Proliferative (mib1, mdm2) versus anti-proliferative (p53) markers in head and neck cancer. An Immunohistochemical study

Formalin fixed and paraffin embedded samples from 36 squamous cell carcinomas of the larynx and the oral cavity (pT₂N₀M₀, R₀) surrounded by non-tumorous mucosa were studied immunohistochemically using a panel of four different anti-p53 antibodies (CM1, PAbl801, D07, PAb240), a monoclonal anti-mdm2 antibody and MIB1, following wet autoclave antigen retrieval. P53 immunoreactivity was detected in 11/14 laryngeal and in 9/22 oral carcinomas. All p53 positive oral, and all but one laryngeal tumors revealed mdm2 positivity as well, whereas in p53 negative tumors 4/12 and 1/3 mdm2 immunopositive cases were demonstrated, respectively. MIB1 labeling indices of the tumors ranged between 18% – 64% in p53 positive cases, and 10% – 53% in p53 negative ones. The difference was not statistically significant. Close spatial coexpression of p53, mdm2 and MIB1 immunoreactivity was observed at the invasive front of the carcinomas and in the basal and suprabasal layers of the non-tumorous epithelium in all p53 positive cases. However, the MIB1 expression was similarly increased at the invasive margins in carcinomas lacking immunohistochemically detectable p53 alterations. Our results strongly suggest that p53 overexpression does not necessarily correspond to increased rate of proliferation, but rather to mdm2 overexpression and is largely dependent on the anatomical site in case of small and localized squamous cell carcinomas of the head and neck region.     

Assessment of left ventricular function: comparison between radionuclide angiography and semiquantitative two-dimensional echocardiographic analysis

Measurement of global left ventricular function is important in the follow-up of cardiac patients and is a good prognostic indicator in acute cardiac situations. We compared quantitative measurements of global left ventricular function made with radionuclide angiography (RNA) and contrast cardiac ventriculography (CVG) to visual semiquantitative estimates from two-dimensional echocardiographic images (2D-echo). Three hundred and thirty-nine consecutive patients who underwent RNA were assessed with 2D-echo within 3 months. In addition, 92 of these patients also underwent CVG (correlation of ejection fraction between CVG and RNA:r=0.82;P<0.0001). The RNA mean ejection fractions in the four 2D-echo groups (0=normal, 1=slightly, 2=moderate, or 3=severe reduced left ventricular function) differed markedly (P<0.0001); however, there was overlapping among the groups (2D-echo score/RNA ejection fraction: 0=57.3%±12.8%; 1=46.0%±12.9%; 2=29.6%±12.2%; and 3=24.6%±11.5%) and the difference between 2D-echo scores 2 and 3 was not significant. 2D-echo showed a good concordance in RNA classes (0=505; 1=35%–49%; 2=21%–34%; and 3=520% ejection fraction) 0 (133/166; 80%) and 3 (18/30; 60%) but low concordance in classes 1 (27/82; 33%) and 2 (21/61; 34%). For accurate assessment of global left ventricular ejection fraction, visual semiquantitative judgement of a 2D echocardiographic image is limited in comparison to CVG or RNA, especially in patients with a slight or moderate reduction in left ventricular ejection fraction.     

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Multispecies toxicity tests using indigenous organisms: Predicting the effects of complex effluents in streams

A study was conducted to determine if contaminant-induced changes in macroinvertebrate communities in laboratory stream microcosms could be used to predict responses of these organisms in a natural stream receiving the same contaminant. Test organisms were transferred to the artificial streams in rock-filled containers previously colonized for 30 days upstream of the effluent outfall. The microcosms were exposed for 20 days to concentrations of the effluent that reflected those at field sites where macroinvertebrates were collected.The stream microcosms maintained most taxa at or above initial densities. However, adult insect emergence from the microcosms must be monitored during such studies. The relative sensitivity of species and the effluent concentrations causing changes in insect density were similar in the microcosms and the field. Mayflies were the most sensitive group, and densities in the microcosms were significantly (P 0.05) reduced at 1.0% or 10.0% effluent concentration depending on species. Conversely, chironomids densities were increased by exposure to the effluent. The mayflies responded at lower concentrations than acute tests withDaphnia magna would have predicted.     

The types of heterosexual gender identity disorder

The rationale for dividing the clinical spectrum of DSM-III-R male heterosexual gender identity disorder into three types was examined. The DSM-III-R category of fetishism for female attire, was included in the analysis. There were 266 male participants divided into three groups: 172 fetishists for female attire or gender identity patients, 52 androphiles, and 42 gynephiles. A 16 item questionnaire was used to examine the groups. A three factor scale ("Fetishism", "Gender Dysphoria" and "Androphilia") was derived from the questionnaire. Only the Gender Dysphoria Factor Scale successfully differentiated between all four conditions, supporting the notion that the three types of gender identity disorder represent a continuum of degree of severity of gender dysphoria. Defining two of the three types of gender identity disorder in terms of the patients' self-reports on fetishism, as DSM-III-R does, is therefore unnecessary.     

An analysis of the effects of implementing the teaching-family model in two community-based group homes

The effects of implementing the Teaching-Family Model in two community-based group homes were assessed through a series of pre-post measures. Data analysis indicates substantial positive change in youth social skills, program quality, youth and staff satisfaction levels, social climate, and staff accountability for care of the children.Requests for reprints, samples of the Staff Accountability Scale, and other forms or the questionnaires in this study should be addressed to Kurt Scheider at The Maryville Academy, 1150 North River Road, Des Plaines, IL 60016     

HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin.

PURPOSE: For the first time a large number (563) of non-small cell lung cancer (NSCLC) samples was used to compare three different technologies for the assessment of HER2 status. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were used for tumor tissue samples, and ELISA for serum samples. The results were compared with other tumor entities, mainly breast. EXPERIMENTAL DESIGN: Samples (563) from patients suffering from primary advanced or metastatic NSCLC were evaluated. RESULTS: HER2 overexpression was demonstrated using IHC in 20% (83 of 410) of the specimens, whereas 2% (7 of 378) were positive by FISH and 6% (31 of 511) showed elevated serum HER2 levels (>15 ng/ml) by ELISA. Sixty-six specimens were positive by IHC only and 13 by ELISA only, whereas none of the specimens was positive only by FISH. Concordance between all of the techniques was seen for only 3 specimens. Of 7 IHC 3+ specimens, 4 showed gene amplification by FISH, and 3 were positive by ELISA (>15 ng/ml), whereas of 76 IHC 2+ cases only 2 were amplified by FISH, and 4 were positive by ELISA. HER2 positivity by at least one of the three techniques was most common in adenocarcinomas, at 29% (42 of 143). CONCLUSION: Gene amplification and HER2 protein overexpression at the 3+ level appear to be uncommon in NSCLC. The concordance between FISH and IHC 3+ disease was good in this study, in addition, ELISA would have detected several patients without IHC/FISH-positive disease.     

Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. EXPERIMENTAL DESIGN: Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. RESULTS: The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). CONCLUSIONS: These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.     

Variation in pediatric aerosol delivery: importance of facemask.

We have quantified in vitro the influence of the facemask on the amount of drug delivered (e.g., inhaled mass) by jet nebulizer and pressurized metered dose inhaler (pMDI) valved holding chamber (VHC) combinations (non-detergent-coated and detergent-coated). Pediatric breathing patterns were used with a breathing simulator, which was connected to a face onto which each device was positioned. An inhaled mass filter interposed between the simulator and the face captured the aerosolized drug. Budesonide inhalation suspension (0.25 mg) was used with the jet nebulizers and fluticasone propionate (220 microg) pMDI with the VHCs. Maximal drug delivery was measured using constant flow through each device. Breathing pattern effects were assessed for sealed devices (no leaks) and with facemasks (possible leaks at the facemask). Inhaled mass from both nebulizers and pMDI VHCs was affected by breathing pattern, but compared to nebulizers the pMDI VHCs were significantly more variable and sensitive to several factors. The influence of VHC conditioning combined with effects of breathing pattern resulted in the inhaled mass ranging from 0.7 +/- 0.5 to 53.3 +/- 6.2%. Nebulizers were less variable (9.6 +/- 0.7 to 24.3 +/- 3.1%). Detergent coating of VHC markedly increased the inhaled mass and reproducibility of drug delivery (27.2 +/- 1.4 to 53.3 +/- 6.2%) for pMDI VHC combinations, but these effects were lost in the presence of facemasks. Using pediatric patterns of breathing, nebulizer/facemask combinations delivered 4.1 +/- 0.8 to 19.3 +/- 2.3% of the label dose while pMDI and detergent-coated VHC delivered 4.0 +/- 1.6 to 28.6 +/- 2.5%. Facemask seal is a key factor in drug delivery. Leaks around the facemask reduce drug delivery and for pMDI VHCs can negate effects of detergent coating.