Inhibition of binding of bacteria to amniochorionic membranes by amniotic fluid.

The immunological composition of amniotic fluids is shown to be of such a lower order of activity that its role in fetal protection may be limited. Also, amniotic fluids were found not to have classical antibiotic activity. Amniotic fluids (25/31), however, were found to inhibit, by 27.5% to 88.2%, three target bacteria from binding to discs of amniochorionic membranes. This inhibition is also demonstrable with the monosaccharides alpha-D(+)-fucose, D(+)-galactose, alpha-D-glucose, alpha-D-lactose and bovine serum albumin-lactose conjugate, whereas other glycoconjugates enhanced bacterial binding. This demonstrates that the test bacteria bind to the amniochorionic membranes using bacterial lectins. In intraamniotic infection bacterial lectins may be complexed by amniotic fluid glycoconjugates which prevent the bacteria from binding to the amniochorionic membranes. This would explain asymptomatic infection and in the absence or reduced levels of the glycoconjugates the bacteria would bind to the amniochorionic membranes giving rise to symptomatic infection.

Immune response: tissue specific T-lymphocytes.

The lymphatic system forms a 'blind' plexus of vessels that in general are found in tissue which has an inherently high replicative capacity. It is this system that is responsible for the rapid deployment and circulation of tissue-specific T-lymphocytes for the inspection of cell-surface aberrations within the tissue. The presence of tissue-specific T-lymphocytes explains why 90% of lymphocytes are found outside the lymphatic system and why they migrate in a selective manner. The tissue-specific T-lymphocyte is considered to express a common lymphocyte cell surface pattern, the homotype, and a tissue-specific cell-surface pattern, the histotype which may involve MHCA and mHCA. It is the histotypic pattern that is responsible for the tissue specificity of the tissue-specific T-lymphocyte. The presence of tissue-specific T-lymphocytes does pose problems for the immune system. If different tissue-specific T-lymphocytes met within a particular tissue, 'lost' lymphocytes, an immune response will be generated against the intruder (lost lymphocyte), and the intruder will not be able to recruit other immunocompetent cells in that tissue. This immune reaction is an attempt to change the histotypic pattern of the intruder. This situation would explain the autologous immune response. This response however is suppressed in the systemic system by immunosuppressive compounds from the liver. It is only in the tissues that the tissue-specific T-lymphocytes are released from this suppression, in order to initiate immune reactions against aberrant cell-surface patterns.

Post-irradiation cytology of cervical cancer patients.

The accuracy of cervicovaginal cytology following radiotherapy for cervical cancer is compromised by the anatomical and tissue changes resulting from irradiation. Collection of representative samples may be more difficult, and benign radiation changes, post-irradiation dysplasia, and the frequent occurrence of repair cells and active stromal cells in post-irradiation smears may cause diagnostic problems. Nevertheless, cytology is a valuable tool for the detection of locally recurrent cervical cancer. It is simple and economical to perform at the time of clinical follow-up examination, and may detect occult tumour recurrence. Awareness of the cellular changes resulting from irradiation, and the varied composition of post-irradiation smears may lead to more accurate interpretation of the cytological findings.

Immunology of pregnancy: towards a unifying hypothesis.

The variable findings of hormonal-immunoregulation and the variable cellular and humoral immune responses in pregnancy have been considered in relationship to the physiological response. From such considerations it appears that the peripheral blood lymphocyte/leukocyte response in pregnancy is not important, but rather the local uterine immune response at implantation and throughout pregnancy. It is proposed, and evidence is presented, that a normal allogeneic immune response is initiated at the time of implantation of the blastocyst. This immune response regulates the invasive nature of the trophoblast and initiates the first stage of parturition. The initiation and maintenance of this immune response is based on an interplay between maternal and paternal HLA and trophoblast antigens. In the case of HLA-incompatible donor-recipient blastocyst transplants, a more pivotal role for immunoregulation by trophoblast antigens is proposed. This is because it is considered that the local uterine immune response suppresses the expression of allogeneic HLA. This concept is further developed in terms of haploid HLA suppression on maternal and fetal lymphocytes that cross the placenta. This is considered to allow the interaction of these lymphocytes with each other and explains maternal transfer of cell-mediated immunity.

Topical treatment of malignant and premalignant skin lesions by very low concentrations of a standard mixture (BEC) of solasodine glycosides.

A cream formulation containing high concentrations (10%) of a standard mixture of solasodine glycosides (BEC) has been shown to be effective in the treatment of malignant and benign human skin tumours. We now report that a preparation (Curaderm) which contains very low concentrations of BEC (0.005%) is effective in the treatment of keratoses, basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin of humans. In an open study, clinical and histological observations indicated that all lesions (56 keratoses, 39 BCCs and 29 SCCs) treated with Curaderm had regressed. A placebo formulation had no effect on a smaller number of treated lesions. Curaderm had no adverse effect on the liver, kidneys or haematopoietic system.

Immune response: self-foreignness.

The classical basic concept of the immune system as a defence system per se and immunological surveillance against neoplasia have never been satisfactorily verified experimentally. The reason for this lies in the historic development of immunology in terms of observations of infectious disease and the interpretation of those observations. Thus, based on a complete lack of understanding of immune events, immunization procedures were developed by Pasteur and his contemporaries. The success of some of these immunization methods, influenced by culture and philosophical thoughts, and based on prima facie evidence allowed the next conceptual step to be taken, culminating in the immune surveillance hypothesis. Central to this hypothesis is selection and tolerance to self-antigens. However, immune reactions to self-antigens are evident and clonal selection is not viable because the number of clones required increases as the frequency of chance of a cell belonging to a particular clone decreases. Also, circadian rhythms in the immune response have not been taken into account. In addition, the problems of haemocytopoiesis have not been addressed, in that it is possible for B-lymphocytes to become terminal macrophages and T-lymphocytes to become mast cells, eosinophils and/or basophils constituting 'dead end' cells in an immune response. The initiation of the immune response begins with a tissue-specific T-lymphocyte being stimulated and undergoes replication. This gives rise to a dual functional helper/suppressor cell and a B-lymphocyte. These basic concepts explain the necessity for auto-reactive lymphocytes, that is the autologous mixed lymphocyte reaction (AMR). The AMR is a natural consequence of having tissue-specific lymphocytes to monitor plasma membrane aberrations.

The accuracy of cervicovaginal cytology in the detection of recurrent cervical carcinoma following radiotherapy.

The accuracy of cervicovaginal cytology testing in the detection of recurrent cervical carcinoma was investigated by correlating clinical and histology records with cytology smear results for two groups of patients. All patients had been treated with radiotherapy, with or without pelvic surgery, for carcinoma of the uterine cervix. Abnormal cervicovaginal smear results were present for 45.7% (32/70) of patients with histologically diagnosed recurrent cervical carcinoma including a correct prediction of recurrent cervical carcinoma in 32.8% (23/70) of cases. A cytologic diagnosis of recurrent carcinoma was present for 48.9% (23/47) of cases with local recurrence. The positive predictive value for a histologic diagnosis of recurrent cervical carcinoma after a positive cytology report for a group of 61 patients was estimated to be 98.4%. A cytologic diagnosis of locally recurrent cervical carcinoma preceded clinical signs in 15/61 (24.6%) of cases. These results indicate that although cervicovaginal cytology after radiotherapy for cervical cancer does not have high sensitivity it is a reliable test for the diagnosis of local recurrence. Cytologic examination of the vaginal vault or cervix after treatment may thus provide an early diagnosis of tumor recurrence or persistence, in some cases prior to the onset of clinical signs.

Solasodine glycosides. Selective cytotoxicity for cancer cells and inhibition of cytotoxicity by rhamnose in mice with sarcoma 180.

BEC, a standard mixture of solasodine glycosides is effective in vivo against murine sarcoma 180 (S180), whereas the aglycone solasodine at equimolar concentrations is ineffective. The efficacy of BEC against S180 in vivo can be inhibited by rhamnose. Mice which are in their terminal stage with S180 can tolerate and become symptom-free of cancer by single dose administration of BEC at concentrations of BEC three times the LD100 for normal mice. These observations suggest that the binding of solasodine glycosides on tumour cells may be mediated through the monosaccharide rhamnose, which forms part of solasonine, solamargine and di-glycosides of solasodine in BEC. Furthermore, these results provide evidence that BEC selectively destroys tumour cells relative to normal cells in vivo.

Solasodine glycosides. In vitro preferential cytotoxicity for human cancer cells.

Solamargine [(22R,25R)-spiro-5-en-3 beta-yl-alpha-L-rhamnopyranosyl- (1----2glu)-O-alpha-L-rhamnopyranozyl (1----4glu)-beta-D-glucopyranoze], a glycoside of solasodine preferentially inhibits the uptake of tritiated thymidine by cancer cells. In contrast, solamargine at equivalent concentration, and the mono- and diglycosides of solasodine have a limited effect on the uptake of tritiated thymidine for other cell types, including unstimulated lymphocytes and lymphocytes stimulated with Con A. In contrast the solasodine glycosides do not inhibit the uptake of tritiated thymidine by lymphocytes stimulated with PHA or PWM. The inhibition of tritiated thymidine uptake by solamargine and the mono- and di-glycosides of solasodine are dependent upon their cellular uptake by endogenous endocytic lectins (EELs). The mode of action of the solasodine glycosides, in particular solamargine, appears to be the induction of cell lysis, as determined by morphological examination.

Seminal plasma biochemistry. III: Characterization of coagulum components.

Human seminal plasma components involved in coagulum formation have been isolated by liquefaction and reformation of the coagulum in acidic and neutral buffers, respectively. The SDS-PAGE profile of the isolated coagulum (recoagulum) is similar to that reported for the native coagulum immediately following liquefaction. Thus the recoagulum may be considered to represent the native coagulum. Electrophoresis of the recoagulum under non-denaturing conditions reveals the presence of both positively and negatively charged components. These components are sialoglycoproteins that bind copper. Based on these results, a possible mechanism for coagulum formation and liquefaction is discussed.

Seminal plasma biochemistry. IV: Enzymes involved in the liquefaction of human seminal plasma.

A significant positive correlation was found between the liquefaction time of human seminal coagula and bound sialic acid. There was also a similar relationship between bound sialic acid and the enzyme sialyl-transferase. This suggests that the degree of sialylation of the components of seminal coagulum are important in determining the liquefaction time of the coagulum. These results support previous findings. The coagulum is considered to be composed of glycoprotein-metal ion complexes, and the initial stage of liquefaction results from the reduction of these metal ions by L-ascorbic acid. The removal of hydrogen peroxide, generated by the oxidation of L-ascorbic acid, requires the presence of glutathione peroxidase and glutathione reductase. These enzymes have been identified in human seminal plasma and their possible physiological importance is discussed.

RISH. VI: General evolutionary aspects of the immune system.

Both the prokaryotic and eukaryotic cells are considered to have arisen from a common progenitor cell. The plasma membrane of the prokaryotic cell became specialized to carry out functions that the eukaryotic cell delegated to cellular organelles. Thus the plasma membrane of the eukaryotic cell remained flexible to evolutionary influences. Thus, provided the structural integrity of the plasma membrane was maintained, alterations within this infrastructure could be tolerated. This gave rise to basic speciation at the cellular level. Such differences in the plasma membrane of these primitive eukaryotic cells were of no importance until the dawn of sexual reproduction, then only like-cells could associate to exchange genetic information. Thus in the protozoa cell-surface, antigens are demonstrable in mating, whereas alloincompatability is intracellular. With the evolution of the Metazoa, in order for like-cells to identify each other, alloincompatability changed from intracellular expression to become expressed on the plasma membrane. Like-cell identification was derived and evolved from the basic feeding mechanism of primitive eukaryotic cells, which involved the induction of lectins that were expressed at the cell-surface. These lectins were induced by the RNA that was complementary to, and complexed with cell surface components of the organisms upon which the eukaryotic cells fed. This RNA was also inserted along with the lectin in the eukaryotic cell plasma membrane, and acted as a template for DNA synthesis. This DNA was then incorporated into the genome of the eukaryotic cell and it became an inheritable characteristic. Thus these lectins could be expressed intracellularly as well as on the plasma membrane. The intracellular expression of these inheritable lectins may have constituted intracellular-alloincompatibility, as well as being used for feeding by agglutination of the organism on the plasma membrane of the eukaryotic cell. With the development of colony formation and the true metazoa, the cell-surface lectins became incorporated into cell-surface components for the identification of like-cells. This represents, in part, the histocompatability antigens of the organisms. At the same time, the lectins were also being increasingly used for the regulation of differentiation, and for what we would classify as immunological reactions.(ABSTRACT TRUNCATED AT 400 WORDS)

RISH. VII: Cell surface patterns--association of like cells.

Like-cells associate to form various tissues, and it has been demonstrated that this specificity resides in the plasma membrane. Membrane bound tissue specific antigens and enzyme substrate mechanisms have been considered to be involved in this phenomena, but these explanations are incomplete. It is proposed that like-cells identify each other by specific complementary cell-surface patterns. This complementarity results from cell division. That is, when cells divide, they give rise to a mirror image of themselves. These complementary patterns are the result of the association of histocompatibility antigens (HCA) with non-histocompatability components in the plasma membrane. This proposal is based on topographic conjecture in that four colours are sufficient for colouring all maps drawn on a plane or sphere so that regions that share a common boundary are of a different colour. It is further proposed that these specific cell-surface patterns can be classified as four overlapping regions: (i) homotypic--which is generally species specific, (ii) allotypic--which is variable within a species, (iii) idiotypic--which represents variation within an individual or family group, and (iv) embryotypic--which identifies the embryonic origin of the tissue.

The Pap smear revisited.

Papanicolaou smear screening for cervical cancer has become an established practice in most developed countries. This is because the cervix is relatively accessible to investigation and treatment, and early stages in the morphogenesis of cervical cancer are both recognizable and easily treated. The Pap smear is a valid test. It is simple, relatively inexpensive, reliable, and free of risk. Although the test has far from perfect sensitivity, it has high specificity, and false-positive results are rare. In most reported series, the majority of false-negative results have been found to be attributable to collection errors rather than laboratory errors. Despite the importance of Pap smear screening, controlled prospective trials have not been undertaken to determine its efficiency in reducing cervical cancer incidence and mortality. However, countries with well-organized programmes, wide population coverage and correct follow-up appear to have had some impact on mortality from cervical cancer. Nevertheless, coverage of high-risk groups, particularly women over 40 years of age, remains the greatest problem. Recommendations on the frequency of testing vary considerably. Statistical models indicate triennial testing may deliver almost all of the effectiveness of annual testing at a substantially reduced cost, but the numerous reports of false-negative results argue strongly in favour of annual screening. It is possible that these problems may be solved in the future by increasing the sensitivity of the test and/or by the use of additional tests.

N-acetylneuraminic acid and hostile mucus infertility.

A total of 39 samples of hostile mucus, as defined by postcoital examination, were examined for N-acetylneuraminic acid (NANA) deficiency, as measured by the enzymatic addition of NANA, spermatozoal penetration and immobilization. Only 56.7% of the mucus samples were deficient in NANA and this did not correlate with spermatozoal penetration or immobilization, which were negatively correlated. Thus, as the spermatozoal hostility in the mucus decreases, spermatozoal penetration increases. This finding also applies to hostile mucus not deficient in NANA. In contrast, resialylation of NANA hostile mucus, deficient and not deficient in NANA, although not enhancing spermatozoal penetration, did reduce spermatozoal immobilization. Thus, components of the mucus deficient in NANA and/or the lack of unbound NANA may contribute to mucus hostility, but it is not the only hostile factor. In addition, SEM studies of NANA-deficient mucin before and after resialylation were shown to have similar structures. Hence ultrastructural changes are not apparent in NANA-deficient mucin, and this supports the previous finding that NANA deficiency does not impede spermatozoal penetration. The spermatozoa from the husbands of the infertile couples formed three distinct groups in terms of spermatozoal penetration and immobilization in normal donor mucus. One group demonstrated normal levels of spermatozoal penetration and immobilization in donor mucus. A second group was demonstrable in which spermatozoal penetration was similar to that in the wife's hostile mucus, but had a normal level of spermatozoal immobilization. In the third group, both spermatozoal penetration and immobilization in donor mucus were similar to that in the wife's hostile mucus. The results demonstrate that not all hostile mucus is deficient in NANA, and that other unknown factors are involved. In addition, there are also male factors which may impede spermatozoal penetration and/or result in the inability of the spermatozoa to survive in normal donor mucus.

The packing of spheres in embryogenesis and carcinogenesis.

Fertilization of the mammalian ova results in the formation of a compact ball of cells, the morula, which then transforms into a hollow sphere of cells, the blastula. The formation of these structures is considered to be dependent on the number and shape of the cells present and approximates to the problem of maximal sphere packing. Similarly, the shape of organs, to some degree, is considered to be dependent upon the shape of the constituent cells which predetermines their maximal packing densities. Implicit in this concept is that like-cells divide until they reach their maximal packing density and are then inhibited from further replication by three dimensional contact inhibition. In this context, tumour cells may be considered as pleomorphic relative to the tissue in which they arise and form a benign tumour, whereas malignant tumours display pleomorphism within the tumour mass.

Ovarian tumor antigens: preliminary histological investigation.

The immunoglobulin IgG was isolated from the immune complexes obtained from the ascitic fluids of patients with ovarian serous cystadenocarcinoma. The IgG isolates did not react in immunoperoxidase staining of normal ovarian, fallopian tube, or endocervical tissue. In contrast, the IgG isolates did react in immunoperoxidase staining of autologous and allogeneic ovarian cancer tissue. However, the staining was variable in terms of areas of positivity and was completely absent in some serial sections. This variability was also evident in control sections of an ovarian mucinous cystadenocarcinoma that was positive for the carcinoembryonic antigen. In addition, it appears that serous and mucinous ovarian cancers may share common antigenic determinants. These results demonstrate the antigenic heterogenous nature of ovarian cancer.