Sudden sensorineural hearing loss: when ophthalmology meets otolaryngology.

OBJECTIVES: Sudden sensorineural hearing loss is a perplexing entity in otology. Susac's syndrome (also called retinocochleocerebral vasculopathy) is a rare disorder that consists of microangiopathy of the brain, retina, and inner ear, and usually affects women in young adulthood. We describe the clinical aspects, radiographic findings, and management of one such case. CASE REPORT: A 30-year-old woman was admitted to the hospital because of sudden onset of bilateral deafness and headache. During her hospitalization, she developed discrete right hemiparesis and hypoesthesia. RESULTS: Magnetic resonance imaging revealed multiple signal hyperintensities and atrophy of the corpus callosum. The differential diagnosis was a myelinating condition, such as multiple sclerosis or acute demyelinating encephalomyelitis. CONCLUSION: Retinal fluorescein angiography helped the diagnosis of Susac's syndrome.

Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis.

Postmenopausal osteoporosis is a progressive disorder characterized by a decreased bone mass and increased susceptibility to fractures. Several investigations have suggested that one of the mechanisms through which estrogen prevents bone loss was a modulation on secretion or release of various cytokines that are known to influence bone remodeling, even if some recent data have challenged this hypothesis. However, in established osteoporosis, the possibility that enhanced cytokines activity may account for the progression of this disease remains unclear and controversial. We sought here to determine whether production of IL-1 beta, IL-6, TNF-alpha, IFN-gamma, GM-CSF and LIF, after direct stimulation in whole blood, was different in healthy (n = 30) or osteoporotic postmenopausal women (n = 24) and whether lumbar bone density (1-BMD) correlated with the values of cytokine production observed in these conditions. A significant difference was observed between the osteoporotic and control subjects for IL-1 beta (p < 0.0001), IL-6 (p < 0.001) and TNF-alpha (p = 0.027) productions, the values being higher in the osteoporotic women. No significant differences between the groups were observed for IFN-gamma (p = 0.51), GM-CSF (p = 0.70) or LIF (p = 0.97). In the whole population, statistically significant negative correlations were observed between lumbar BMD and IL-1 beta (r = -0.46) (p < 0.0005), IL-6 (r = -0.50) (p < 0.0001) and TNF-alpha (r = -0.39) (p < 0.005) production while no such correlations were observed for IFN-gamma, GM-CSF or LIF. In conclusion, the study of cytokine production by immune cells cultured in autologous whole blood suggests that in women more than 10 years past the menopause and presenting a decrease in lumbar bone density corresponding to the new WHO definition of "osteoporosis', production of IL-1 beta, IL-6 and TNF-alpha is still increased compared to controls matched for age and ovarian function, while no differences are reported for IFN-gamma, GM-CSF or LIF production.

Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood: II. Application to rheumatoid arthritis and osteoarthritis.

Rheumatoid arthritis (RA) is an immune disease in which the pathological immune reaction is thought to be initiated by the presentation of an (auto) antigen or superantigen by MHC class II positive cells to CD4 T cells. These successive immunological events can be studied by the cytokines produced at the different stages. Cytokine secretion by stimulated cells in autologous diluted whole blood has allowed the study of the immune profile characteristic of rheumatoid arthritis. The pattern of RA patient whole blood cells cultured in autologous blood is characterized by hyperactivity of the mononuclear cells with high secretion of IL-1 beta, TNF-alpha and IL-6 and low production of IFN-gamma, in comparison with the normal (N) and osteoarthrosis (OA) populations. The IL-2 secretion pattern is unique, arising from production followed by consumption. This production-consumption turnover is the most elevated in the RA group. The T cells are indeed activated in rheumatoid arthritis but regulatory events suppress some of their functions. A correlation was found between the inflammatory proteins and mediators of cellular immunity and macrophagic function: IL-1 beta and the sedimentation rate; IL-6 and fibrinogen; TNF-alpha and the number of blood monocytes. The secretion of OA-stimulated whole blood cells was similar to RA for two monokines (overproduction of TNF-alpha and IL-6) and different for IL-1 beta, not different from normal in OA. Stimulated whole blood cell cytokine secretion profile from RA and OA groups, was the same as previously observed in synovial fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation.

Production of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), interferon gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) after stimulation by lipopolysaccharide (LPS) and phytohemagglutinin (PHA) was studied in 1/10 diluted whole blood (WB) culture and in peripheral blood mononuclear cell (PBMC) culture. Cytokines IL-1 beta, TNF-alpha and IL-6 are preferentially stimulated by LPS whereas IL-2, IFN-gamma and GM-CSF are stimulated by PHA. Combination of 5 micrograms/ml PHA and 25 micrograms/ml LPS gave the most reliable production of the six cytokines studied. IL-1 beta, TNF-alpha and IL-6 represent a homogeneous group of early-produced cytokines positively correlated among themselves and with the number of monocytes in the culture (LeuM3). Furthermore, IL-1 beta was negatively correlated with the number of T8 lymphocytes. IL-2, IFN-gamma and GM-CSF represent a group of late-produced cytokines. Kinetics and production levels of IL-6 and GM-CSF are similar in WB and PBMC cultures. In contrast, production levels of TNF-alpha and IFN-gamma are higher in WB than in PBMC whereas production levels of IL-6 and IL-2 are lower in WB than in PBMC. Individual variation in responses to PHA + LPS was always higher in PBMC cultures than in WB cultures. The capacity of cytokine production in relation to the number of mononuclear cells is higher in WB, or in PBMC having the same mononuclear cell concentration as WB, than in conventional cultures of concentrated PBMC (10(6)/ml). Because it mimics the natural environment, diluted WB culture may be the most appropriate milieu in which to study cytokine production in vitro.

Neurophysins as markers of vasopressin and oxytocin release. A study in carcinoma of the lung.

Vasopressin-neurophysin (hNpI), oxytocin-neurophysin (hNpII) and blood osmolality were assayed before any treatment in basal conditions in 35 patients suffering from lung carcinoma (20 oat cell, 6 undifferentiated and 9 well-differentiated epidermoid cell carcinomas). Plasma vasopressin (antidiuretic hormone, ADH) was also assayed in 7 of the 20 patients suffering from oat cell carcinoma. We found a close correlation (r = 0.98) between plasma ADH and hNpI levels in the 7 patients. Further, hNpI was elevated in 13 out of the 20 oat cell carcinoma patients and in none of the epidermoid-cell carcinoma group; however, searching for an abnormality of ADH secretion as reflected by a detectable plasma hNpI level together with subnormal plasma osmolality revealed 2 additional positive results in the oat cell carcinoma group, and 2 out of the 6 in the undifferentiated-cell carcinoma group. hNpII was increased together with an increase in hNpI in 6 oat cell carcinoma patients; it was specifically increased without hNpI increment in 2 additional oat cell carcinoma patients and in 2 patients of the undifferentiated-cell carcinoma group (different from the 2 positive for the hNpI-osmolality ratio). hNpI and hNpII were normal in the majority of undifferentiated and all of the differentiated epidermoid-cell carcinoma group. Hence, our results show that simultaneous measurements of hNpI, hNpII, and blood osmolality could detect abnormalities in 17 out of 20 oat cell carcinoma patients, in 4 of the 9 undifferentiated-cell carcinoma patients, but in none of the differentiated epidermoid-cell carcinoma patients, suggesting that the neurophysin assay can be used for the early detection of oat cell- and possibly other neuroendocrine-derived carcinomas.

Pattern of Lyme arthritis in Europe: report of 14 cases.

Fourteen cases of Lyme arthritis are reported. The most frequent picture was that of oligoarthritis appearing in that part of the leg where the cutaneous or neurological complications, or both, of Lyme disease had developed before the arthritis. In most cases recovery followed a single 10 day course of intravenous (IV) penicillin therapy. Arthritis was the presenting feature of Lyme disease in three cases.

Breast cyst fluid proteins and breast cancer.

A specific breast cyst fluid protein was purified by the following steps: ultracentrifugation, gel filtration, DEAE and Con A chromatography, and gel filtration with guanidine, 6 M. The protein was pure, having a molecular weight of 17,800 daltons on SDS-PAGE and 68,000 daltons on gel filtration. The GCDFP 17,800 is immunologically distinct from other breast cyst fluid components and known milk and plasma proteins. A specific radioimmunoassay was developed and used to determine GCDFP 17,800 in 158 samples of breast cancer cytosol. The GCDFP 17,800 levels were significantly different between grade I tumors (mean of 813 ng protein per mg +/- 430 SEM) and grade III tumors (mean 184 ng protein per mg +/- 59 SEM) and were correlated with progesterone receptor values in postmenopausal women (Spearman's correlation, p = 0.03) but not in premenopausal women. The value of GCDFP 17,800 did not differ between the pre- and the postmenopausal women. By immunocytochemistry the intracellular localization of the GCDFP 17,800 was also found in relation to tumor grading and in correlation with PR values. GCDFP 17,800 appears as a hormone-induced protein of the breast cells. Its intracellular detection by means of radiolabeling allows a more sensitive and precise evaluation of the hormone-dependence of the breast cancer cells and emphasizes the heterogeneity of the tumor cell population.

Validation of radioimmunoassay for human lactalbumin in the serum by testing the endogenous antibodies interference.

For re-establishing the value of human lactalbumin as a functional marker of normal and pathological activity of the breast a sensitive and specific radioimmunoassay was established with the prior important control of the interference of endogenous antibodies. The specificity of the assay was assessed by the absence of interference from other proteins in milk or in breast cyst fluid, various hormones and tumor markers. Bovine lactalbumin showed incomplete and weak cross-reactivity. By an enzymoimmunoassay method it was shown that all the 222 human sera studied contain IgG immunoglobulins which bind bovine and human lactalbumin with greater reactivity of children's serum and without relationship to the blood groups. The maximum affinity constant of these endogenous immunoglobulins determined by the radioimmunoassay method is 4.5 times greater for bovine (Kd = 18 X 4(-11) M) than for human (Kd = 4 X 10(-11) M) lactalbumin. These endogenous anti-lactalbumin immunoglobulins caused no interference in the radioimmunoassay as shown by the complete correlation between the concentrations of human lactalbumin previously incubated and added to sera containing high-affinity antibodies and those measured directly in the radioimmunoassay. This lack of interference was explained by the higher (22-fold) affinity constant of the rabbit antiserum against human lactalbumin (Kd = 9 X 10(-12) M). The study of endogenous antibodies by the two enzymes and radioimmunoassay methods is needed before assessing and using a radioimmunoassay of human lactalbumin in serum.

Immunohistochemistry of a component protein of the breast cystic disease fluid with mol. wt 15,000.

A specific protein from the liquid of a mammary cyst with a molecular weight of 15,000 (GCDFP 15) was studied in normal and pathological mammary tissue using an immunohistochemical method (peroxidase-anti-peroxidase complex). An immunoreactivity of the GCDFP type was found in normal idrosadenoid glands having an apocrine secretion. Histologically normal mammary tissue was not immunoreactive. In benign breast tissue the GCDFP was found particularly in epithelium undergoing apocrine metaplasia (55/55) and in atypical lobular epithelial hyperplasia (8/10). Of the adenocarcinomas of the breast 136/161 (84%) were immunoreactive, especially lobular carcinoma (13/13). The proportion of tumors with a high percentage of immunoreactive cells (76-100%) was greater for Bloom's grade I (1/29: 34%) than for grade III (10/66: 15%). A significant correlation was found between the percentage of immunoreactive cells and the cytosolic concentration of progesterone receptors. The morphological intracellular identification of GCDFP (due to its greater sensitivity) and its correlation with progesterone receptors allowed a more precise evaluation of the functional state and the hormonal dependency of the breast cells by underlining the heterogeneity of the tumoral cell population.

Immunohistochemical detection of alphalactalbumin in breast lesions.

Alphalactalbumin was investigated in breast cells using the immunoperoxidase technique with a specific anti-alphalactalbumin serum. In 50 benign tumors alphalactalbumin immunoreactivity was demonstrated in the epithelium of fibroadenomas and in fibrocystic disease showing apocrine metaplasia. Alphalactalbumin immunoreactivity, investigated in 124 breast cancers, was present in all cells of lobular tumors but in only 76% of other cancers where the pattern was heterogeneous. Perineoplastic mammary tissue of normal appearance was not labeled with the anti-alphalactalbumin antiserum except where lobular hyperplasia was present. The presence of alphalactalbumin-type immunoreactivity was not correlated with the histopathological staging of Bloom and Richardson, nor with menopausal status. The incidence of positivity was 90% when estrogen and progesterone receptors were present in the tumor. The demonstration of alphalactalbumin using immunoperoxidase could be used to complement the histological classification of breast cancers.

[Value of radioimmunological serum levels of carcinoembryonic antigen in the postoperative monitoring of rectocolonic cancer]. / Intérêt du dosage sérique radio-immunologique de l'antigène carcino-embryonnaire (CEA) dans la surveillance des cancers rectocoliques opérés.

Fifty four patients, operated for colorectal cancer have been followed up for 2 to 100 months after surgery by carcino-embryonic antigen (CEA) determinations and classical, clinical, biological, radiological, echographical, isotopical and tomoscanninvestigations. Each new serum sample has been assayed for CEA with previously collected samples within the same patients. This repetition of CEA on the same samples allows to check the good reproducibility of CEA radioimmunoassay (variation coefficient between assay is less than 10%) and to get a complete profile of CEA level evaluation within the same assay. There is a good correlation between clinical evolution and CEA levels. In 42 patients, CEA levels remained or became normal (less than 10 ng ml) after surgical resection of the tumors and no metastasis or local recurrence were detected. In 12 cases, CEA levels remained or became abnormally high (greater than 20 ng ml) at the same time or before clinical and/or paraclinical evidences for metastases or local recurrence. These results showed CEA assay in a quantitative parameter to assess the follow-up of colorectal cancer complementary to clinical, biological, radiological, echographical and isotopical criterias.

[Are chorionic gonadotropin (HCG) and its alpha and beta subunits useful markers in non-trophoblastic tumors?]. / L'hormone chorionique gonadotrope (HCG) et ses sous-unités alpha et beta sont-elles des marqueurs utiles dans les tumeurs non trophoblastiques?

HCG and its subunits alpha and beta are produced by trophoblastic cancers constituting an index of early detection and monitoring for these tumors. Unlike HCG-alpha, we can obtain specific HCG and HCG-beta assays with LH-neutralized antiserum. Many normal non-trophoblastic tissues exhibit a HCG-like immunoreactivity. All choriocarcinomatous testicular tumors produce HCG and HCG-beta. Half of all testicular teratomas produce HCG and its subunits while a third of all seminomas exhibit an HCG-like immunoreactivity, whether choriocarcinomatous component is present or not. Serum HCG levels are elevated in seminomas (5 to 22%) as well as teratomas '55 to 89%). Less than 15% of breast, digestive and lung cancers have increased serum levels of HCG and/or its 2 subunits. HCG is most often produced by undifferentiated lung cancers, hepatoblastomas and adrenal carcinomas. There is usually a parallel relation between these serum levels and the clinical evolution of the disease under chemotherapy. In breast cancer, these levels do not constitue a "prognosis index". HCG production by non-trophoblastic tumors can induce clinical symptoms such as precocious puberty and gynecomastia.

[Products of exocrine secretion of the breast and breast cancer]. / Produits de la sécrétion exocrine du sein et cancer mammaire.

The breast is an exocrine gland which secretes the proteins present in breast milk, such as casein and lactalbumin. The apocrine metaplasia which often accompanies cystic transformation may result in the production of proteins in the cystic fluid: GCDFP (Gross cystic disease fluid protein). The production of these proteins by breast cancer and their secretion into the blood enable them to be considered as markers of tumour differentiation. They are useful to the clinical oncologist as quantifiable parameters of tumour extension and response to treatment. In the future, they may provide an index of malignant transformation and hormone dependence.

[Tumor markers]. / Les marqueurs tumoraux.

Several substances, referred to as tumor markers, are associated with neoplasms development. The specificity of these cancer related substances or antigens depends on their nature (onco-fetal antigens, placental antigens) or on their concentration and physico-chemical forms (hormones, exocrine products, enzymes,...). On the basis of physico-chemical, immunochemical and biochemical analogies which exist between these tumor markers and substances normally found at particular times of life, a classification of these markers may be proposed. Tumor markers are almost constantly found within carcinoma cells by immunocytochemical techniques and are secreted by carcinoma explants in culture medium. On the hand, the release of tumor markers in biological fluids (blood, cerebrospinal fluid, urines,...) is less frequently detected by sensitive methods such as radioimmunoassay. Several factors are responsible for this discrepancy between the intra-tumoral presence of tumor markers and the lower incidence of their detection in biological fluids. These factors are discussed. These tumor markers have attracted considerable attention from pathologists and clinicians. Thus, detection of these substances, especially by immunocytochemical methods, may be related to a situation of neoplastic transformation and allow a functional classification superimposed to histological classification superimposed to histological classification of tumors. Moreover, ectopic production of hormones and/or neuromediators explains some clinical symptoms in cancer processes. Furthermore, products of normal cell activity at the origin of cancer (hormones, enzymes, exocrine products) when evidenced within the neoplastic cells or within serum might constitute a hormonal dependence index useful for therapeutical orientation. Finally, tumor marker levels are related to the local and systemic extension of the neoplasia and may be considered as valid index of prognosis. The determination of the levels of these tumor markers provides a quantitative criterion of the evolution of the neoplastic disorder and for following the efficacy or inefficacy of treatment.