Adsorption of linear and star‐shaped poly(acrylic acid) to model surfaces formed by amphiphiles at the air/water interface

Monolayers of dioctadecyldimethylammonium bromide (DODA) and an azobenzene containing ammonium amphiphile at the air/water interface have been used as model surfaces to study the polyelectrolyte adsorption. The influence of the polyelectrolyte architecture on the adsorption process was studied using linear and star‐shaped poly(acrylic acid)s, which have been synthesized by atom transfer radical polymerization. The differences in the polyelectrolyte structure result in different structures of the polyelectrolyte‐amphiphile‐complex monolayer at the air/water interface. Compared to the amphiphiles on pure water the area per molecule is significantly enlarged for all polyelectrolyte complexes, the most for complex with the six‐arm‐star. Moreover, UV/Vis‐spectroscopical measurements indicate that chromophore aggregation is supressed by the complexation with poly(acrylic acid)s. The differences in monolayer properties between the pure amphiphile monolayer and the polyelectrolyte complexes monolayer can be employed for the in situ investigation of the adsorption of the polyelectrolyte to an already compressed amphiphile monolayer. Preliminary experiments were carried out by monitoring the change of the surface pressure during adsorption over time, and significant differences between linear and star‐shaped poly(acrylic acid) were found.     

Comparison of palmar aponeuroses from individuals with diabetes Mellitus and Dupuytren's contracture

It is well known that Dupuytren's contracture is often associated with diabetes mellitus. Palmar fascia from individuals with diabetes mellitus and/or Dupuytren's contracture as well as controls were subjected to differential scanning calorimetry, biomechanical and biochemical analysis. The collagen denaturation temperature of the palmar aponeurosis from individuals with diabetes mellitus in the presence (71.0°C) or absence of Dupuytren's contracture (70.6°C) was increased as compared with controls (68.5°C), while this parameter was significantly reduced (about 3.5°C) in contracture bands of Dupuytren's contracture. Stress relaxation experiments revealed that the viscous fraction was slightly reduced in diabetes mellitus (6.5%) vs. controls (8.3%), whereas in Dupuytren's contracture, irrespective of additional diabetes mellitus, a pronounced increase of this parameter was seen (36.5% vs. 24.5%) in the presence of diabetes mellitus. The time constants were significantly elevated by both disorders, this increase being more pronounced in Dupuytren's contracture. Taken together, these changes can be explained by increased cross‐linking in diabetes mellitus, while in Dupuytren's contracture other structural changes, such as increased collagen type III content and loss of fascicular organization, play an additional role besides the finding of reduced cross linking. Anat Rec 255:401–406, 1999. © 1999 Wiley‐Liss, Inc.     

Neoadjuvant bevacizumab,docetaxel and capecitabine combination therapy for HER2/neu-negative invasive breast cancer: Efficacy and safety in a phase II pilot study

Purpose

To evaluate the triplet combination of bevacizumab, capecitabine and docetaxel (XTA) as neoadjuvant therapy for breast cancer.

Experimental design

Patients with invasive, HER2-negative, nonmetastatic breast cancer (T2–4c >2 cm) and no prior systemic therapy received six 21-day cycles of XTA (bevacizumab 15 mg/kg, day 1, cycles 1–5; docetaxel 75 mg/m², day 1 of each cycle; capecitabine 950 mg/m² twice daily for 14 days of each cycle). Patients underwent surgery 2–4 weeks after completing XTA, followed by radiotherapy, chemotherapy and hormone therapy according to institution guidelines. Pathologic complete response (pCR), the primary endpoint, was defined as no evidence of invasive tumour in the final surgical sample. Secondary endpoints included rates of clinical response and breast-conserving surgery and safety.

Results

Median age of the 18 enrolled patients was 48 years (range 34–69). Most patients (72%) received six cycles of neoadjuvant therapy. pCR rate was 22% (95% confidence interval [CI]: 6–48). Nine of the patients without pCR achieved clinical partial response, giving a 72% overall clinical response rate (95% CI: 47–90). Fifteen patients underwent breast-conserving surgery (83%; 95% CI: 59–96). One additional patient had breast-conserving surgery, followed by mastectomy 1 month later. The remaining 2 patients underwent modified radical mastectomy. XTA was reasonably well tolerated, with no unexpected toxicities or treatment-related deaths.

Conclusions

The 22% pCR rate in a HER2-negative population suggests that addition of bevacizumab increases the activity of neoadjuvant capecitabine–docetaxel. Further evaluation of this regimen in early breast cancer is recommended.     

Regional cerebral blood flow single-photon emission tomography with 99mTc-HMPAO and the acetazolamide test in the evaluation of vascular and Alzheimer’s dementia

The diagnostic potential of technetium-99m hexamethylpropylene amine oxime (HMPAO) following systemic administration of the cerebral vasodilator acetazolamide (acetazolamide test) was evaluated by regional cerebral blood flow (rCBF) single-photon emission tomography (SPET) in patients with Alzheimer’s disease (AD) or vascular dementia (VD). An initial, high-resolution SPET study was performed with ^99mTc-HMPAO, and after 2 days the patients were re-evaluated with ^99mTc-HMPAO following systemic administration of acetazolamide. Reconstructed SPET slices were evaluated visually and semiquantitatively by a semi-automatic rCBF map method. When ^99mTc-HMPAO alone was used, bilateral hypoperfusion was found in the temporal and/or parietal regions in 33% (6/18) of the VD patients and in 70% (23/33) of the AD patients. The corresponding data obtained by quantitative evaluation were 41% (7/17) and 71% (15/21), respectively. The vascular reserve capacity, as determined with the acetazolamide test, was preserved visually in 22% (4/18) and quantitatively in 29% (5/17) of the VD patients, but in 73% (24/33) and 76% (16/21) of the AD patients. The differences in the perfusion patterns between the VD and AD patients were statistically significant (P<0.01, Fischer’s exact test). Of the VD patients with hypoperfusion (bilateral temporal and/or parietal), 4/6 (67%, visual evaluation) and 4/7 (57%, quantitative evaluation) had a decreased vascular reserve capacity as determined with the acetazolamide test. In the AD group of patients the corresponding results were 3/23 (13%) and 4/15 (27%). It is concluded that the acetazolamide test is promising in rCBF SPET to differentiate VD from AD. Received 1 August and in revised form 30 October 1998     

Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions

Atherosclerosis is a fibroproliferative disease of the arterial intima. It was recently found that wild-type p53 (wt p53) accumulates in human atherosclerotic tissue. Wt p53 is a cell cycle regulator involved in DNA repair, DNA synthesis, cell differentiation, and apoptosis and might therefore make an important contribution to the cellularity of atherosclerotic plaques. The product of the MDM2 gene is a nuclear protein which forms a complex with p53, thereby inhibiting the negative regulatory effects of wt p53 on cell cycle progression. In order to address a potential role of the interaction of p53 with MDM2 for the regulation of cellularity in atherosclerotic tissue, 22 carotid atheromatous plaques from patients undergoing endarterectomy were studied to determine the presence of p53 immunoreactivity (IR), MDM2 IR, cell proliferation as evidenced by MIB1/Ki-67 IR and DNA fragmentation by in situterminal transferase-mediated dUTP 3′ end labelling (TUNEL), as a marker for apoptosis. p53 IR localized to areas with evidence of chronic inflammation (22/22) and was observed in virtually all cell types in 68·79±7·51 per cent of the nuclei. p53 staining in the control tissue from human internal mammary arteries was present in 0·2±0·29 per cent of the cells (P≤0·002). MDM2 IR was present in all cases (22/22) in macrophages and smooth muscle cells (SMCs) in 60·53±8·32 per cent of the nuclei (controls: 0·8±0·65 per cent, P≤0·002) and co-localized with p53 IR as shown by examination of adjacent sections and by double immunofluorescence labelling. Importantly, co-immunoprecipitation and western blot analysis revealed that p53 and MDM2 were physically associated, indicating that MDM2–p53 complex formation takes place in vivoin human atherosclerotic tissue. Positive TUNEL staining and MIB1/Ki-67 IR present in 3·01±1·27 per cent of the nuclei (controls: 0 per cent, P≤0·002) localized to the same plaque compartments as p53 IR and MDM2 IR. Thus, the fate of cells with p53 accumulation may depend on the interaction and the stoichiometry of the p53 and MDM2 proteins. Cells were indeed found with strong p53 accumulation and nuclear morphology typical for apoptosis and there were a few MIB1/Ki-67-positive cells with co-expression of MDM2, indicating a possible role for MDM2 in reversing the negative regulatory effects of p53 for cell cycle progression. The nuclear co-localization of p53 IR with MDM2 IR and the co-immunoprecipitation assay indicate the presence of p53–MDM2 complex formation in vivo in human atherosclerotic tissue. The destiny of individual p53 and MDM2-co-expressing cells either to undergo p53-dependent apoptosis or to re-enter the cycle of cell proliferation may depend on the relative ratios of the two proteins. p53 and MDM2 may therefore play an important role in regulating cellularity and inflammatory activity in human atherosclerotic plaques. © 1998 John Wiley & Sons, Ltd.     

Bidimensional accelerations of lumbar vertebrae and estimation of internal spinal load during sinusoidal vertical whole-body vibration: a pilot study

Accelerations, a, in z- and x-directions were measured on the skin over spinous processes L₃ and L₄ in three subjects during sinusoidal whole-body vibration (WBV) at 4·5 and 8 Hz and 1·5 and 3·0 ms⁻² r.m.s. A method for the prediction of bone accelerations was applied using measurements on the skin. Relative accelerations were calculated by subtracting a_L4 from a_L3. The phase relations between relative accelerations in the z-direction indicating compression and the absolute maximum a_z of L₄ exhibited marked between-subject variability. One subject was selected for a detailed analysis in the time domain of head, shoulder and upper trunk accelerations, and for comparison with an invasive study. Bidimensional acceleration data confirmed the suggestion that relative motions in the z-direction are combined with angular motions. The results indicate complex internal loads with coupled bending, compression and shear forces.