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Biomedical subjects

H Ben-Hur

Publications and source records attributed to H Ben-Hur.

At least 19 recordsLinked to original sources

Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

ADP-ribosyl Cyclase

Engraftment of human kidney tissue in rat radiation chimera: II. Human fetal kidneys display reduced immunogenicity to adoptively transferred human peripheral blood mononuclear cells and exhibit rapid growth and development.

BACKGROUND: Transplantation of human kidney tissue under the kidney capsule of immunodeficient animals (severe combined immunodeficiency [SCID]/Lewis and SCID/nude chimeric rats), and the subsequent intraperitoneal infusion of allogeneic human peripheral blood mononuclear cells (PBMC), results in a rapid and consistent human renal allograft rejection. We investigated the consequences of grafting human fetal kidney fragments instead of the adult tissue. METHODS: The development of human fetal kidney tissue and its interaction with allogeneic human PBMC in chimeric rats were analyzed by histology, immunohistochemistry, and in situ hybridization. RESULTS: We report successful establishment of human fetal kidney to SCID/Lewis and SCID/nude chimeric rats. The intrarenal human fetal renal implants displayed rapid growth and maintained numerous developing glomeruli and tubular structures up to 4 months after transplantation. In contrast to the adult human kidney, infusion of allogeneic human PBMC resulted in either minimal human T-cell infiltration or abundant nonrejecting T-cell infiltrates, characterized by a reduced number of T cells of the CD45RO+ or HLA-DR+ subsets, both leading to less tissue destruction as well as to continued growth of the human fetal renal tissue. This observation was found to be related to the reduced protein expression of tissue HLA class I and II, intercellular adhesion molecule 1, and vascular adhesion molecule 1 in the fetal grafts compared with the adult grafts. Lack of tissue expression of Fas ligand in the fetal grafts suggests that the latter does not contribute to the delayed rejection of human fetal kidneys. CONCLUSIONS: Our model should be useful for the study of human fetal renal development and the human alloresponse against fetal tissue.

Adoptive Transfer

Subcutaneous, omentum and tumor fatty acid composition, and serum insulin status in patients with benign or cancerous ovarian or endometrial tumors. Do tumors preferentially utilize polyunsaturated fatty acids?

The relationships between the fatty acid composition of cancerous endometrium and ovary, and peripheral adipose tissues were studied in Israeli Jewish women, and are presented together since no differences were shown between them. The results suggest a mobilization of linoleic acid from subcutaneous and omental depots and its incorporation into tumors accompanied by a high degree of desaturation. High blood insulin concentrations characterized patients with stage I and II disease, and low concentrations characterized patients with advanced degrees of malignancy.

Adipose Tissue

Metastasizing placental site trophoblastic tumor: immunohistochemical and DNA analysis. 2 case reports and a review of the literature.

Placental-site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasia. The clinical behaviour of PSTT is usually benign, but sometimes it can be highly malignant with late recurrence and metastasis. We describe two cases of PSTT with pulmonary metastasis in patients aged 35 and 29 years respectively. The mitotic rate was elevated to 9 and 13 mitotic figures per 10 high-power fields respectively. Immunohistochemical staining showed a predominance of human placental lactogen (hPL) positive cells when compared with human chorionic gonadotropin (hCG) reactive cells in one case, and a reverse pattern in the other one. DNA measurement in one case showed an aneuploid tumor with a tetraploid DNA peak. The clinical behaviour of PSTT remains unpredictable, and there are no reliable means of predicting clinical outcome.

Adult

Estrogen, progesterone and testosterone receptors in human fetal cartilaginous tissue: immunohistochemical studies.

Computerized image analysis was used to study the distribution in cartilage of receptors to estrogen, progesterone, and testosterone during human fetal development. We have examined three histologically distinct cell groups (hypertrophic, proliferating, and reserve zones) in long bones, vertebrae, and trachea from 19 fetuses. Comparisons were made across gender and gestational age. Contrasting with controls, we examined the density of receptors, the size of the nuclear area in which the receptors were detected, the number of hormone receptor-bearing cells, and the total receptor quantity per sample. We found that estrogen, progesterone, and testosterone receptors were detected in the nuclei of all cell types, in both female and male embryonic cartilaginous tissue. Gender differences were small and inconsistent. Changes associated with gestational age depicted a pattern of hormone receptor manifestation, shifting from the immature cell types to more differentiated cells. This was evident from the receptor densities and from the cellular area in which receptors were sighted. These dynamics are accompanied by a general increase in receptor content per sample, brought about by the concomitant increase in receptor containing area size and cell number. The increase in receptor levels seems to reflect the maturation and growth of the fetal skeleton.

Cartilage

Distribution of glutamate transporter subtypes during human brain development.

In the mature brain, removal of glutamate from the synaptic cleft plays an important role in the maintenance of subtoxic levels of glutamate. This requirement is handled by a family of glutamate transporters, EAAT1, EAAT2, EAAT3, and EAAT4. Due to the involvement of glutamate also in neuronal development, it is believed that glutamate transport plays a role in developmental processes as well. Therefore, we have used immunohistochemical and immunoblot analysis to determine the distribution of the four glutamate transporters during human brain development using human pre- and postnatal brain tissue. Regional analysis showed that each transporter subtype has a unique distribution during development. EAAT2 was the most prominent glutamate transporter subtype and was highly enriched in cortex, basal ganglia, cerebellum, and thalamus in all ages examined. EAAT1 immunoreactivity was lower than that of EAAT2, with predominant localization in cortex, basal ganglia, hippocampus, and periventricular region. EAAT3 was located mainly in cortex, basal ganglia, and hippocampus, and EAAT4 was found only in cortex, hippocampus, and cerebellar cortex. The distinct regional distribution of various EAAT subtypes and also the transient expression of specific EAAT subtypes during development suggest multiple functional roles for glutamate transporters in the developing brain.

ATP-Binding Cassette Transporters

Immunoglobulin A in the epithelium of the respiratory tract and intrahepatic bile ducts of fetuses and newborns with pneumonia and sepsis.

The level of different immunoglobulins (IgA, IgG, IgM) in the tissues of 28 late fetuses and newborns was studied with peroxidase-labeled monoclonal antibodies. IgA+ and IgM+ lymphocytes were found in the spleen, lymph nodes and sometimes in the liver. IgG+ lymphocytes were not found. A high level of IgA+ material was found in the epithelium of the trachea, the epithelium and submucosal glands of the bronchi, but not the bronchioles, and in the epithelium of hepatic bile ducts and in their lumina. Such IgA is considered to be secretory--sIgA. Secretory IgA-containing epithelial cells appeared at 20 to 21 weeks of gestation; their number increased from 2.5 cells/10,000 microns2 in 23- to 26-week-old fetuses, to 8 cells/10,000 microns2 in 36- to 40-week-old fetuses. Secretory IgG and IgM were not detected. In fetuses with pneumonia or sepsis, the number of IgM+ and IgA+ lymphocytes increased significantly. IgM+ lymphocytes appeared not only in the spleen and lymph nodes, but also in the lungs. In such cases, the number of sIgA-containing epithelial cells in the trachea, bronchi and intrahepatic bile ducts decreased, sometimes completely disappearing. The amount of IgA+ material in the lumina of these organs increased, reflecting an intensification of sIgA secretion during infections. The presence of a marked amount of sIgA in fetuses from week 20 of gestation is considered to reflect the high importance of this immunoglobulin against normal contamination by microbes after birth, and to evidence the early maturation of the immune system.

B-Lymphocytes

Serological and immunohistochemical determinations of p53 protein in diagnosis of endometrial cancer: a comparative study.

BACKGROUND: The role of different methods for the determination of p53 protein was evaluated for the detection of endometrial cancer in humans. METHODS: p53 antigen was detected immunohistochemically in the cell nuclei of endometrial tumors and serologically in the serum of the same patients. The high performance liquid chromatography (HPLC) technique was used to measure serum levels of p53 protein after its partial purification on gel fiberglass affinity chromatography columns. RESULTS: Image analysis of cellular concentrations of p53 protein revealed an increase from 12% in hyperplastic endometrium to 74% in adenocarcinomas. Image analysis has also revealed a strong correlation between cellular concentrations of p53 antigen and tumor grade (r = 0.54). Visual cell determination of p53 antigen was effective mainly among patients with benign lesions (r = 0.61). There was a positive correlation between cellular concentration of p53 protein in tumor tissue and its serum level in cancer patients (r = 0.44). The serum level of the cytoplasmic form of p53 antigen significantly increased in cancer patients (3 mg/ml) compared to the concentration in patients with benign disorders (0.7 mg/ml); a consequence of its higher concentration in tumor cells. Serum level of p53 antigen was highly active both in patients with non-cancerous lesions (r = 0.42) and in patients with cancer (r = 0.51). Diagnostic significance of tissue concentrations of estrogen and progesterone applies only to cancer patients: coefficients of correlation between these parameters and tumor gradation were 0.58 and 0.89, respectively. CONCLUSIONS: Serum determination of cytoplasmic p53 antigen can reveal this oncoprotein in the early stages of cancer, or even foretell its development.

Adenocarcinoma

Cytogenetic analysis of fetal chondrocytes: a comparative study.

Progress in the prevention and prenatal detection of birth defects has led to a relative increase in the number of interruption of pregnancies associated with chromosomal abnormalities. There is an inverse relationship between the rate of success of fetal cell cultures and the interval between fetal demise and the initiation of culture. This report describes the cytogenetic analyses of cultured fetal chondrocytes compared with tissue cultures of fetal skin, fetal membranes, and placenta. The results show that cells obtained from the fetal chondrocostal junction and/or patella from missed abortions, intrauterine fetal deaths, or stillbirths can be cultured and successfully karyotyped. Since cartilage cells remain viable for some time after fetal demise, the culture of fetal chondrocytes is a complementary method for fetal chromosome analysis, especially in cases of tissue maceration after fetal demise. The success rate of chondrocyte cultures is similar to that of conventional fetal tissue cultures.

Biopsy

Hyperestrogenemia and presence of estrogen receptors associated with an epithelial ovarian tumor of low malignant potential.

An 80-year-old woman presented with breast congestion, tenderness and pain. Mammography was normal. Circulating estradiol was markedly elevated, while LH and FSH were low. Pelvic examination and imaging revealed an ovarian mass which was extirpated during total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathology revealed an ovarian mucinous cystadenocarcinoma of low malignant potential, stage 1. The tumor was positively stained for estrogen receptors. Estradiol levels returned to normal post-operatively, with a corresponding adjustment of LH/FSH. Possible autocrine steroid production is discussed.

Aged

Recurrent mucinous adenocarcinoma of the ovary presenting as an inguino-labial hernia.

We report a case of a 65-year-old woman who nine years previously had undergone total abdominal hysterectomy and bilateral salpingoophorectomy for a large ovarian cyst. During surgery the cyst had ruptured and some mucinous material had been spilled intraabdominally. Histopathological studies demonstrated the cyst to be a mucinous adenocarcinoma of low malignant potential. Appendectomy had also been performed due to an enlarged appendix, which proved to be a mucocoele. The patient had been lost to subsequent follow-up. Her current presenting symptom was a giant inguino-labial hernia of 25 cm diameter with two small skin perforations leaking a gelatinous discharge. Subsequent laparotomy and inguinal exploration have disclosed herniated small intestine with an attached metastatic multicystic mucinous adenocarcinoma. This case represents a case of borderline mucinous adeno-carcinoma-pseudomyxoma peritonei recurring in a unique pattern as a huge inguino-labial hernia, and serves to emphasize the possible consequences of spillage of ovarian cyst contents during surgery.

Adenocarcinoma, Mucinous

Cytokeratin expression in human thymus: immunohistochemical mapping.

Cytokeratin expression in normal postnatal human thymus was studied immunohistochemically by using monoclonal antibodies against various cytokeratin polypeptides. An attempt was made to characterize cell populations giving rise to the cornified structures of Hassal's corpuscles. Monoclonal antibody KB-37, a marker of squamous epithelium basal cells, was applied to distinguish the earliest cells capable of undergoing squamous differentiation. Parts of the subcapsular epithelium were extensively stained with this reagent. This epithelium, like the basal layer of certain squamous epithelia, exhibited a high incidence of cytokeratins 13 and 14, and pronounced expression of cytokeratin 19. Simple epithelium cytokeratins 8, 18, and 19 were present in the cortex. Scattered cells reacted with KB-37 antibody. All stellate epithelial cells in the medulla were positive for cytokeratin 19. Most of the medullar epithelial cells were positive for cytokeratins 13, 14 and 17 of complex epithelium, in contrast to the cortex, where only a few cells were positive for these cytokeratins. A significant proportion of the medullar cells was positive for KB-37 antigen. Cytokeratins 8 and 18 were expressed in single cells and in groups of cells surrounding Hassal's corpuscles. The outermost cells of these corpuscles were positive for cytokeratin 19 and KB-37. In the peripheral parts of Hassal's corpuscles, simple epithelium cytokeratins 7, 8, 18, and cytokeratins 4, 13, 14, and 17, characteristic of stratified nonkeratinizing epithelia, were coexpressed with keratinization-specific cytokeratins 10/11. The inner parts of the swirls were uniformly positive for cytokeratins 10/11. However, the expression of other cytokeratins was reduced.

Antibodies, Monoclonal

Pathology of lymphoid organs in low birth weight infants subjected to antigen-related diseases: a morphological and morphometric study.

The pathology of lymphoid organs in 38 low birth weight (LBW) human infants has been evaluated by morphological and morphometric features. The gestational ages of infants ranged from 22 to 32 wks and their age at death varied from 1 hr to 153 days post partum. Infants were divided into 3 groups: 1) without antigenic effects, 2) with mild (bronchopneumonia), and 3) with severe antigenic effects, mainly sepsis. In mildly affected LBW infants, the fetal type of the immune reaction was found. It continued during the period studied (till 5 mths) and was manifested in the reaction of macrophages and the transformation of lymphocytes to lymphoblasts. Reactive centres of follicles and mature plasmocytes were not found. During the first months of postnatal development, an increase in the amount of lymphocytes in the lymphoid organs and in the rate of proliferation of reticular epithelium and a decrease in the area of the cortex in the thymus were found in all infants. In severely affected infants, the number and the size of follicles in the spleen decreased significantly and the total number of cells decreased more than 3 times. Similar changes were found in lymph nodes. These changes as well as the weak reaction of the thymus are the main features of the insufficiency and fast devastation of the lymphoid system. A compensatory increase in the number of neutrophils and eosinophils in the red pulp of the spleen and lymph nodes was found after the second week.

Bronchopneumonia

Carcinoma of the clitoris: a histologic study with cytokeratin profile.

A carcinoma of the clitoris showed a variety of histologic features not usually encountered in squamous cell carcinoma of the vulva. In addition to poorly differentiated nonkeratinizing squamous cell carcinoma, there were large areas showing a transitional cell carcinoma pattern, as well as foci of spindle and anaplastic cells. The clitoral neoplasm also differed in its cytokeratin (CK) profile from that described in invasive squamous cell carcinoma of the vulva, especially with regard to the widespread staining for CK 18 and 19 in the former. Thus, our study suggests that some carcinomas of the clitoris differ from those of ordinary squamous cell carcinomas of the vulva. More cases should be studied using immunohistochemical methods in order to establish the full histopathologic and CK range of the former.

Aged

Menopause is associated with a significant increase in blood monocyte number and a relative decrease in the expression of estrogen receptors in human peripheral monocytes.

PROBLEM: The clinical significance of the differential expression of estrogen receptor (ER) in human monocytes was evaluated. METHOD: Two color flow cytometry analysis was used on peripheral blood samples of young and postmenopausal females and postmenopausal females treated with estrogen replacement therapy. In addition, the monocyte and lymphocyte counts and the blood estrogen levels of each patient were determine. RESULTS: During menopause there is a significant decrease in the percentage of ER positive monocytes, and an increase in blood monocyte number, which declines following estrogen replacement therapy to values of the young. CONCLUSIONS: These findings suggest that estrogen modulates the monocyte numbers and its effects may be mediated through the ER in the monocytes.

Adolescent

Alternative leader sequences in insulin-like growth factor I mRNAs modulate translational efficiency and encode multiple signal peptides.

Rat insulin-like growth factor I (IGF-I) mRNAs contain multiple 5'-untranslated regions due to the use of leader exons transcribed from several transcription initiation sites and to alternative splicing within leader exon 1. Synthetic RNAs with 5'-ends corresponding to the use of exon 1 transcription initiation sites were translated in vitro into prepro-IGF-I peptides initiated at a Met-48 codon in exon 1 or a Met-22 codon in exon 3, and RNAs with a 5'-end corresponding to the major exon 2 transcription start site were translated into a prepro-IGF-I peptide initiated at a Met-32 codon in exon 2. All forms of prepro-IGF-I were processed by canine pancreatic microsomes, suggesting that all these prepeptides function as signal peptides. The translational efficiency of IGF-I RNAs was inversely proportional to the length of the 5'-untranslated region. Mutation of the first of three upstream AUG codons in exon 1, which potentially initiates a 14-amino acid open reading frame, did not affect prepro-IGF-I translation. The other two AUG codons are immediately followed by stop codons. The absence of both upstream AUG codons in a completely spliced exon 1-derived RNA enhanced the in vitro and in vivo translatability of this RNA as compared with the full-length RNA. Mutation of the downstream initiation codon in particular increased translational efficiency in vitro and in intact cells, suggesting that an inefficient reinitiation event at the Met-48 codon contributes to the poorer translation of IGF-I mRNAs in which these upstream AUGUGA motifs occur. We conclude that IGF-I mRNAs potentially encode multiple forms of preproIGF and that specific differences in their 5'-untranslated regions provide a molecular basis for translational control of IGF-I biosynthesis.

Animals

Assessment of estrogen receptor distribution in human endometrium by direct immunofluorescence.

OBJECTIVE: To use a direct immunofluorescence technique employing a fluorescein labeled anti-idiotypic antibody that recognizes the estrogen receptor (ER) order to assess the distribution of ER in the uteri of normal women throughout the normal menstrual cycle and of a woman exposed prenatally to diethylstilbestrol (DES). SUBJECTS: Included in the study were 25 women aged between 35 and 50 years and an amenorrheic patient diagnosed as "DES Syndrome". LOCALIZATION: Localization of ER expression in frozen sections of uterine tissue was achieved by direct immunofluorescence using a fluorescein labeled anti-idiotypic antibody that interacts with ER. RESULTS: Analysis of the immunofluorescence staining indicated that in the normal human endometrium the intensity of ER staining varied according to the phase of the cycle as well as according to the cell type. On the other hand, endometrial ER evaluation of the patient with DES syndrome showed minimal expression of ER and after treatment with conjugated estrogens, endometrial biopsy revealed a significant increase in ER expression. CONCLUSIONS: These findings indicate that the fluorescein labeled anti-idiotypic antibody can be used to detect ER in normal and pathological human endometrium and to monitor changes in ER expression in the endometrium during hormonal therapy.

Adult

Insulin and glucose status, tissue and plasma lipids in patients with tumours of the ovary or endometrium: possible dietary implications.

The relationship between tumour growth, insulin status, blood lipids and adipose linoleic acid (LA, reflecting long-term LA intake) was studied in 19 Jewish women suffering from early and advanced stages (ES and AS) of ovarian and endometrial tumours. Blood insulin in patients with ES tumours was four times higher than the control value in cancer-free subjects, but fell to normal levels at AS and after ES surgery (PES). Tumours and abdominal adipose tissue (AAT) had 4-6 and 1.4-1.7 times as much insulin as non-cancerous control organs. Serum total cholesterol (CHOL) and LDL-cholesterol were high at ES, dropped below normal at AS, but normalised at PES, while HDL-cholesterol increased after ES surgery. Linoleic acid in subcutaneous adipose tissue (SAT) was high in controls (26.4 + 1.5% of total fatty acids), but lower in cancer patients (20.5 + 3.7%, P < 0.05), while palmitic acid showed the opposite change. The results suggest mobilisation of glucose, cholesterol and linoleic acid for the supply of energy and structural lipids to rapidly multiplying tumour cells and possibly for prostaglandin synthesis. They also raise the question of whether the high linoleic acid intake by the Jewish population in Israel predisposes individuals to tumour development.

Adipose Tissue