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A subclass of lattice conditional independence models is introduced. The new class of models is called totally ordered independence models. The class is based on an assumption that the index set which orders the random variables is a chain. It is shown that there is a jump in the chain if and only if there is a conditional independence relation. Some comparisons between the lattice conditional independence models and totally ordered independence models are presented. [ABSTRACT FROM AUTHOR]

Prostate cancer cells are characterized by a remarkably low proliferative rate and the production of high levels of prostate-specific proteases. Protein-based toxins are attractive candidates for prostate cancer therapy because they kill cells via proliferation-independent mechanisms. However, the non-specific cytotoxicity of these potent cytotoxins must be redirected to avoid toxicity to normal tissues. Prostate-Specific Membrane Antigen (PSMA) is membrane-bound carboxypeptidase that is highly expressed by prostate cancer cells. Potent dipeptide PSMA inhibitors have been developed that can selectively deliver and concentrate imaging agents within prostate cancer cells based on continuous PSMA internalization and endosomal cycling. On this basis, we conjugated a PSMA inhibitor to the apoptosis-inducing human protease Granzyme B and the potent Pseudomonas exotoxin protein toxin fragment, PE35. We assessed selective PSMA binding and entrance into tumor cell to induce cell death. We demonstrated these agents selectively bound to PSMA and became internalized. PSMA-targeted PE35 toxin was selectively toxic to PSMA producing cells in vitro. Intratumoral and intravenous administration of this toxin produced marked tumor killing of PSMA-producing xenografts with minimal host toxicity. These studies demonstrate that urea-based PSMA inhibitors represent a simpler, less expensive alternative to antibodies as a means to deliver cytotoxic proteins to prostate cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: Estrogen receptor-alpha (ER) is a therapeutic target of ER-positive (ER+) breast cancers. Although ER signaling is complex, many mediators of this pathway have been identified. Specifically, phosphorylation of ER at serine 118 affects responses to estrogen and therapeutic ligands and has been correlated with clinical outcomes in ER+ breast cancer patients. We hypothesized that a newly described germline variant (S118P) at this residue would drive cellular changes consistent with breast cancer development and/or hormone resistance.Methods: Isogenic human breast epithelial cell line models harboring ER S118P were developed via genome editing and characterized to determine the functional effects of this variant. We also examined the frequency of ER S118P in a case-control study (N = 536) of women with and without breast cancer with a familial risk.Results: In heterozygous knock-in models, the S118P variant demonstrated no significant change in proliferation, migration, MAP Kinase pathway signaling, or response to the endocrine therapies tamoxifen and fulvestrant. Further, there was no difference in the prevalence of S118P between women with and without cancer relative to population registry databases.Conclusions: This study suggests that the ER S118P variant does not affect risk for breast cancer or hormone therapy resistance. Germline screening and modification of treatments for patients harboring this variant are likely not warranted. [ABSTRACT FROM AUTHOR]

Incarcerated populations have relatively high HIV prevalence but little has been reported about their aggregate HIV risk behaviors or perceptions of risk. A random selection of HIV-negative men (n = 855) entering a US state prison system were surveyed to assess five risk behaviors and his self-perceived HIV risk. Using multivariate logistic regression, we identified factors associated with having elevated actual but low perceived risk (EALPR). Of the 826 men with complete data, 88% were at elevated risk. While 64% of the sample had risk perceptions concordant with their actual risk, 14% had EALPR (with the remainder at low actual but high perceived risk). EALPR rates were lower in those with a pre-incarceration HIV test but higher for those with a negative prison entry HIV test. HIV testing counseling should assess for discordance between actual and perceived risk and communicate the continued risk of HIV despite a negative result. [ABSTRACT FROM AUTHOR]

The general multivariate analysis of variance model has been extensively studied in the statistical literature and successfully applied in many different fields for analyzing longitudinal data. In this article, we consider the extension of this model having two sets of regressors constituting a growth curve portion and a multivariate analysis of variance portion, respectively. Nowadays, the data collected in empirical studies have relatively complex structures though often demanding a parsimonious modeling. This can be achieved for example through imposing rank constraints on the regression coefficient matrices. The reduced rank regression structure also provides a theoretical interpretation in terms of latent variables. We derive likelihood based estimators for the mean parameters and covariance matrix in this type of models. A numerical example is provided to illustrate the obtained results. [ABSTRACT FROM AUTHOR]

Background/purpose: The combined contributions of oncogenes and tumor suppressor genes toward carcinogenesis remain poorly understood. Elucidation of cancer gene cooperativity can provide new insights leading to more effective use of therapies. Experimental design/Methods: We used somatic cell genome editing to introduce singly and in combination PIK3CA mutations (E545K or H1047R) with TP53 alterations (R248W or knockout), to assess any enhanced cancerous phenotypes. The non-tumorigenic human breast epithelial cell line, MCF10A, was used as the parental cell line, and resultant cells were assessed via various in vitro assays, growth as xenografts, and drug sensitivity assays using targeted agents and chemotherapies. Results: Compared to single-gene-targeted cells and parental controls, cells with both a PIK3CA mutation and TP53 alteration had increased cancerous phenotypes including cell proliferation, soft agar colony formation, aberrant morphology in acinar formation assays, and genomic heterogeneity. Cells also displayed varying sensitivities to anti-neoplastic drugs, although all cells with PIK3CA mutations showed a relative increased sensitivity to paclitaxel. All cell lines remained non-tumorigenic. Conclusions: This cell line panel provides a resource for further elucidating cooperative genetic mediators of carcinogenesis and response to therapies. [ABSTRACT FROM AUTHOR]

Polarbear-2 (PB-2) is a next-generation receiver that is part of the Simons Array cosmic microwave background (CMB) polarization experiment which is located in the Atacama desert in Northern Chile. The primary scientific goals of the Simons Array are a deep search for the CMB B-mode signature of gravitational waves from inflation and the characterization of large-scale structure using its effect on CMB polarization. The PB-2 receiver will deploy with 1897 dual-polarization sinuous antenna-coupled pixels, each with a directly contacting extended hemispherical silicon lens. Every pixel has dual polarization sensitivity in two spectral bands centered at 95 and 150 GHz, for a total of 7588 transition edge sensor bolometers operating at 270 mK. To achieve the PB-2 detector requirements, we developed a broadband anti-reflection (AR) coating for the extended hemispherical lenses that uses two molds to apply two layers of epoxy, Stycast 1090 and Stycast 2850FT. Our measurements of the absorption loss from the AR coating on a flat surface at cryogenic temperatures show less than 1 % absorption, and the coating has survived multiple thermal cycles. We can control the diameter of the coating within 25 $${\upmu }$$ m and translation errors are within 25 $${\upmu }$$ m in all directions, which results in less than 1 % decrease in transmittance. We also find the performance of the AR-coated lens matches very well with simulations. [ABSTRACT FROM AUTHOR]

In this paper we consider the extended generalized multivariate analysis of variance (GMANOVA) with a linearly structured covariance matrix. The main theme is to find explicit estimators for the mean and for the linearly structured covariance matrix.We show how to decompose the residual space, the orthogonal complement to the mean space, into m + 1 orthogonal subspaces and how to derive explicit estimators of the covariance matrix from the sum of squared residuals obtained by projecting observations on those subspaces. Also an explicit estimator of the mean is derived and some properties of the proposed estimators are studied. [ABSTRACT FROM AUTHOR]

This paper considers how to detect influential observations in crossover models with random individual effects. Two influence measures, the delta-beta influence and variance-ratio influence, are utilized as tools to evaluate the influence of the model on the estimates of mean and variance parameters with respect to case-weighted perturbations, which are introduced to the model for studying the 'influence' of cases. The paper provides explicit expressions of the delta-beta and variance-ratio influences for the general two-treatment balanced crossover models when the proposed decompositions for the perturbed models hold. The influence measures for each parameter turn out to be closed-form functions of orthogonal projections of specific residuals in the unperturbed model. [ABSTRACT FROM AUTHOR]

The authors review the literature concerning the mental health and social effects of industrialization, urbanization and the transition from a rural to an industrial society. They point out the need for prospective and longitudinal studies. To illustrate a working model of the type of research needed, the authors describe a long-term study now underway in the Shetland Islands. This research investigates the effects that rapid social and ecological change (from the North Sea oil developments) will have on the islanders. To test the hypothesis that the changes, associated with the construction of Europe's largest oil port in these previously isolated rural islands, will have a deleterious effect on the Shetlanders' health and way of life, a prospective study has been initiated that contains two sub-studies. The General Survey involves monitoring reported data on ecological, epidemiological and sociological change and is intended to provide an overview of the general impact of the oil developments. The Individual Survey involves interviewing two populations (total N = 533) and is designed to examine individuals' reactions to change and variables associated with those reactions. The target population live in a conservation region where they are not likely to be directly affected by the oil developments. Baseline findings are presented from the General Survey concerning psychiatric morbidity, crime, divorce and suicide and from the Individual Survey that focus on the prevalence of medical and psychiatric symptoms and illnesses. [ABSTRACT FROM AUTHOR]

We are developing multi-chroic antenna-coupled Transition Edge Sensor (TES) bolometer detectors for Cosmic Microwave Background (CMB) polarimetry. Multi-chroic detectors increase focal plane area efficiency, and thus the mapping speed per focal plane area, and provide greater discrimination against polarized galactic foregrounds with no increase in weight or cryogenic cost. In each pixel, a silicon lens-coupled dual-polarized sinuous antenna collects photons over a two-octave frequency band. The antenna couples the broadband millimeter wave signal into microstrip transmission lines, and on-chip filter banks split the broadband signal into multiple frequency bands. Separate TES bolometers detect the power in each frequency band and linear polarization state. We will describe the design and performance of these devices and present optical data taken. Our measurements of dual-polarization pixels in multiple frequency bands show beams with percent-level ellipticity, and percent-level cross-polarization leakage. We will also describe the development of large arrays of these multi-chroic pixels. Finally, we will describe kilo-pixel arrays of these detectors planned for the future CMB experiments that will achieve unprecedented mapping speed. [ABSTRACT FROM AUTHOR]

Protein kinase C (PKC)ɛ, a member of the novel PKC family, has key roles in mitogenesis and survival in normal and cancer cells. PKCɛ is frequently overexpressed in epithelial cancers, particularly in lung cancer. Using a short-hairpin RNA approach, here we established that PKCɛ is required for non-small cell lung carcinoma (NSCLC) growth in vitro as well as tumor growth when inoculated into athymic mice. Moreover, sustained delivery of a PKCɛ-selective inhibitor peptide, ɛV1-2, reduced xenograft growth in mice. Both RNA interference depletion and pharmacological inhibition of PKCɛ caused a marked elevation in the number of apoptotic cells in NSCLC tumors. PKCɛ-depleted NSCLC cells show elevated expression of pro-apoptotic proteins of the Bcl-2 family, caspase recruitment domain-containing proteins and tumor necrosis factor ligands/receptor superfamily members. Moreover, a Gene Set Enrichment Analysis revealed that a vast majority of the genes changed in PKCɛ-depleted cells were also deregulated in human NSCLC. Our results strongly suggest that PKCɛ is required for NSCLC cell survival and maintenance of NSCLC tumor growth. Therefore, PKCɛ may represent an attractive therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Metastasis is the major reason for breast cancer-related deaths. Although there is a host of indirect evidence for a role of protein kinase C (PKC) α in primary breast cancer growth, its role in the molecular pathways leading to metastasis has not been studied comprehensively. By treating mice with αV5-3, a novel peptide inhibitor selective for PKCα, we were able to determine how PKCα regulates metastasis of mammary cancer cells using a syngeneic and orthotopic model. The primary tumor growth was not affected by αV5-3 treatment. However, the mortality rate was reduced and metastasis in the lung decreased by more than 90% in the αV5-3-treated mice relative to the control-treated mice. αV5-3 treatment reduced intravasation by reducing matrix metalloproteinase-9 activities. αV5-3 treatment also reduced lung seeding of tumor cells and decreased cell migration, effects that were accompanied by a reduction in nuclear factor kappa B activity and cell surface levels of the CXCL12 receptor, CXCR4. αV5-3 treatment caused no apparent toxicity in non-tumor-bearing naïve mice. Rather, inhibiting PKCα protected against liver damage and increased the number of immune cells in tumor-bearing mice. Importantly, αV5-3 showed superior efficacy relative to anti-CXCR4 antibody in reducing metastasis in vivo. Together, these data show that pharmacological inhibition of PKCα effectively reduces mammary cancer metastasis by targeting intravasation and lung seeding steps in the metastatic process and suggest that PKCα-specific inhibitors, such as αV5-3, can be used to study the mechanistic roles of PKCα specifically and may provide a safe and effective treatment for the prevention of lung metastasis of breast cancer patients. [ABSTRACT FROM AUTHOR]

The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. To evaluate the biological and clinical relevance of p53 loss, human somatic cell gene targeting was used to delete the TP53 gene in the non-tumorigenic epithelial cell line, MCF-10A. In all four p53−/− clones generated, cells acquired the capability for epidermal growth factor-independent growth and were defective in appropriate downstream signaling and cell cycle checkpoints in response to DNA damage. Interestingly, p53 loss induced chromosomal instability leading to features of transformation and the selection of clones with varying phenotypes. For example, p53-deficient clones were heterogeneous in their capacity for anchorage-independent growth and invasion. In addition, and of clinical importance, the cohort of p53-null clones showed sensitivity to chemotherapeutic interventions that varied depending not only on the type of chemotherapeutic agent, but also on the treatment schedule. In conclusion, deletion of the TP53 gene from MCF-10A cells eliminated p53 functions, as well as produced p53−/− clones with varying phenotypes possibly stemming from the distinct chromosomal changes observed. Such a model system will be useful to further understand the cancer-specific phenotypic changes that accompany p53 loss, as well as help to provide future treatment strategies for human malignancies that harbor aberrant p53. [ABSTRACT FROM AUTHOR]

In this article we consider a pq-dimensional random vector x distributed normally with mean vector θ and covariance matrix Λ assumed to be positive definite. On the basis of N independent observations on the random vector x, we want to estimate parameters and test the hypothesis H: Λ = Ψ ⊗ Σ, where Ψ = ( ψ ij ): q × q, ψ qq = 1, and Σ = ( σ ij ): p × p, and Λ = ( ψ ij Σ), the Kronecker product of Ψ and Σ. That is instead of 1/2 pq( pq + 1) parameters, it has only 1/2 p( p + 1) + 1/2 q( q + 1) − 1 parameters. A test based on the likelihood ratio is given to check if this model holds. And, when this model holds, we test the hypothesis that Ψ is a matrix with intraclass correlation structure. The maximum likelihood estimators (MLE) are obtained under the hypothesis as well as under the alternatives. Using these estimators the likelihood ratio tests (LRT) are obtained. One of the main objects of the paper is to show that the likelihood equations provide unique estimators. [ABSTRACT FROM AUTHOR]

The objective of this paper is to consider shift invariance, a specific type of exchangeability, of random factors in linearmodels. The randomfactors are described via their covariance matrices and it is shown that shift invariance implies circular Toeplitz covariancematrices and marginally shift invariance implies block circular Toeplitz covariance matrices. In order to get interpretable linear models reparametrization is performed. It is shown that by putting restrictions on the spectrum of the shift invariant covariance matrices natural reparametrization conditions for the corresponding factors are obtained which then, among others, can be used to obtain unique parametrizations under shift invariance. [ABSTRACT FROM AUTHOR]

The risk of developing ovarian cancer is about 1% over a lifetime, but it is the most deadly gynecologic cancer, in part due to lack of diagnostic markers for early-stage disease and cell model system for studying early neoplastic changes. Most existing immortal human ovarian surface epithelial cells were achieved by using viral protein such as SV40 T/t antigen or E6/E7, which inactivate multiple cellular pathways. In the current study, we used a small interfering RNA (siRNA) against the retinoblastoma gene (pRb) and ectopic expression of human telomerase reverse transcriptase (hTERT) to immortalize the primary ovarian epithelial cell line OSE137 and two additional human ovarian surface epithelial cells. The immortalized OSE137 showed increased telomerase activity, lengthened telomeres, increased G2/M phase, altered cell-cycle regulatory proteins but nontumorigenic. As both Rb and hTERT pathways are commonly altered in human ovarian cancer and these genetic changes are faithfully modeled in these cells without using viral protein, these immortal cells represent an authentic in vitro model system with which to study the initiation and progression of human ovarian cancer.Oncogene (2007) 26, 1492–1498. doi:10.1038/sj.onc.1209905; published online 4 September 2006 [ABSTRACT FROM AUTHOR]

A cavity-enhanced spectrometer is developed for detection of exhaled nitric oxide in human breath. A thermoelectrically cooled, pulsed, quantum cascade laser, coupled to a high-finesse cavity, is used for trace-gas measurements. The trace-gas analyzer operates at 5.2 microns and utilizes integrated cavity output spectroscopy. Effective optical path lengths of 1.5 km are achieved in a 50-cm-length cell with a sample volume of 60 mL. The instrument is also capable of simultaneously measuringCO2 concentration in exhaled breath. Measurements were performed on human breath samples as well as simulated breath samples. Here we report a detection limit of ≤ 1 ppbv in 4 s for NO in human breath samples. [ABSTRACT FROM AUTHOR]

Background and aims: This study compared two histopathological examinations for the diagnosis of neurogenic appendicopathy (NA), assessed the frequency of NA, and evaluated whether it is a clinical disease entity distinct from acute appendicitis. Patients and methods: In a prospective observational multicenter study (surgical departments of five hospitals with one reference pathology) we evaluated 282 patients who underwent appendectomy for suspected appendicitis; we examined the frequency of NA in acute appendicitis and in the negative appendectomy group. For the diagnosis two staining methods were compared. We also attempted to determine clinical features of NA. Results: We observed 93% accuracy for hematoxylin-eosin staining compared with S-100 staining (reference standard) in the diagnosis of NA. There was NA in 3.8% of patients with acute appendicitis and in 47% of those with negative appendectomy. We observed significant differences between the three groups (NA without appendicitis, acute appendicitis, and negative appendectomy without neurogenic appendicopathy) only for sex, age, vomiting, similar previous complaints, rebound tenderness, guarding, rigidity, leukocytes (univariate analysis) and sex (multivariate analysis). Conclusion: Neurogenic appendicopathy is a histopathological entity that can be identified by hematoxylin-eosin staining. History and clinical examination do not enable us preoperatively to differentiate between acute appendicitis, NA, and negative appendectomy. [ABSTRACT FROM AUTHOR]

We consider the Hecke groups generated by $ S(z)=z+\lambda $ and $ T(z)=-1/z $ with $ \lambda=2\cos(\pi/q) $ for $ q\geqq 3 $ . We show that when $ q=4 $ or 6, the units in $ \mathbb{Z}[\lambda] $ are infinite pure periodic $ \lambda $ -fractions, and hence cannot be cusp points (images of $ \infty $ by a member of the group.) The case when $ q=7 $ is quite different; examples of units that are finite $ \lambda $ -fractions and units that are infinite $ \lambda $ -fractions are given. We conclude with a conjecture on the structure of these infinite repeating units. [ABSTRACT FROM AUTHOR]

Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin compound agent that has entered clinical trials. Studies were performed in mice to: (1) define the plasma pharmacokinetics, tissue distribution, and urinary excretion of 17AAG after i.v. delivery; (2) to define the bioavailability of 17AAG after i.p. and oral delivery; and (3) to characterize the concentrations of 17AAG metabolites in plasma and tissue. Materials and methods: All studies were performed in female CD2F1 mice. Preliminary toxicity studies used 17AAG i.v. bolus doses of 20, 40 and 60 mg/kg. Pharmacokinetic studies used i.v. 17AAG doses of 60, 40, and 26.67 mg/kg and i.p. and oral doses of 40 mg/kg. The plasma concentration versus time data were analyzed by compartmental and noncompartmental methods. The concentrations of 17AAG were also determined in brain, heart, lung, liver, kidney, spleen, skeletal muscle, and fat. Urinary drug excretion was calculated until 24 h after treatment. Results: A 60 mg/kg dose of 17AAG, in its initial, microdispersed formulation, caused no changes in appearance, appetite, waste elimination, or survival of treated animals as compared to vehicle-treated controls. Bolus i.v. delivery of 60 mg/kg microdispersed 17AAG produced "peak" plasma 17AAG concentrations between 5.8 and 19.3 µg/ml in mice killed 5 min after injection. Sequential reduction of the 17AAG dose to 40 and 26.67 mg/kg resulted in "peak" plasma 17AAG concentrations between 8.9 and 19.0 µg/ml, and 4.8 and 6.1 µg/ml, respectively. Noncompartmental analysis of the plasma 17AAG concentration versus time data showed an increase in AUC from 402 to 625 and 1738 μg/ml·min when the 17AAG dose increased from 26.67 to 40 and 60 mg/kg, respectively. Across the range of doses studied, 17AAG total body clearance varied from 34 to 66 ml/min per kg. Compartmental modeling of the plasma 17AAG concentration versus time data showed that the data were fitted best by a two-compartment, open, linear model. In each study, substantial concentrations of a material, subsequently identified as 17-(amino)-17-demethoxygeldanamycin (17AG), were measured in plasma. A subsequent, lyophilized formulation of 17AAG proved excessively toxic when delivered i.v. at 60 mg/kg. A repeat i.v. study using a 40 mg/kg dose of this new formulation produced peak plasma 17AAG concentrations of 20.2–38.4 µg/ml, and a 17AAG AUC of 912 µg/ml·min, which was approximately 50% greater than the AUC produced by a 40 mg/kg dose of microdispersed 17AAG. The bioavailabilities of 17AAG after i.p. and oral delivery were 99% and 24%, respectively. Minimal amounts of 17AAG and 17AG were detected in the urine. After i.v. bolus delivery to mice, 17AAG distributed rapidly to all tissues, except the brain. Substantial concentrations of 17AG were measured in each tissue. Conclusions: 17AAG has excellent bioavailability when given i.p. but only modest bioavailability when given orally and is metabolized to 17AG and other metabolites when given i.v., i.p., or orally. 17AAG is widely distributed to tissues. These pharmacokinetic data generated have proven relevant to the design of recently initiated clinical trials of 17AAG and could be useful in their interpretation. [ABSTRACT FROM AUTHOR]

Purpose: The efficacy of 13- cis-retinoic acid (13-CRA) given as a single agent or in combination with tamoxifen (TAM) was determined in athymic nude mice bearing advanced s.c. MCF-7 human breast cancers. Methods: 13-CRA alone was given by gavage at doses ranging from 26.4 to 200 mg/kg. TAM alone was given by gavage at doses of 7.5, 15, 30, or 60 mg/kg. For combination studies, each dose of TAM was followed 4 h later by 13-CRA at doses of 25, 50, 100, or 200 mg/kg. All treatments began on day 12 and were continued for 3 weeks. Results: The median time to two doublings recorded for the control and for 13-CRA and TAM given as single agents at the highest dose were 22.2, 29.2, and 54.7 days, respectively. In combination, 100 and 200 mg/kg 13-CRA with 7.5 mg/kg TAM resulted in a delay in tumor growth at least as high as that achieved with highest-dose TAM alone, but the effect was not synergistic. Pharmacokinetic analysis of 13-CRA was performed in plasma, liver, and tumor from mice bearing 0.5- to 2.0 g carcinomas following a single dose of 100 mg/kg 13-CRA. Results showed that 13-CRA was metabolized differently in various tissues, but concentrations of 13-CRA detected in tumor were in the range reported to be active in vitro. all-trans-Retinoic acid (ATRA) concentrations were about 5% of the 13-CRA concentrations detected in plasma, 68% of those found in liver, and 20% of those found in tumor. 4-oxo-CRA represented between 2% and 10% of 13-CRA concentrations detected in plasma and liver but was not detected in tumor. Furthermore there was no difference in peak plasma 13-CRA concentrations found in the same tissues at 30 min after a single dose or after the eighth dose of 100 mg/kg 13-CRA or 13-CRA and TAM. Mean 13-CRA concentrations detected in liver and tumor were 50–90% and 16–30% of plasma peak concentrations, respectively. No difference in 4-oxo-CRA concentration was observed between the treatment groups. Conclusions: These data suggest that 13-CRA is not effective against established human breast tumor xenografts despite the stability of the pharmacokinetics of 13-CRA and the generation of ATRA as a metabolite. The addition of 13-CRA to TAM did not improve the efficacy of TAM against these estrogen-receptor-positive xenografts. [ABSTRACT FROM AUTHOR]

For the last 20 years there has been a trend of dynamic change in the relative composition of the parasite complex of the Florida red scale, Chrysomphalus aonidum (L.), in Israel - Aphytis holoxanthus DeBach (an ectoparasite) being gradually replaced by Pteroptrix smithi (Compere) (an endoparasite). Monthly sampling of fruits and leaves in citrus groves located along the coastal plain in Israel indicated that the Florida red scale is effectively controlled by its parasites. The two parasite species coexist in the citrus groves, P. smithi generally being the dominant species. Parasitism by A. holoxanthus is relatively low during autumn and winter, increasing gradually during the spring and reaching a peak between May and August. Parasitism by P. smithi remains relatively high throughout the year. [ABSTRACT FROM AUTHOR]

Laboratory experiments employing two test procedures were carried out to evaluate the effect of three commercial pesticides commonly used against apple pests in Israel, on the spider Chiracanthium mildei L. Koch. When spiders were confined in porous nylon bags that had been treated with aqueous emulsions or suspensions, and dried, the order of toxicity during the first 4 days was endosulfan > azinphos-methyl > cyhexatin; the order of toxicity was the same by topical application. In a field experiment on apple trees which were sprayed with azinphos-methyl or methidathion, both organophosphorus compounds, the spider population was suppressed. [ABSTRACT FROM AUTHOR]

Aspects of the mathematical specialty of topology appear within several seemingly distinct areas of engineering design and engineering design theory. Indeed, the expression 'topology of a design' is often used informally. In this article a primary intent is to demonstrate the diversity of applications of topology within engineering design. A complementary goal is to introduce the engineering design community to topology as a rich, formal, well-established mathematical discipline that may be of value for wider study. Upon reviewing some of these topological applications, it appears that topology holds promise as a basis for formalizing engineering design theory. This article considers topology as a basis for unifying design abstractions. The potential benefit may be the realization of commonalities between design aspects previously considered separately, where each now has its own attendant specialized, expensive analyses. [ABSTRACT FROM AUTHOR]

Sixteen-week-old Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated and housed for 8 weeks to develop osteopenia prior to systemic administration of rhIGF-I (0.9 and 2.6 mg/kg) alone or the rhIGF-I/IGFBP-3 (0.9, 2.6 and 7.5 mg/kg) complex. After 8 weeks of treatment, proximal femurs were fixed, embedded, and cut through the midneck region. Structural and dynamic histomorphometric analyses were performed using standard techniques. Ovx increased endocortical resorption and modeling-dependent periosteal formation which resulted in decreased cortical bone area. Despite increased bone formation, trabecular number, thickness, and area were all reduced due to increased resorption. Structural changes following Ovx included fewer struts and nodes, a higher percentage of the simpler strut forms, and reduced endocortico-trabecular connectivity. Eight weeks of treatment with rhIGF-I or rhIGF-I/IGFBP-3 promoted periosteal and endocortical bone formation and reduced the endocortical resorption induced by Ovx. Both rhIGF-I formulations stimulated bone formation on existing trabecular surfaces which increased trabecular thickness and area but not trabecular number. These treatments prevented further deterioration of the trabecular network caused by Ovx and preserved endocortico-trabecular connectivity. In summary, changes in the femoral neck following Ovx appear to be similar in rats and humans. The highest dose of rhIGF-I/IGFBP-3 used in this study showed the best results in promoting cortical and cancellous bone formation, and appears to be promising therapy for human osteopenias. [ABSTRACT FROM AUTHOR]

This retrospective study examines data from 55 patients sedated in a paediatric intensive care unit (PICU) with midazolam. Midazolam sedation was initiated with a bolus of 0.25 mg.kg-1 followed by a continuous infusion of 0.4-4 micrograms.kg-1.min-1. Physiological and metabolic parameters, infusion rates, duration, and sedation scores were monitored. Midazolam infusions were effective in sedating all the children studied during all or part of their PICU admission. The median duration of sedation was 74 h with a range of 4 to 1272 h. Haemodynamics were unchanged. Of the patients 46% were effectively alimented by the enteral route, and enteral alimentation was successful in all patients in whom it was attempted. Unassisted ventilation occurred in 44% of the patients during infusion. Oxygen consumption was 28% lower than in the control. Disadvantages of midazolam infusion have included inability to sedate during extracorporeal membrane oxygenation and development of acute tolerance. [ABSTRACT FROM AUTHOR]

Improvements in computer-aided design (CAD) tools can significantly increase designer productivity, since the ability to explore a variety of possible designs quickly and effectively is essential for a designer. Using an optimization tool, systematic exploration of design spaces can be achieved readily. The general goal of the work presented here is to aid design by combining the strengths of optimization techniques with those of CAD systems. The specific objective of this paper is to introduce goal directed geometry (GDG) as a computational framework for parametric design, aiding the formulation of engineering problems with geometric considerations and their solution with a multi-objective optimization package. Using GDG, ‘What if’ questions can be posed and answered in a systematic fashion. Specific issues to be addressed include the development of a general parametric design problem formulation, development of static and dynamic geometric non-interference constraints for use in this formulation, and investigation of the efficacy of the adaptive linear programming (ALP) multiobjective optimization algorithm in solving such problems. Two examples are presented, one each to illustrate the use of the static and dynamic non-interference constraints. Results demonstrate that the GDG formulation can be applied readily to a wide variety of parametric design problems. Additionally, the ALP algorithm successfully navigates around geometric constraints, although care must be taken when linearizing highly non-linear design spaces. [ABSTRACT FROM AUTHOR]

A new feature based shape optimization technique is presented that is capable of modifying the topology (configuration) and shape to reduce the area of 2-D components based on the stress distribution in the component. Shape optimization attempts to maximize material usage to achieve a uniform stress distribution near the allowable limit of the material. Features can be added to the component, or can be modified, in order to optimize the material usage. By using features as a basis for shape modification, the problem of component connectivity can be handled in a consistent, intelligent manner, and the problem of smoothness is eliminated. A program was written to implement the optimization technique and was applied to two example problems, including one from the literature that used a different modification technique. The other example illustrates shape modification capabilities with more complicated geometry. Results from both examples are compared to results obtained using other topological modification techniques. [ABSTRACT FROM AUTHOR]

The therapeutic effect of fluoride alone or fluoride followed by calcium and vitamin D administration on the osteoporosis induced by immobilization of the rat tail vertebrae was investigated. Tail immobilization was carried out by musclectomy and tendectomy. After 60 days of immobilization, the vertebrae were examined for bone mass, breaking strength, ash percentage and Ca, P and F content. NaF or Ca and vitamin D as separate treatments improved the osteoporosis induced by immobilization. The effects of NaF treatment were more pronounced than those of Ca and vitamin D. NaF and NaF followed by Ca and vitamin D produced a similar degree of improvement in breaking strength. The fact that fluoride and calcium and vitamin D were administered separately and sequentially may explain the absence of a synergistic effect. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies directed against the cholinergic binding site of the acetylcholine receptor were found to alter the ion channel properties in cultured chick "myoballs." Time and dose dependent reduction in acetylcholine sensitivity was observed. Noise analysis experiments indicated a decrease in the mean single channel conductance and an increase in the mean single channel open time. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the enzymes responsible for and metabolites produced from the metabolism of halomon, a halogenated monoterpene that is isolated from the red algae Portieria hornemanii and has in vitro activity in the NCI screen against brain, renal, and colon cancer cell lines. Materials and methods: Mouse and human liver fractions, prepared by homogenization and differential centrifugation, were incubated with halomon, extracted with toluene, and analyzed by gas chromatography. Results: In the presence of NADPH, mouse-liver 9,000- g supernatant (S9) fractions metabolized halomon, but boiled S9 fractions did not. NADH could not substitute for NADPH. Further separation of murine hepatic S9 fractions produced a microsomal fraction that contained all of the halomon-metabolizing activity; cytosol had none. Carbon monoxide reduced murine hepatic microsomal metabolism of halomon, whereas an anaerobic, N2 environment greatly accelerated the disappearance of halomon. Human hepatic microsomes metabolized halomon and required NADPH to do so. Carbon monoxide completely inhibited human hepatic microsomal metabolism of halomon. Unlike murine hepatic microsomal metabolism of halomon, anaerobic conditions did not enhance the metabolism of halomon by human hepatic microsomes. Neither 100 μ M diethyldithiocarbamate, 1 μ M quinidine, 100 μ M ciprofloxacin, 3 μ M ketoconazole, nor 100 μ M sulfinpyrazone inhibited the metabolism of halomon by human hepatic microsomes. Both murine and human hepatic microsomes produced a metabolite of halomon. The mass spectrum of this metabolite indicated the loss of one chlorine atom and one bromine atom. Conclusions: Halomon is metabolized by mouse and human hepatic cytochrome P-450 enzymes, the identities of which remain unknown. Hepatic metabolism of halomon is very consistent with the concentrations of halomon measured in mouse tissues and urine after i.v. administration of the drug. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to define the plasma pharmacokinetics, bioavailability, and tissue distribution in mice of halomon, a halogenated monoterpene from Portieria hornemanii that is active in vitro against brain-, renal-, and colon-cancer cell lines. Halomon formulated in cremophor : ethanol : 0.154 M NaCl (1 : 1 : 6, by vol.) was injected i.v. at 20, 60, 90, or 135 mg/kg into female CDF mice. Doses of 135 mg/kg were also given i.p., s.c., and by enteral gavage to female CDF mice and i.v. to male CDF mice. Plasma halomon concentrations were measured with a gas-chromatography system using electron-capture detection. Halomon concentrations were also determined in the brains, hearts, lungs, livers, kidneys, spleens, skeletal muscles, fat, red blood cells, and, if present, testes of mice given 135 mg/kg i.v. Halomon plasma pharmacokinetics were well fit by a two-compartment, open linear model and were linear between 20 and 135 mg/kg. Population estimates of parameters describing halomon plasma pharmacokinetics in female CDF mice were developed with a standard two-stage technique and also by simultaneous modeling of data from 20-, 60-, 90-, and 135-mg/kg i.v. studies in female mice. Halomon bioavailability was 45%, 47%, and 4% after i.p., s.c., and enteral dosing, respectively. Urinary excretion of the parent compound was minimal. Halomon was distributed widely to all tissues studied but was concentrated and persisted in fat. Halomon concentrations measured in the brain were comparable with concomitant concentrations detected in plasma and most other tissues. These data and models are helpful in the simulation and evaluation of conditions produced by preclinical screening and toxicology studies. [ABSTRACT FROM AUTHOR]

This paper presents two empirical studies of software production conducted at two large Canadian banks. For this purpose, we introduce a new model of software production that considers more outputs than those previously cited in the literature. The first study analyses a group of software development projects and compares the ratio approach lo performance measurement to the results of DEA. It is shown that the main deficiencies of the performance ratio method can be avoided with the latter. Two different approaches are employed to constrain the DEA multipliers with respect to subjective managerial goals. As is further shown, incorporating subjective values into efficiency measures must be done in a careful and rigorous manner, within a framework familiar to management. The second study investigates the effect of quality on software maintenance (enhancement) projects. Quality appears to have a significant impact on the efficiency and cost of software projects in the data set. We further show the problems that may result when quality is excluded from the production models for efficiency assessment. In particular, we show some of the misleading results that can be obtained when the simple, traditional, ratio definition of productivity is used for this purpose. [ABSTRACT FROM AUTHOR]

Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F 1 F O -ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)