and BT-483 are human as expressed by chromosome morphology and aneuploid with a modal number of 55 and 72 chromosomes, respectively. Trypsin-Giemsa banding did not reveal the presence of obvious HeLa markers, and the glucose 6-phosphate dehydrogenase electrophoretic migration pattern was of the B-type. Furthermore, the migration of lactic dehydrogenase, malic dehydrogenase, and 6-phosphogluconate dehydrogenase isoenzymes was consistent with a human pattern and different from that of the mouse, rat, or hamster. Quarterly tests to detect the presence of aerobic and anaerobic mycoplasmas were repeatedly negative. A culture medium containing insulin, increased amounts of amino acids, vitamins, and glucose facilitated the isolation of the tumor cells. Cell replication was maintained with 10% fetal calf serum absorbed with activated charcoal and dextran. No production of alpha-lactalbumin was detected by radioimmunoassays, but high levels of progesterone receptors were found in both cell lines.

Animals

[Radiological examination of the thorax and abdomen in new-born babies with Rhesus incompatibility (author's transl)].

The results of radiological examination of the thorax and abdomen were studied in premature babies with Rhesus incompatibility. In the 53 cases where Rhesus incompatibility was the only abnormal finding, various measurements were made on the radiological images: cardiothoracic index, liver and spleen, distances between the digestive tract loops and the thoracic wall. The same measurements were made in two groups of premature babies, born at the same period of gestation, who acted as controls. The most frequently observed thoracic abnormality was interstitial edema with hypervascularization (50% of the moderate forms) which was present in 14 of the 18 severe cases. Total opacity of both lung fields was noted with the same frequency in the severe forms with anasarca as in the moderate forms without clinical edema. The cardiothoracic index was increased in 40% of the moderate cases and in all severe cases (normal values for premature babies of 30 to 36 weeks: 0.48 +/- 0.04). Pleural effusions were present in 20% of the moderate, and 6 out of 18 severe cases. Abdominal organ measurements in the two control groups were as follows: --premature babies (34 to 36 weeks): --liver: 47 mm +/- 5.3, --spleen: 11.5 mm +/- 2.1, --distance between loops and wall: 7.1 mm +/- 1.4. --premature babies (30 to 33 weeks): --liver: 41 mm +/- 4.7, --spleen: 10.4 mm +/- 3.4, --distance between loops and wall: 6.4 mm +/- 1.2. The babies with Rhesus incompatibility had hepatosplenomegaly which was constant in all severe cases but present in only 70% of moderate cases, an increased distance between the digestive loops and the thoracic wall in all severe forms, and in 15% of moderate forms without clinical ascites. Normal radiological images developed after about 5 days for thoracic signs, and between 7 and 10 days for abdominal signs. Complete recovery occurred in all cases, even severe, except one case, where Rhesus incompatibility was the only abnormality. In 22 cases, Rhesus incompatibility was associated with another disorder: in 12 cases a hyaline membrane was present which radically changed the prognosis (8 deaths secondary to this infection out of a total of 12 deaths). Apart from the study of the Rhesus abnormality, a systematic examination of the size of the liver and the spleen, and measurements of the distances between digestive tract loops and thoracic wall in the first thoraco-abdominal radiological image in a premature baby, can be of diagnostic value for intraperitoneal infections and eflusions of the new-born.

Erythroblastosis, Fetal