Fabrication of large binary colloidal crystals with a NaCl structure.

Binary colloidal crystals offer great potential for tuning material properties for applications in, for example, photonics, semiconductors and spintronics, because they allow the positioning of particles with quite different characteristics on one lattice. For micrometer-sized colloids, it is believed that gravity and slow crystallization rates hinder the formation of high-quality binary crystals. Here, we present methods for growing binary colloidal crystals with a NaCl structure from relatively heavy, hard-sphere-like, micrometer-sized silica particles by exploring the following external fields: electric, gravitational, and dielectrophoretic fields and a structured surface (colloidal epitaxy). Our simulations show that the free-energy difference between the NaCl and NiAs structures, which differ in their stacking of the hexagonal planes of the larger spheres, is very small (approximately 0.002 k(B)T). However, we demonstrate that the fcc stacking of the large spheres, which is crucial for obtaining the pure NaCl structure, can be favored by using a combination of the above-mentioned external fields. In this way, we have successfully fabricated large, 3D, oriented single crystals having a NaCl structure without stacking disorder.

Dynamics of hard sphere suspensions using dynamic light scattering and X-ray photon correlation spectroscopy: dynamics and scaling of the intermediate scattering function.

Intermediate scattering functions are measured for colloidal hard sphere systems using both dynamic light scattering and x-ray photon correlation spectroscopy. We compare the techniques, and discuss the advantages and disadvantages of each. Both techniques agree in the overlapping range of scattering vectors. We investigate the scaling behavior found by Segré and Pusey [Phys. Rev. Lett. 77, 771 (1996)] but challenged by Lurio et al. [Phys. Rev. Lett. 84, 785 (2000)]. We observe a scaling behavior over several decades in time but not in the long-time regime. Moreover, we do not observe long-time diffusive regimes at scattering vectors away from the peak of the structure factor and so question the existence of long-time diffusion coefficients at these scattering vectors.

Comparing photonic band structure calculation methods for diamond and pyrochlore crystals.

The photonic band diagrams of close-packed colloidal diamond and pyrochlore structures, have been studied using Korringa-Kohn-Rostoker (KKR) and plane-wave calculations. In addition, the occurrence of a band gap has been investigated for the binary Laves structures and their constituent large- and small-sphere substructures. It was recently shown that these Laves structures give the possibility to fabricate the diamond and pyrochlore structures by self-organization. The comparison of the two calculation methods opens the possibility to study the validity and the convergence of the results, which have been an issue for diamond-related structures in the past. The KKR calculations systematically give a lower value for the gap width than the plane-wave calculations. This difference can partly be ascribed to a convergence issue in the plane-wave code when a contact point of two spheres coincides with the grid.

Interfacial rheology of model particles at liquid interfaces and its relation to (bicontinuous) Pickering emulsions.

Interface-dominated materials are commonly encountered in both science and technology, and typical examples include foams and emulsions. Conventionally stabilised by surfactants, emulsions can also be stabilised by micron-sized particles. These so-called Pickering-Ramsden (PR) emulsions have received substantial interest, as they are model arrested systems, rather ubiquitous in industry and promising templates for advanced materials. The mechanical properties of the particle-laden liquid-liquid interface, probed via interfacial rheology, have been shown to play an important role in the formation and stability of PR emulsions. However, the morphological processes which control the formation of emulsions and foams in mixing devices, such as deformation, break-up, and coalescence, are complex and diverse, making it difficult to identify the precise role of the interfacial rheological properties. Interestingly, the role of interfacial rheology in the stability of bicontinuous PR emulsions (bijels) has been virtually unexplored, even though the phase separation process which leads to the formation of these systems is relatively simple and the interfacial deformation processes can be better conceptualised. Hence, the aims of this topical review are twofold. First, we review the existing literature on the interfacial rheology of particle-laden liquid interfaces in rheometrical flows, focussing mainly on model latex suspensions consisting of polystyrene particles carrying sulfate groups, which have been most extensively studied to date. The goal of this part of the review is to identify the generic features of the rheology of such systems. Secondly, we will discuss the relevance of these results to the formation and stability of PR emulsions and bijels.

Relationship between steroid excretion patterns and breast cancer incidence in Israeli women of various origins.

A nationwide study of the steroid excretion patterns in postmenopausal Israeli migrant women demonstrated differences between high- and low-risk groups for breast cancer in the following variables: age at first parturition, number of pregnancies, number of live births, height, and weight. The direction of the differnces was in line with those observed for breast cancer patients. The groups also differed in the exretion of estriol, 17-ketosteroids, and allotetrahydrocortisol. Multiple regression analysis revealed that the exretion of estriol was significantly lower in population groups in whom breast cancer incidence was high. Possibly this trend--which has also been observed in adolescent and premenopausal women--reflected environmental influences on peripheral estrogen metabolism.

Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue.

The endogenous concentrations and subcellular distribution of estrone and estradiol were measured in malignant and nonmalignant human breast tissue from pre- and postmenopausal women. The most striking finding was the significantly higher concentration of estradiol per g of tissue in the malignant tissues than in the nonmalignant tissues. The tissue concentrations of estradiol in pre- and postmenopausal women were similar despite the large differences in the peripheral plasma levels. No correlation was found between the estradiol receptor content and endogenous concentration and subcellular distribution of estradiol. No difference in the estrone tissue concentration was found between malignant and nonmalignant tissues. In comparison with human uterine tissues, which we have reported previously, human breast tissue "handles" estrogenic hormones differently from human uterine tissue. At equal concentrations of the estradiol receptor, concentrations and subcellular distribution of the estrogens are different in both tissues. It is concluded that the mechanism of action of estradiol via its receptor, a mechanism mainly based on studies in animal uterine tissue, applies only qualitatively to human breast cancer tissue.

Endogenous concentration and subcellular distribution of androgens in normal and malignant human breast tissue.

The endogenous concentrations and the subcellular distribution of dehydroepiandrosterone (DHEA) and 5-androstene-3 beta,17 beta-diol (ADIOL) were measured in malignant and nonmalignant human breast tissue from both pre- and postmenopausal women. DHEA 3-sulfate was measured only in the cytosol. A greater tissue-plasma gradient of DHEA was present with large variations. The highest concentration of DHEA and ADIOL occurred in the nuclear fraction (average, 2.9 and 1.6 times the concentration in cytosol). With respect to DHEA, this finding is remarkable because no specific binding protein in human breast tissue has been reported. The concentration of DHEA 3-sulfate was significantly higher in the cytosol of nonmalignant than in malignant breast tissues. No significant differences in tissue concentrations of DHEA and ADIOL were found in malignant and nonmalignant breast tissue. The concentration of estrogens was measured in the cytosol and the nuclear fraction of the same tissues, as reported in a previous paper. We found a significantly higher estradiol concentration in malignant tissue as compared to nonmalignant tissue. When the ratio of ADIOL to estradiol was calculated from the combined data, a significant difference was found only in the cytosol of premenopausal cancer patients versus normal women. No difference was seen in the postmenopausal women. No difference in the ADIOL:estradiol ratio was found between normal and malignant breast tissue of patients of the same menopausal status.

Search for estrogen receptors in human meningioma tissue sections with a monoclonal antibody against the human estrogen receptor.

Meningiomas are rich in progestin receptors, whereas estrogen receptors (ER) are virtually undetectable. The present experiments were performed to evaluate whether the absence of ER from the majority of human meningioma cytosols can be attributed to: occurrence of only a small number of ER-positive cells in an otherwise ER-negative tissue; resistance of nuclear receptors to extraction; or impairment of steroid binding. Twenty-one specimens were selected from our total series of 67 meningiomas. Based on cytosol assays, five of these meningiomas were considered to be ER positive (10-42 fmol/mg protein) and five had marginal ER concentrations (4-9 fmol/mg protein), whereas the remaining tissues were ER negative. For comparison, human breast cancer tissues were used. Tissues were sectioned at 6 micron and stained immunocytochemically using a monoclonal antibody against the human ER. The breast cancer specimens showed specific nuclear staining in part of the tumor cells. The sensitivity of the immunocytochemical assay was found to be sufficient to detect staining in breast cancer tissues containing as little as 17 fmol ER/mg cytosol protein. No specific staining was observed in meningioma tissues. It is concluded that the majority of meningiomas are truly devoid of ER and that the estrogen binding agent detected in low concentration in some meningioma cytosols is immunologically different from the human breast cancer ER. The presence of progestin receptors in meningioma apparently does not require the continuous presence of ER.

Inhibition of breast cancer tissue aromatase activity and estrogen concentrations by the third-generation aromatase inhibitor vorozole.

In about one-third of advanced breast cancers, estrogen deprivation causes tumor regression. Estrogen concentrations in tumor tissue seem to depend largely on local production. The aromatase enzyme complex is thought to be the key enzyme in this respect. In the present study, the effect of the new third-generation nonsteroidal aromatase inhibitor vorozole (Rivizor) on tumor tissue aromatase activity and estrogen concentrations was evaluated. During 7 days preceding mastectomy, 11 postmenopausal breast cancer patients were treated with 2.5 mg of vorozole once daily. Eight patients could be evaluated. Intratumoral aromatase activity and estrone and estradiol levels were measured and compared to the values of nine untreated postmenopausal breast cancer patients. In treated patients, median tissue aromatase activity was 89% lower than that in controls (P < 0.001). Similarly, median tissue estrone and estradiol concentrations were 64 and 80% lower, respectively, in treated patients (P = 0.001 and P < 0.05, respectively). These results support the hypothesis that depleting the tumor of estrogens, thus impairing estrogenic stimulation, is an important mechanism in the antitumor activity of aromatase inhibitors.

Inhibition of the in vivo conversion of androstenedione to estrone by the aromatase inhibitor vorozole in healthy postmenopausal women.

Vorozole is a new, potent, and highly selective nonsteroidal aromatase inhibitor, which in animal and human studies was found to be about 1000-fold more potent than aminoglutethimide. Almost all aromatase-inhibiting activity resides in the dextro-enantiomer currently undergoing clinical trials. A marked decrease in circulating estrogens was found in several studies of healthy premenopausal women and male volunteers treated with the racemate, referred to as vorozole racemate. To further evaluate the aromatase-inhibiting potency of this drug, the in vivo conversion of androstenedione to estrone was studied in 12 healthy postmenopausal women. Four h after a single oral dose of vorozole racemate, [14C]androstenedione and [3H]estrone were infused at a constant rate for 2 h. Women were randomized to receive vorozole racemate orally in one of three different doses, i.e., 1, 2.5, and 5 mg, in a double-blind protocol. Each woman acted as her own control in an identical experiment with a placebo carried out 2-4 weeks either before or after the test with vorozole racemate. In the urine, collected for 4 days after each experiment, estrogens were extracted and purified until a constant 3H/14C ratio of estrone was achieved. The percentage conversion of androstenedione to estrone in the 12 placebo experiments was 2.19 +/- 0.60% (mean +/- SD, n = 12). Following a single administration of vorozole racemate, the conversion decreased to 0.14 +/- 0.04%. The percentage inhibition was 93.0 +/- 2.5 (n = 4) following administration of 1 mg vorozole racemate; administration of 2.5 or 5 mg resulted in an inhibition percentage of 93.2 +/- 1.6 or 94.4 +/- 1.2, respectively. It is concluded that a single oral dose of 1-5 mg vorozole racemate results in an almost complete inhibition of in vivo aromatase activity.

Hormonal aspects in the causation of human breast cancer: epidemiological hypotheses reviewed, with special reference to nutritional status and first pregnancy.

Epidemiology of breast cancer has identified early age at menarche, late first pregnancy, low parity and late menopause as risk factors, but in addition genetic factors, height, weight and living in western countries play a significant role. The international variation in incidence is almost exclusively due to non-genetic factors. Hypotheses in prevention-oriented research are reviewed: 1. obesity-related oestrogen production as a stimulus of the tumour in postmenopausal women; 2. nutritional status and energy expenditure during puberty and adolescence, developed for fertility and fecundity and extended later to breast cancer; 3. reproductive life during early adulthood, age at first pregnancy and its specific effects on breast tissues. The message of preventability of breast cancer is that mammary epithelial differentiation should come early. Our insight concerning events in puberty and early adulthood can be consolidated in one concept on the risk of extended proliferation of breast epithelium during early adulthood in the absence of full differentiation induced by pregnancy. The combined effects of Western-type nutrition, lack of exercise and Western-type women's emancipation sets the stage for breast cancer already at a young age. Since it is unlikely that emancipated women in affluent societies will return to the original life-style of getting pregnant as soon as it is biologically possible, a novel daring way of protection has to be considered. Could a "Breast Differentiation Pill" be developed to offer protection?

Aromatase and comparative response to its inhibitors in two types of endometrial cancer.

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R(s)=+0.63, p=0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p=0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.

Decrease of circulating insulin antibodies in two patients treated with continuous subcutaneous infusion of human insulin (recombinant DNA).

Circulating insulin antibodies (CIA) were measured in two patients treated with continuous subcutaneous infusion (CSII) of human insulin (recombinant DNA). CIA were determined by a kinetic equilibrium assay after pretreatment of the serum to remove bound and free insulin. We observed that by changing from either purified bovine or purified porcine insulin to human insulin given by CSII, there is a gradual decrease in CIA detectable after 3 wk and more pronounced 3 mo after changing. These findings suggest that human insulin in combination with the improved metabolic control by CSII considerably reduces the antibody formation in patients with IDDM.

C-peptide reactivity as a measure of insulin dependency in obese diabetic patients treated with insulin.

The C-peptide increase after an oral glucose tolerance test (OGTT) and intravenous glucagon test (GT) was assessed to establish actual insulin dependency in 16 obese diabetic patients treated with insulin for years. The results, compared to five reference groups, showed two types of reaction: first, a negative response in 3 patients with a minimal C-peptide increase after either stimulation (range 0-0.1 ng/ml during GT, 0-0.5 during OGTT), not different from that in the insulin-dependent reference group (GT: 0.1 +/- 0.2, OGTT: 0.1 +/- 0.3. means +/- SD). Second, a positive response in 13 patients with a C-peptide increase, different from that in the insulin-dependent group after glucagon (range 0.7-5.6), and in 6 patients after OGTT (range 0.8-1.8). When insulin treatment was discontinued in two nonresponders, the B-hydroxybutyrate levels and ketobutyrate levels increased to over 2.1 and 0.60 mmol/L within 10 days, proving insulin dependency, and thus type I diabetes. B-hydroxybutyrate and ketobutyrate levels increased to maximal 0.4 and 0.17 after stopping insulin therapy in nine positive responders. No ketoacidosis developed during a 4-wk follow-up, indicating non-insulin dependency (type II diabetes). Measuring C-peptide after glucagon is a simple test that may be a discriminative method to establish insulin dependency in obese diabetic patients treated with insulin.

C-peptide.

C-peptide is a polypeptide originating from proinsulin after its cleavage in the B-cell. It is secreted equimolarly with the other cleavage product, insulin, into the portal circulation. Only a minimal fraction of C-peptide is extracted by the liver; it is supposed to be mainly removed by the kidney. A small, constant proportion is excreted in the urine. C-peptide is measured in serum and urine by radioimmunoassay. The major sources of error of the assay are related to standard, tracer, antiserum specificity and reactivity with proinsulin, and to degradation of C-peptide. Many secretagogues are used to evaluate the B-cell function, of which glucagon is the most simple. Clinical applications of C-peptide include differentiating between endogenous and exogenous hyperinsulinism and establishing the need of insulin therapy in diabetic patients already treated with insulin. The primary value of C-peptide, however, is in clinical research, where it offers a unique opportunity to follow the B-cell secretion in diabetic subjects and to evaluate the difference that various factors may exert on its activity.

Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.

OBJECTIVE: The pharmacokinetics and glucodynamics of a new insulin analog, insulin lispro, and regular human insulin were compared and contrasted after subcutaneous administrations in femoral, deltoid, and abdominal injection sites. RESEARCH DESIGN AND METHODS: Single 0.2 U/kg doses of insulin lispro and regular insulin were administered to 12 healthy subjects in a six-way randomized crossover fashion. Each dose was given after an overnight fast in one of three injection sites: abdominal, deltoid, or femoral. Study drugs were given during a manual euglycemic glucose clamp. Blood samples were collected over the 12-h clamp for measurement of insulin-reactive components, with pharmacokinetic and glucodynamic measurements derived from these serum insulin and clamp measurements. RESULTS: Glucodynamic comparisons between insulin lispro and regular insulin showed a greater maximum infusion rate (Rmax) at an earlier time (TRmax), regardless of injection site. The total glucose infused (Gtot) showed nearly identical values between sites for insulin lispro. Regular insulin showed greater Gtot values from deltoid and femoral injections. When comparisons were made between drugs, regular insulin produced significantly greater Gtot, primarily driven by the increased Gtot from deltoid and femoral injections. Greater maximum serum insulin concentrations (Cmax) were experienced with insulin lispro at earlier times (tmax), regardless of the injection site (P < 0.001). Abdominal administrations produced the greatest Cmax values at the earliest tmax for both regular insulin and insulin lispro. Deltoid and femoral injections had lower Cmax values for both compounds. Shifts also occurred with tmax, although these shifts were much greater with regular insulin than with insulin lispro. Equivalent area under the curve (AUC) values were found when compared between compounds. CONCLUSIONS: Slower absorption from deltoid and femoral administrations resulted in an increased duration of action for both regular insulin and insulin lispro when compared to abdominal administration. However, notable increases in the onset of action were only apparent with regular insulin. The consistency with insulin lispro response from abdominal and extremity injection sites allows more potential sites for subcutaneous injection with an assured rapid response.

[Comparison of letrozole and exemestane used in non-adjuvant therapy of endometrial carcinoma].

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.

Particle-size effects in the formation of bicontinuous Pickering emulsions.

We demonstrate that the formation of bicontinuous emulsions stabilized by interfacial particles (bijels) is more robust when nanoparticles rather than microparticles are used. Emulsification via spinodal demixing in the presence of nearly neutrally wetting particles is induced by rapid heating. Using confocal microscopy, we show that nanospheres allow successful bijel formation at heating rates two orders of magnitude slower than is possible with microspheres. In order to explain our results, we introduce the concept of mechanical leeway, i.e., nanoparticles benefit from a smaller driving force towards disruptive curvature. Finally, we suggest that leeway mechanisms may benefit any formulation in which challenges arise due to tight restrictions on a pivotal parameter, but where the restrictions can be relaxed by rationally changing the value of a more accessible parameter.

Actions and interactions of delta 5-androstene-3 beta, 17 beta-diol and 17 beta-estradiol in the immature rat uterus.

delta 5-Androstene-3 beta, 17 beta-diol (Adiol), in a dosage of 1000 microgram/24 h injected ip into immature female Wistar rats (21-23 days old), induced 72 h after the injection the same elevations of uterine weight, cytosol protein, nuclear DNA, cytosol estrogen and progesterone receptors, and nuclear estrogen receptor levels as did 17 beta-estradiol (E2) in a dosage of 2.5 microgram/24 h. Adiol appeared to translocate the estrogen receptor and induce the synthesis of estrogen and progesterone cytosol receptors in a manner almost identical to that of E2. Studies on the metabolism of tritiated Adiol ruled out the possibility that the estrogenic effects of Adiol might be mediated by conversion to E2. Small doses of Adiol (100 microgram), which alone did not result in estrogenic effects, enhanced the effect of 2.5 microgram E2 on uterine weight and progesterone receptor levels, whereas a dosage of 100 microgram dihydrotestosterone neither enhanced nor inhibited the uterine growth induced by 2.5 microgram E2. A role for the androgen receptor in the synergism between Adiol and E2, therefore, appears to be ruled out. When Adiol in a dosage of 1000 microgram was administered together with 2.5 microgram E2, there was no important difference compared to either steroid alone up to 6 h. Thereafter, a very pronounced and prolonged secondary wave of translocation of the E2 receptor to the nucleus occurred which can explain the synergism between E2 and Adiol that became apparent in the same time interval. This secondary wave of translocation is most likely related to the persistent presence of both Adiol and E2 at the time of replenishment of the cytosol receptor (3-6 h after the injection). It is concluded that delta 5-androstene-3 beta, 17 beta-diol acts in the immature rat uterus like a fully potent estrogen with a complete lack of antiestrogenic effects. In this respect it differs from androgens like testosterone and dihydrotestosterone which can display both estrogenic and antiestrogenic activities.

Spontaneous hypercortisolism without Cushing's syndrome.

A very high cortisol production rate (CPR) with elevated plasma ACTH was found in a hypertensive, hypokalemic, but otherwise healthy male patient. There were no symptoms or signs of Cushing's syndrome. The hypercortisolism appeared to be of the pituitary dependent type. During the follow-up of 36 months, no changes in outward appearance occurred, notwithstanding persistent hypercortisolism. The possibility of either Conn's syndrome or of an enzymatic defect in steroidogenesis could be ruled out. One of the three children (a healthy boy of 20 years) also showed hypertension and hypercortisolism. A possibly genetically determined hyposensitivity to the glucocorticoid action of cortisol is postulated.