Targeting of RAGE-ligand signaling impairs breast cancer cell invasion and metastasis.

The receptor for advanced glycation end products (RAGE) is highly expressed in various cancers and is correlated with poorer outcome in breast and other cancers. Here we tested the role of targeting RAGE by multiple approaches in the tumor and tumor microenvironment, to inhibit the metastatic process. We first tested how RAGE impacts tumor cell-intrinsic mechanisms using either RAGE overexpression or knockdown with short hairpin RNAs (shRNAs). RAGE ectopic overexpression in breast cancer cells increased MEK-EMT (MEK-epithelial-to-mesenchymal transition) signaling, transwell invasion and soft agar colony formation, and in vivo promoted lung metastasis independent of tumor growth. RAGE knockdown with multiple independent shRNAs in breast cancer cells led to decreased transwell invasion and soft agar colony formation, without affecting proliferation. In vivo, targeting RAGE shRNA knockdown in human and mouse breast cancer cells, decreased orthotopic tumor growth, reduced tumor angiogenesis and recruitment of inflammatory cells, and markedly decreased metastasis to the lung and liver in multiple xenograft and syngeneic mouse models. To test the non-tumor cell microenvironment role of RAGE, we performed syngeneic studies with orthotopically injected breast cancer cells in wild-type and RAGE-knockout C57BL6 mice. RAGE-knockout mice displayed striking impairment of tumor cell growth compared with wild-type mice, along with decreased mitogen-activated protein kinase signaling, tumor angiogenesis and inflammatory cell recruitment. To test the combined inhibition of RAGE in both tumor cell-intrinsic and non-tumor cells of the microenvironment, we performed in vivo treatment of xenografted tumors with FPS-ZM1 (1 mg/kg, two times per week). Compared with vehicle, FPS-ZM1 inhibited primary tumor growth, inhibited tumor angiogenesis and inflammatory cell recruitment and, most importantly, prevented metastasis to the lung and liver. These data demonstrate that RAGE drives tumor progression and metastasis through distinct tumor cell-intrinsic and -extrinsic mechanisms, and may represent a novel and therapeutically viable approach for treating metastatic cancers.

Investigations into the source of two fungicides measured in the air for 24 hours following application to a cereal crop.

Airborne pesticides can be detected near to recently-treated arable fields for a period of days following the application. Identifying the source of such pesticides is important in developing predictive models for use in exposure and risk assessments. Previous work showed levels of pesticide in the air that were higher than expected for a low-vapour-pressure active ingredient, epoxiconazole, and comparable with an active ingredient of a significantly higher vapour pressure, fenpropidin. It was possible that the measured concentrations could be attributed to 'dust' particles emitted from the crop, either biological material contaminated with pesticide or solid dried deposits of active ingredient and other formulation components. A second experiment was therefore undertaken to measure airborne concentrations of the same active ingredients and to determine whether some or all of the measured airborne pesticide could be attributed to particles, using a Marple personal cascade impactor, which collects particles in the range 0.3 - 50 microm. Such samplers are not optimised to give good sampling efficiencies under the proposed field conditions, so some initial tests were undertaken in the Silsoe wind tunnel to assess its ability to sample particles in an air flow. In the subsequent field trial, a 192 m square plot in a commercially established winter cereal crop was sprayed with a tank mix of commercial formulations of epoxiconazole and fenpropidin. Measurements of airborne pesticides were made for 24 hours following the application with suction samplers attached to tenax tubes to evaluate vapour concentrations and with the cascade impactor to determine whether contaminated airborne particles were present. The concentrations of pesticide measured with the tenax tubes were significantly higher than the particulate component detected on the cascade impactor plates and it is therefore it was very unlikely that there was a significant contribution from pesticide-laden particles to the airborne concentration. Although it is clear that under these particular experimental conditions, airborne contaminated particles were not detected in significant quantities after the application, it is possible that this could occur under different circumstances, such as during pollen release or harvest.

Comparative molecular field analysis as a tool to evaluate mode of action of chemical hybridization agents.

The 3D-QSAR method of comparative molecular field analysis (CoMFA) was applied to three patent families of chemical hybridization agents (CHAs) in the MON21200 class of chemistry. The models for each CHA family gave good correlations between the variations in log percent male sterility and in the steric-electrostatic properties of the patent set. For all CHA families, observed sterility rates are generally higher for the sodium salts than for the corresponding esters. This is consistent with our CoMFA models which show that negative charge is favored in the region of the carboxylate group. The CoMFA models also indicated that for the MON21200 family increased steric bulk at the 4-position on the phenyl ring is associated with enhanced activity. However, for the RH0007 and the HYBRID families, male sterility is generally enhanced with increased steric bulk at the 2- or 3-position on the phenyl ring. Although the models cannot provide unambiguous conclusions about a common mode of action, similarities in the CoMFA contour maps provided some clues for a common agrophore for these three CHA families.

Enduring and different: a meta-analysis of the similarity in parents' child rearing.

The assessment of child-rearing beliefs and behavior has predominantly focused on qualities and characteristics believed to reflect consistent, enduring qualities of parenting--the similarity in child rearing. This review evaluates the evidence for similarity and differences among 3 types of child-rearing data and includes comparisons across time, children, and situations. Both relative stability and mean level differences were found in all 3 domains. The most similarity was found in the across-time and across-children domains, although it depended on the child-rearing construct and methodology used. It is argued that attention to the variability and change in child rearing must be incorporated into theoretical models of parenting to better understand the nature of child rearing and, in turn, parental influence on children's development.

Demonstration of improved automatic target-recognition performance by moment analysis of correlation peaks.

We report the results of experimental tests of an optical-correlator-based automatic target recognition (ATR) system that uses the correlation-peak moment analysis technique of Caprari [Appl. Opt. 38, 1317 (1999)] to assist in discrimination between target and clutter peaks. The ATR system and its operation are briefly described with particular attention devoted to a practical scheme for enhancing the basic ATR system with correlation-peak moment detectors. We investigate the variation of detection and false-alarm rates of moment detectors with moment threshold values. For fixed moment thresholds, we present receiver operating characteristics of both basic and enhanced systems as the conventionally used correlation-peak energy threshold is varied. Results demonstrate that correlation-peak moment analysis materially improves ATR system target-detection performance.

Comparison of automatic target recognition system performance with full- and reduced-resolution correlators.

The performance of an automatic target recognition (ATR) system with full- and reduced-resolution correlators was compared. In addition, the ATR system performance with reduced-resolution filter sets designed by use of multiresolution analyasis (MA) and downsampling (DS) techniques was also compared. It was discovered that results obtained at the optical correlator subsystem level, pertaining to the relative merits of the MA and the DS techniques, could not be extrapolated to the system level. This was because target signature differences between the test and the training imagery were discovered to have a greater influence on system performance than the choice of filter design technique. In addition, it was found that, for the case in which the target signature and the reduced-resolution filter were of the same size, there was some degradation in the receiver-operating-characteristic curve for reduced resolution compared with full. Nevertheless, this was deemed to have no practical significance, and thus the use of reduced-resolution optical correlators for ATR merits serious consideration.

Clinical predictability of the waist-to-hip ratio in assessment of cardiovascular disease risk factors in overweight, premenopausal women.

The waist-to-hip ratio (WHR) is one of the most commonly used anthropometric measures to indicate a central obesity pattern and an increased risk of cardiovascular disease in normal-weight women. Although the American Heart Association has reported that a WHR >0.80 be used to indicate increased risk of cardiovascular disease in women, the present study assessed the WHR above which is seen elevations in cardiovascular disease risk factors in a sample of overweight women. Using data from 240 women aged 27.5-47.5 y enrolled in a university weight-loss program, we determined WHR quartiles: <0.80, 0.80 to <0.84, 0.84 to <0.90, and > or =0.90. Subjects were placed into high-risk categories for cardiovascular disease on the basis of age- and population-defined norms. Women had an increased likelihood of elevated VLDL cholesterol, triacylglycerol, diastolic blood pressure, and composite risk (ie, having > or =4 cardiovascular disease risk factors) and an increased risk of having low concentrations of HDL at a WHR > or =0.90. All aforementioned variables had a significant odds ratio at a WHR > or =20.90 after adjustment for smoking, whereas elevated VLDL, triacylglycerol, and diastolic blood pressure were observed at this WHR after adjustment for a body mass index (in kg/m2) < or > or =35. Only 2 variables, VLDL and triacylglycerol, had a significant odds ratio at a WHR <0.90 before and after adjustment for BMI and smoking. These data suggest an upward shift in the critical threshold for WHR to > or =0.90, at which point there was an elevation in cardiovascular disease risk factors in already overweight women. This trend persisted regardless of whether the women smoked or whether their body mass index was < or > or =35.

The relationship between fat distribution and coronary risk factors in sedentary postmenopausal women on and off hormone replacement therapy.

The purpose of this study was to examine the relationship between fat distribution and coronary risk factors (CRF) in sedentary overweight postmenopausal women both on and off hormone replacement therapy (HRT). Medical records and information were abstracted from nonsmoking women entering a weight loss program. A total of 33 women on HRT (mean age=50.12+/-5.2) and 51 nonusers (mean age=52.52+/-7.8) fulfilled subject eligibility requirements and were included in the data analysis. Results showed a significantly lower waist-to-hip ratio (WHR) (p=0.009) and waist (p=0.010) and greater levels of high-density lipoprotein cholesterol (HDL-C) (p=0.035) in HRT users than in nonusers. After converting correlations to standard Z-scores and performing z-tests, the correlation between total cholesterol (T-Chol) and WHR was significantly greater in nonusers than in HRT users (p=0.038). A multiple regression analysis showed differences between groups in the ability of age and anthropometric variables to predict CRF. Although T-Chol could be predicted in nonusers (r2=0.24; p=0.011), very low-density lipoprotein cholesterol (VLDL-C) and systolic blood pressure (SBP) could be significantly predicted in HRT users only (r2=0.28, p=0.055 and r2=0.40, p=0.005 for VLDL-C and SBP, respectively). These data suggest that there are differences between HRT users and nonusers in predictors of CRF, central adiposity, HDL-C, and the relationship between WHR and T-Chol. It is concluded that the significantly lower levels of central adiposity observed in HRT users may have clinical benefits with regard to CRF.

Investigations into reduced-resolution optical correlators with realistic spatial light modulator fill factors.

The design of reduced-resolution filters by multiresolution analysis (MA) or by downsampling is extended to spatial light modulators with fill factors less than one. Analysis shows that the dependence of the zero-order correlation peaks with fill factor varies with target size for both design techniques. Also, a practicable performance improvement is obtained for MA compared with downsampling for small- to medium-sized targets that is greater for larger fill factors. The validity of the analysis is confirmed by simulation. A reduced-resolution optical correlator is constructed, and a comparison of MA and downsampling filters is performed for different-sized targets. The experimental results show good qualitative agreement with the simulation; however, the first-order correlation peaks were found to be greater for the experimental results. A possible reason for this is that the manufacturer's fill-factor specification might be too large; therefore a new technique for measuring the fill factor is proposed.

Relation between anthropometric measures of fat distribution and cardiovascular risk factors in overweight pre- and postmenopausal women.

This study compared three different measures of central adiposity: waist-to-hip ratio (WHR), waist-to-height ratio (WSHT), and waist circumference with cardiovascular risk factors, including serum lipoproteins and blood pressure in overweight pre- (n = 115) and postmenopausal (n = 46) women. Premenopausal women had a mean age of 35.6 +/- 6.79 y and a mean body mass index (BMI; in kg/m2) of 37.08 +/- 6.01. Postmenopausal women had a mean age of 52.5 +/- 8.19 y and a mean BMI of 38.75 +/- 6.9. Although several correlations between central adiposity and serum lipoproteins and blood pressure were significant, they were unaffected by menopausal status. There were also no significant differences among the three measures of central adiposity in relation to cardiovascular risk factors within premenopausal and postmenopausal groups. An analysis of covariance controlling for BMI showed that after stratifying WSHT into tertiles, a significant interaction of WSHT group by menopausal status was found for systolic blood pressure (SBP) (P = 0.019). Postmenopausal women had a significantly greater SBP than premenopausal women in the lowest and highest tertiles (P = 0.001); however, this pattern was not shown in the middle WSHT tertile. The relation between central adiposity and cardiovascular risk factors appears to be unchanged after menopause, except when WSHT is used to indicate SBP. Because increased central adiposity may also indicate an increase in cardiovascular risk factors, measurements of central adiposity can be used to supplement the routine clinical evaluation of cardiovascular risk factors in both pre- and postmenopausal overweight women.

Fitness, diet and coronary risk factors in a sample of southeastern U.S. children.

The purpose of this study was to evaluate the relationship between physical fitness variables and nutrient intake to coronary risk factors (CRF) in a sample of children living in the Southeastern U.S. A total of 22 sixth-grade children of whom 10 were boys (mean age = 11.83 +/- 0.3) and 12 were girls (mean age 11.7 +/- 0.3) volunteered for this study. Results indicated that boys in comparison to girls weighed more (54.0 +/- 10.8 kg versus 42.1 +/- 8.0 kg; p < 0.05), had a higher body mass index (BMI) (23.6 +/- 2.7 versus 20.2 +/- 3.3; p < 0.05), a higher lean body mass (37.8 +/- 6.0 kg versus 30.7 +/- 3.8 kg; p < 0.01), and a higher systolic blood pressure (115.7 +/- 11.1 versus 106.4 +/- 8.1; p < .0001). There were, however, no significant gender differences in serum lipoproteins or nutrient intake. Stepwise multiple regression analyses indicated that physical fitness variables which included VO2max, one-mile run for time, grip strength, and leg strength could significantly predict resting diastolic blood pressure (DBP) (F = 3.06; p < 0.05) and percent body fat (F = 4.98; p < 0.01) in children. Analysis of food intake revealed that total and saturated fat, and carbohydrate intake could predict serum triglycerides (TG) (F = 5.18; p = 0.01) while total kilocalorie, fat, and carbohydrate intake could significantly predict percent body fat (F = 3.42; p < 0.03). These findings may be clinically relevant since both serum triglyceride levels and percent body fat were well above the 50th percentile according to U.S. norms. In summary, the present study showed that measurements of muscular strength in addition to aerobic fitness are associated with DBP and percent body fat in children. Furthermore, it is recommended that nutrient intake be used when evaluating CRF in children due to its ability to predict TG and percent body fat.

Nutrient intake and psychological and physiological assessment in eumenorrheic and amenorrheic female athletes: a preliminary study.

The present study showed that amenorrheic athletes (AAs) scored higher on the Eating Attitudes Test (EAT) (p < .05) than eumenorrheic athletes (EAs), indicating more aberrant eating patterns in the first group. Scores on the EAT were inversely correlated with fat intake (p < .05), simple carbohydrate intake (p < .01), and percentage saturation of iron (p < .05) and were positively correlated with total iron binding capacity (p < .01) for the total sample. Physiological assessment of athletes revealed that there were no significant differences between groups in serum lipoproteins, with both EAs and AAs having serum lipid profiles indicative of low cardiovascular risk. Furthermore, low-density lipoprotein cholesterol was the only lipoprotein significantly and positively correlated with serum estradiol levels for the entire sample (p = .01). The present study was in agreement with previous work showing that scores of the EAT represent a primary difference between EAs and AAs; the present study was somewhat different than previous work in that serum lipoproteins were not significantly related to menstrual status.

Human Y-box transcription factors: sequences of two new YB-1 alleles.

The complete nucleotide (nt) sequences of two new alleles of the human Y-box-binding protein are described. These alleles show over 93% nt similarity to published sequences of YB-1.

Reduced-resolution synthetic-discriminant-function design by multiresolution wavelet analysis.

Several approaches to the design of reduced-resolution synthetic discriminant functions (SDF's) using multiresolution wavelet analysis (MWA) techniques are investigated. In the first approach, reducedresolution approximations of a full-resolution SDF are obtained by MWA. In the second approach, reduced-resolution approximations of the training-image Fourier transforms are obtained by MWA, and a reduced-resolution SDF is obtained directly by training on these. For both approaches, reducedresolution MICE-SDF filters were designed with MWA and conventional down-sampling techniques. Simulations showed that filters designed by the second approach with MWA techniques permitted reductions in the number of filter pixels from 128 × 128 to 32 × 32, while still satisfying the design constraints. In comparison, the performances of 32 × 32 filters designed by conventional downsampling techniques were significantly degraded.

Augmentation of transfers for a quadriplegic patient using an implanted FNS system. Case report.

A 22 year old man with incomplete quadriplegia (C6-7) was unable to perform either a sliding or a pivot transfer. He was instrumented with an implanted functional neuromuscular stimulation (FNS) system, radio frequency-linked to a belt-worn controller. The system activated eight muscles selected from among quadriceps, hamstrings, posterior portion of the adductor magnus, gluteus maximus, and erector spinae, bilaterally. The two-stage implantation procedure included electrode implantation with percutaneous leads followed by stimulator implantation and removal of the percutaneous leads. All implants were well tolerated with no adverse effects. The subject was able independently to put on the external controller portion of the system and to perform a standing pivot transfer with only standby assistance. An unexpected outcome of the FNS system use was increased voluntary upper body strength that resulted in improvement of the sliding transfer from 'inability' to 'independent'.

Norplant® implant use-dynamics diagnostic study: indonesia 1991.

Indonesia's national family planning program constitutes the largest introduction of the NORPLANT® implant in the world. With the first five-year removals occurring in late 1991, the program was at a critical stage. In Fall 1991, the ANEORTA Project conducted a Use-Dynamics Study to look systematically at NORPLANT® implant use in the field. To prepare for that study, and to get early information on program functioning, BKKBN and the Population Council, in conjunction with Andalas University in West Sumatra and BKS-PENFIN in West Java, undertook a diagnostic study of six clinics in each of two provinces, interviewing service providers and examining records. A total of 120 acceptors were visited to determine the feasibility of locating them and whether they were still using implants. About 70 percent of the acceptors had accepted from non-clinical sources, either "safaris" or mobile team visits. The four-year life-table continuation rate was 78 percent. No written information specifically devoted to the NORPLANT® implant was available either to providers or to clients. Available records generally matched official records, although significant gaps were found. All physicians and nurse-midwives, as well as many nurses, had some training, formal or informal in NORPLANT® implant insertion and removal. Contrary to expectation, clinical staff, records, and logistics all seemed generally adequate for five-year removal, although some problems were anticipated.

Trends in the management of childhood diarrhoea in Egypt: 1979-1990.

Until 1979, diarrhoeal disease accounted for roughly half of all infant and childhood deaths in Egypt, partly because curative care was largely inappropriate. The National Control of Diarrhoeal Diseases Project (NCDDP) addressed this problem from 1982 to 1991. Since 1979 many aspects of diarrhoeal disease in Egypt have been addressed in many studies. This paper reviews that literature, finding considerable improvements in case management, particularly in the use of oral rehydration solution and in feeding during diarrhoeal episodes. This is due primarily to the NCDDP. At the same time diarrhoeal mortality declined rapidly, both absolutely and as a percentage of total mortality. Persistent diarrhoeas, which have become an increasing proportion of the remaining mortality, have not been satisfactorily addressed, and irrational treatment with drugs remains a major problem.

PIP: In Egypt, roughly half of all the mortality among infants and children during the 1970s was from diarrhea. The Ministry of Health established a special program in 1982 to improve the case management of childhood diarrhea, the National Control of Diarrheal Diseases Project (NCDDP). Between 1983 and 1987, infant and childhood mortality rates from diarrhea were reduced by more than half, primarily through improved treatment. Diarrhea had customarily been treated by a combination of popular remedies and traditional and modern medicine, antidiarrheal drugs, or antibiotics. It was not widely appreciated that oral rehydration therapy (ORT) and nutritional support alone could eliminate the worst effects of diarrhea. In fact, the opposite was practiced. Breastfeeding was discontinued for days at a time, solid foods curtailed or stopped. In several surveys in the governorate of Menoufia during 1980-82, between 51% and 65% of lactating mothers stopped breastfeeding during the last diarrhea episode, and between 34% and 65% of mothers discontinued solid foods. The NCDDP program became national in 1984. By November 1985, 98% of Egyptian mothers had heard of ORT, 73% knew how to mix it properly, 64% had used it at some time in the past, 58% had used it in the child's last diarrheal episode, and 83% of those currently breastfeeding had continued during the most recent episode. There were moderately low ORT rates through 1983, rapid increases in 1984 and 1985, and stable rates since then. ORS was used for 1/3 to 1/5 of all diarrhea episodes during the late 1980s. Antidiarrheals and antiemetics are inappropriate, and antibiotics are to be used in dysentery and suspected cholera cases only, although they are still widely prescribed. In 1987 several studies were launched to investigate the epidemiology and management of persistent diarrhea.

Programmable liquid-crystal TV spatial light modulator: modified drive electronics to improve device performance for spatial-light-modulation operation.

Liquid crystal television (LCTV) continues to play a useful role as a spatial light modulator in the development and evaluation of systems for optical image processing. We outline new addressing electronics developed for a commercially available LCTV that permit writing to individual pixels at an improved display up-date rate and allow the input video signal to cover a much greater transmittance range of the TV display for black and white pixels. We illustrate this by measuring the diffraction efficiency for gratings written onto the display. For vertical gratings written along the display columns the diffraction efficiency is increased significantly, but there is no improvement for horizontal gratings. Some merits of the modified LCTV modulator for optical processing applications are considered briefly.

Seizures after primary intracerebral hemorrhage.

We followed 123 patients with primary intracerebral hemorrhage (ICH), defined as bleeding without known precipitating cause except hypertension, for an average of 4.6 years or until death in order to determine the incidence, prevalence, and type of epileptic seizures. Twenty-five percent had seizures. In one-half of these, the seizures began within 24 hours of the hemorrhage. Survival table analysis predicted a potential cumulative seizure incidence of 50%, had all patients survived 5 years. Seizure incidence was high with bleeding into lobar cortical structures (54%), low with basal ganglionic hemorrhages (19%), and zero with thalamic hemorrhages. Within the basal ganglia, caudate involvement predicted seizures; within the cortex, temporal or parietal involvement predicted seizures. Although seizure incidence was high, prevalence of chronic epilepsy was much lower: 13% in 30-day to 2-year survivors and 6.5% in 2- to 5-year survivors. Seizure incidence is higher than previously reported after ICH because small lobar hemorrhages are the most epileptogenic and are now easily recognized with computed tomography.