Biomedical subjects
R Mayer
Publications and source records attributed to R Mayer.
Abstinence education: resources from the National Center for Education in Maternal and Child Health for program design, implementation, and evaluation.
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The direct agglutination test: a non-specific test specific for the diagnosis of visceral leishmaniasis?
Serology has an important role to play in the diagnosis of the severe clinical syndrome of visceral leishmaniasis (VL). The direct agglutination test (DAT), a simple agglutination test which requires no laboratory facilities, has become the preferred test, particularly for field studies. The nature of the antigens responsible for the agglutination of leishmanial promastigotes by the serum of VL patients is not known. A series of experiments which provide some clues to the molecular basis for the test and which indicate that there might be more in DAT than meets the eye is reported.
Langerhans cells in the development of skin cancer: a qualitative and quantitative comparison of cell markers in normal, acanthotic and neoplastic ovine skin.
The distribution of Langerhans cells in normal, acanthotic and neoplastic ovine epithelium was examined using the enzyme marker Acetylcholinesterase (AchE) and monoclonal antibodies (MoAb) to CD1 (20.27) and MHC Class II (49.1 and 28.1) molecules. In normal skin, where Langerhans cells were regularly spaced within the basal layer, qualitative observations and direct pairwise testing showed that AChE was superior to the MoAb in detecting these cells. Significantly more (P < 0.01) dendritic cells were also detected with MoAb 49.1 than MoAb 20.27 or 28.1, suggesting differential expression of MHC Class II subsets and the presence of CD1- MHC Class II+ granule- dendritic cells in sheep analogous to indeterminate cells of man. In acanthotic skin, compared to normal skin, Langerhans cells were less numerous, irregular and more suprabasal in distribution and their morphology was occasionally swollen and indistinct. No difference was seen in the ability of AChE and MoAb in detecting Langerhans cells, however pairwise testing of markers did demonstrate that significantly more (P < 0.05) cells without dendritic processes were stained with MoAb 49.1 than with 20.27 or 28.1. In all squamous cell carcinomas examined dendritic cells that stained for AChE, CD1 or MHC Class II antigens were concentrated at the peripheral areas of neoplastic epithelium. Many dendritic cells were detected with MoAb to MHC Class II antigens, whereas CD1 and AChE positive dendritic cells were rare in tumor bearing tissue. The quantitative differences in the immunohistochemical staining of Langerhans cells between normal, acanthotic and neoplastic epithelium were consistent with ultrastructural studies. When compared with those of a newborn lamb, which had had very little exposure to antigens or ultraviolet radiation (UVR), the Langerhans cells of the aged sheep were deformed and contained far fewer Birbeck granules. The abnormalities were progressively more severe in acanthotic and neoplastic skin. These observed changes may have resulted from UVR induced damage and may be indicative of impaired function involved in the development of skin cancer.
Cytosolic and nuclear delivery of oligonucleotides mediated by an amphiphilic anionic peptide.
Antisense oligonucleotides (ODN) were easily introduced into the cytosol of mammalian cells on permeabilization of the plasma membrane by an amphiphilic anionic peptide. The E5CA peptide (GLFEAIAEFIEGGWEGLIEGCA) is an E5 peptide analog derived from the N-terminal segment of the HA2 subunit of influenza virus hemagglutinin. This peptide undergoes a conformational change when the pH shifts from neutral to around 6.0, inducing a transient permeabilization of the plasma membrane. In the presence of the E5CA peptide at pH close to 6.0, fluoresceinylated ODN were rapidly taken up by cells and diffused into the nucleus. The uptake of ODN was dependent on the E5CA peptide concentration and on the duration of the incubation at low pH, as shown by confocal microscopy and flow cytometry analyses. This procedure is suitable for loading adherent cells as well as nonadherent cells with single-stranded or double-stranded ODN. Under optimal conditions, a high percentage of cells were nuclei loaded, and the viability was not affected. This method makes use of a well-defined chemical product without the requirement of any special equipment. It will be useful to study the interactions of single-stranded or double-stranded ODN used as antisense, antigenes, or decoys.
Prenatally detected reversal of donor-recipient roles in twin-to-twin transfusion syndrome following in utero treatment.
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Two-dimensional film dosimetry application in heterogeneous materials exposed to megavoltage photon beams.
Measurement of dose within tissues and tissue interfaces having sharp density discontinuities and heterogeneities (such as in the lung, esophagus, and rectum) is essential for treatment plan verification and accurate prediction of the prescribed dose. This study examines the feasibility and utility of simplifying standard film dosimetry to measure dose distributions deposited by megavoltage beams in tissue substitutes (such as cork for lung) and anthropomorphic phantoms which closely resemble human tissues having large density heterogeneities and having sharp tissue interfaces. In addition, film dosimetry determined the dose distribution involving superposition of multiple radiation fields and helped evaluate the accuracy of a commercial treatment planning program which incorporates tissue heterogeneity effects through the "effective path length" algorithm. This study shows that these treatment planning programs and simple calculations overestimate the dose delivered within the lower density material in heterogeneous regions.
Primary choriocarcinoma of the pulmonary artery mimicking pulmonary embolism.
Due to their rarity, primary tumours of the pulmonary arteries are often incorrectly diagnosed as more common diseases such as pulmonary thromboembolism and are seldom diagnosed during a patient's lifetime. Surgery or potentially curative chemotherapy may therefore be withheld. We report a patient with a primary choriocarcinoma of the left pulmonary artery, which was first suspected on a CT scan. The neoplastic nature of the obstruction of the pulmonary arteries was confirmed by positron emission tomography.
Postoperative radiotherapy in radically resected non-small cell lung cancer.
PURPOSE: To evaluate the value of adjuvant postoperative external-beam radiation (EBR) in patients with radically resected non-small cell lung cancer (NSCLC) pT1-3 pN0-2 compared to patients with resected NSCLC without adjuvant EBR. MATERIALS AND METHODS: In 155 patients (121 male, 34 female; mean age, 59 years) 105 lobectomies, 12 bilobectomies, and 38 pneumonectomies with radical lymph node dissection of the contralateral [corrected] side were performed. Postoperative staging was done according to the TNM system and was as follows: pT1 (n=38), pT2 (n=89), pT3 (n=28); pN0 (n=39), pN1 (n=67) and pN2 (n=49). Histopathologic study revealed 68 squamous cell carcinomas, 53 adenocarcinomas, 21 large cell carcinomas, 6 adenosquamous cell carcinomas, and 7 bronchioloalveolar cell carcinomas. All patients were randomly assigned into two treatment groups: 72 patients with no further treatment (control group), and 83 patients (EBR group) with adjuvant postoperative EBR of the bronchial stump and mediastinum (50 to 56 Gy, 8 or 23 MV photons, 2 Gy/d, 5 d/wk) beginning 4 to 6 weeks after surgery. RESULTS: The overall 5-year survival rate (median observation time, 43 months) of all patients was 24.1% (EBR group, 29.7%; control group, 20.4%; p>0.05, not significant). The relative risk of the EBR group was 0.85 with a two-sided confidence interval of 0.66 to 1.09. The overall 5-year recurrence-free survival was 20.6% (EBR, 27.1%; control group, 15.6%; p=0.07). The relative risk of the EBR group was 0.80 with a confidence interval of 0.63 to 1.01. The rate of local recurrences at the bronchial stump and/or mediastinum was significantly smaller in the EBR group (n=5) than in the control group (n=17) (p<0.01). Multivariate analysis (chi2 test) demonstrated an independent influence of postoperative EBR on the incidence of local recurrences. The incidence of distant metastases was slightly but not significantly higher in patients without EBR (38 patients) compared to those who had EBR (32 patients). CONCLUSION: High-dose postoperative EBR to the mediastinum significantly reduces the risk of local recurrence at the bronchial stump and/or mediastinum. Age, sex, histologic subtype, tumor size, surgical approach, or extent of lymph node involvement had no prognostic value--only postoperative EBR had an independent influence on the risk of local recurrence. The effect of postoperative EBR was on the verge of significance with respect to recurrence-free survival and showed the same tendency in overall survival, however with an attenuated relative risk.
Intracellular routing and inhibitory activity of oligonucleopeptides containing a KDEL motif.
On internalization, oligonucleotides (ODN) remain mostly sequestered in endocytic compartments. To increase their delivery into the cytosol and/or nucleus, which contain their targets, we attempted to guide them into compartments containing the KDEL receptor. Antisense ODN, phosphodiester protected at both ends, that are complementary to the AUG initiation site of gagHIV-1 mRNA (odn) were linked to a peptide ending with the Lys-Asp-Glu-Leu (KDEL) motif in a carboxyl-terminal position (odn-p-KDEL) or with the Lys-Asp-Glu-Ala (odn-p-KDEA) as a control. The effect of odn substitution with a peptide was examined with regard to its accumulation, subcellular location, and activity in HepG2 cells. Although odn-p-KDEL was internalized 4-fold less than the corresponding peptide-free odn, it was 5-fold more efficient in inhibiting gagHIV-1 gene expression in HepG2 cells. The internalization of odn-p-KDEA was as low as that of odn-p-KDEL, but its biological activity was lower, close to that of the peptide-free odn. On endocytosis at 37 degrees, both conjugates as well as the peptide-free odn were found in a neutral environment. However, the substitution of an odn with a KDEL motif altered its intracellular trafficking; most of the odn-p-KDEL was found in the endoplasmic reticulum and in the intermediate compartment as identified by colabeling with either anti-ERGIC-53 or anti-KDEL receptor antibodies. Conversely, odn-p-KDEA and peptide-free odn were localized in vesicular compartments not labeled with these antibodies. In addition, pulse-chase experiments showed that odn-p-KDEL and odn-p-KDEA had a lower efflux than peptide-free odn. Therefore, the large increase in efficiency was due to the KDEL motif.
Biotin-labelled peptidyl diazomethane inhibitors derived from the substrate-like sequence of cystatin: targeting of the active site of cruzipain, the major cysteine proteinase of Trypanosoma cruzi.
Biotin-labelled peptidyl diazomethane inhibitors of cysteine proteinases, based on the N-terminal substrate-like segment of human cystatin C, a natural inhibitor of cysteine proteinases, were synthesized. These synthetic derivatives were tested as irreversible inhibitors of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, to compare the kinetics of the inhibition of the parasite proteinase with that of the mammalian cathepsins B and L. The accessibility of the active sites of these proteinases to these probes was also investigated. The inhibition of cruzipain by Biot-LVG-CHN2 (where Biot represents biotinyl and L,V and G are single-letter amino acid residue abbreviations) and Biot-Ahx-LVG-CHN2 (where Ahx represents 6-aminohexanoic acid) was similar to that of unlabelled inhibitor. Biotin labelling of the inhibitor slowed the inhibition of both cathepsin B and cathepsin L. Adding a spacer arm (Ahx) between the biotin and the peptide moiety of the derivative increased the inhibition of cathepsin B but not that of cathepsin L. The discrimination provided by this spacer is probably due to differences in the topologies of the binding sites of proteinases, a feature that can be exploited to improve targeting of individual cysteine proteinases. Analysis of the blotted proteinases revealed marked differences in the accessibility of extravidin-peroxidase conjugate to the proteinase-bound biotinylated inhibitor. Cruzipain molecules exposed to Biot-LVG-CHN2 or Biot-Ahx-LVG-CHN2 were readily identified, but the reaction was much stronger when the enzyme was treated with the spacer-containing inhibitor. In contrast with the parasite enzyme, rat cathepsin B and cathepsin L treated with either Biot-LVG-CHN2 or Biot-Ahx-LVG-CHN2 produced no detectable bands. Papain, the archetype of this family of proteinases, was poorly labelled with Biot-LVG-CHN2, but strong staining was obtained with Biot-Ahx-LVG-CHN2. These findings suggest that optimized biotinylated diazomethanes might considerably improve their selectivity for the T. cruzi target enzyme.
Outpatient interstitial thermoradiotherapy.
BACKGROUND: Hyperthermia enhances the cytocidal effect of ionizing radiation. Several pilot studies demonstrated that the combination of interstitial hyperthermia and interstitial radiotherapy (interstitial thermoradiotherapy) is safe and effective. However, these studies mainly utilized low dose rate brachytherapy, and therefore, required hospitalization. With the availability of median or high dose rate brachytherapy devices, we piloted a study to evaluate the feasibility, toxicity and efficacy of interstitial thermoradiotherapy performed in an outpatient setting. METHODS: Between 1989 and 1993, 27 patients with a diagnosis of carcinoma of the head and neck region (n = 23), carcinoma of the breast (n = 3), or malignant melanoma (n = 1) received 1 or 2 sessions of interstitial thermoradiotherapy. Median patient age was 66 years (range: 37-83 years). Treatment consisted of 60 minutes of 915 MHz microwave interstitial hyperthermia, followed by iridium-192 seed implants, either by Micro-Selectron HDR (10-12 Gray [Gy] in 8.5-21 minutes) or high activity (5-8 mCi per seed) seeds (10-15 Gy in 2-4 hours). In addition to interstitial temperature measurements, a real-time thermal camera was used to monitor the surface temperature spatial distribution. power supply and/or position of interstitial microwave applicators was adjusted when appropriate. All but one patient also received external beam irradiation prior to implants. RESULTS: Patients tolerated treatments well although 16 (59%) of them required analgesics during hyperthermia sessions. Skin blisters or ulcerations occurred in only 6 (22%), and all but 2 healed. Complete response occurred in 24 patients (89%), partial in 3 (11%). With a median follow up of 16 months (range: 3-43 months), the 2-year actuarial local control rate was 74%. CONCLUSIONS: The results of this study indicate that outpatient interstitial thermoradiotherapy is convenient, safe, and efficacious for treating human neoplasms.
The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion.
The MRP gene encodes a 190-kDa integral membrane glycoprotein which functions as a primary-active ATP-dependent export pump for amphiphilic anions. The MRP gene-encoded conjugate export pump and its canalicular isoform represent the transport activity which has been described earlier as multispecific organic anion transporter, non-bile acid organic anion transporter, glutathione S-conjugate export pump, or leukotriene export pump. Analyses of the substrate specificity of the human MRP pump were performed in plasma membrane vesicles from MRP-overexpressing drug-selected cells (7) and cells transfected with an MRP expression vector (8). Substrates for MRP include thioether-linked conjugates of lipophilic compounds with glutathione, cysteinyl glycine, cysteine, and N-acetyl cysteine, but also glutathione disulfide, and glucuronate conjugates such as etoposide glucuronide. This broad-specificity ATP-dependent export pump is not only overexpressed in several multidrug resistant tumor cells and tissues, but is also present in most normal cells and tissues. The expression of cMRP and MRP in human liver and of cMrp and its homolog Mrp in rat liver was demonstrated by reverse transcription PCR, cDNA sequencing, and immunoblotting (13). The important function of the cMRP gene-encoded broad-specificity conjugate export pump in hepatobiliary excretion is illustrated by the selective absence of this canalicular isoform from the hepatocyte canalicular membrane in transport-deficient mutant rats. This altered lack of cMrp is the basis for the hereditary detect of the hepatobiliary excretion of anionic conjugates in the mutant animals (13). The absence of this canalicular Mrp in the mutants is analogous to the defect in the human Dubin-Johnson syndrome which is characterized by an impaired excretion of conjugated anions across the canalicular membrane.
"Adjuvant" external radiation of the mediastinum in radically resected non-small cell lung cancer.
OBJECTIVE: The effect of postoperative external beam radiation in MO non-small cell lung cancer resected with curative intention was evaluated in a randomized trial. METHODS: In 155 patients (121 males, 34 females; mean age: 59 years) 105 lobectomies, 12 bilobectomies and 38 pneumonectomies with radical lymph node dissection to the contralateral side were carried out. Histology revealed squamous cell (n = 68), adeno- (n = 53), large cell (n = 21), adenosquamous (n = 6) or bronchioloalveolar type (n = 7) carcinomas. The pathologic stages T1 (n = 38), T2 (n = 89), T3 (n = 28); NO (n = 39), N1 (n = 67), and N2 (n = 49) were evenly distributed between the two treatment groups: group A (72 patients) had no further oncologic treatment, while group B (83 patients) had external beam radiation to the mediastinum (50-56 Gy, 8 or 23 MeV photons, 2 Gy/day, 5 days a week) beginning 4 weeks after the operation. RESULTS: The overall 5-year survival rate of the whole collective was 24.1% without any significant difference between the radiotherapy group B (29.7%) and the control group A (20.4%) (log-rank test: P > 0.05). The overall 5-year recurrence-free survival rate was 20.1%, with no difference between groups B and A (radiotherapy: 22.7, controls: 15.6%, long-rank test: P > 0.05). There was no difference in the incidence of distant metastases (external beam radiation: n = 32; controls: n = 38). The rate of local recurrences at the bronchial stump or in the mediastinum, however, was significantly reduced in the radiotherapy group (n = 5) compared with 17 in the controls (P < 0.01 chi-square test). A multivariate analysis confirmed the independent influence of postoperative radiotherapy on the incidence of local recurrence. CONCLUSIONS: External radiation of the mediastinum in radically resected non-small cell lung cancer reduces the risk of local recurrence, but has no influence on distant metastastic spread and overall survival.
Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome.
The Dubin-Johnson syndrome is characterized by an inherited defect in the secretion of amphiphilic anionic conjugates from hepatocytes into the bile. We have recently identified the membrane protein mediating the adenosine triphosphate (ATP)-dependent transport of glutathione and glucuronate conjugates as a multidrug-resistance protein (MRP) and localized it to the canalicular as well as to the lateral hepatocyte plasma membrane. In the present study we show the selective absence of the canalicular isoform of MRP (cMRP) from the hepatocytes in a patient with Dubin-Johnson syndrome by double-label immunofluorescence and confocal laser scanning microscopy using antibodies directed against MRP and dipeptidyl-peptidase IV (DPPIV). Another isoform of MRP was detected, however, in the lateral hepatocyte membrane of the patient. Moreover, MRP was present on immunoblots of erythrocyte membranes from Dubin-Johnson syndrome and normal humans. These findings are analogous to our recent observations on the localization of the rat homolog of MRP and its canalicular isoform, cMrp, in normal and transport-deficient GY/TR- Wistar rat liver. The elucidation of the selective absence of an isoform of MRP and from the canalicular membrane domain in conjunction with the defined substrate specificity of the MRP and cMRP gene-encoded conjugate export pumps contributes to the molecular definition of the transport defect in Dubin-Johnson syndrome.
Positron emission tomography helps to diagnose tumor emboli and residual disease in choriocarcinoma.
BACKGROUND: Positron emission tomography (PET) has been shown capable of identifying malignant tissues. PATIENTS AND METHODS: WB-PET imaging in two women with metastatic choriocarcinoma is described. RESULTS: In a woman with tumor emboli secondary to a choriocarcinoma, WB-PET was the only noninvasive investigation to differentiate between tumor and blood clots. Moreover, PET helped to localize residual tumor tissue in another woman with persisting high beta-HCG serum levels after chemotherapy. CONCLUSIONS: WB-PET helps to localize tumor tissue in patients suffering from choriocarcinoma.
Psychological factors associated with urinary incontinence.
This nursing study about women with urinary incontinence was designed to explore (1) the incidence of depression in women with urinary incontinence, (2) the correlation between mastery and depression and/or self-esteem and depression in women with urinary incontinence, and (3) depression as a mediating factor in the quality of life (QOL) in these women. This study found a higher incidence of depression in women with urinary incontinence compared with the general population. Correlational and multiple regression analyses both revealed strong and significant relationships between the independent variables of mastery and self-esteem and the dependent variable of depression. Depression did not emerge as a mediator in QOL. When mastery, depression, and self-esteem were considered together, mastery was the only predictor with a direct effect on QOL in women with urinary incontinence. Nursing interventions aimed at increasing women's sense of mastery may be effective in decreasing depression and improving the QOL.
Protozoan infections in the male genital tract.
PURPOSE: We reviewed the literature on protozoan infections in the male genital tract, with special reference to histopathological findings and their repercussions on different andrological functions. MATERIALS AND METHODS: A literature search of the MEDLINE data base from 1966 to May 1995 was done and related articles were identified. The considered terms were parasitology and the male genital organs. Additional searches on infertility, semen and sexually transmitted diseases were performed. RESULTS: Protozoan infections of the male genital tract are rare and only a few species of parasites are involved. Trichomonas vaginalis, Trypanosoma species, Leishmania donovani, Entamoeba histolytica, Acanthamoeba species, Toxoplasma gondii and Plasmodium falciparum have been described in the male genital tract as producing testicular damage or secondary hypogonadism via hypothalamic-hypophyseal axis alterations. CONCLUSIONS: Topics of interest were the role of sexual transmission by some parasites, principally T. vaginalis, relationship with subfertility or infertility in the male subject, clinical significance in differential diagnosis with other inflammatory processes, and for some parasites the relationship with opportunistic behavior and immunodeficiency syndromes, including the acquired immunodeficiency syndrome.