Global feedforward active noise control in vibro-acoustic cavities without increasing structural vibrations.

Interior noise in vibro-acoustic cavities may be generated due to acoustic and structural disturbances. Earlier studies have shown that for global control, the maximum reduction in acoustic potential energy can be realised by using an optimum combination of acoustic and structural actuators. However, it is observed that this reduction in interior noise may also be accompanied with an increase in kinetic energy of the cavity structure. This paper presents the development of a feedforward technique for active noise control in vibro-acoustic cavities ensuring that the noise reduction does not lead to an increase in kinetic energy. The problem is formulated as a constrained minimisation problem to minimise the acoustic potential energy subject to a constraint that the kinetic energy does not increase. Through a numerical study, it is shown that the optimum solution of the above problem indeed is favourable in terms of reduction in acoustic potential energy in the cavity and kinetic energy of the structure. The paper further proposes a method for solution of this constrained minimisation problem using a penalty function method and solution of sequential unconstrained problems. The proposed method is validated through a numerical study on a car-like cavity for single- and multi-tonal noise.

Structural sensing of interior sound for active control of noise in structural-acoustic cavities.

This paper proposes a method for structural sensing of acoustic potential energy for active control of noise in a structural-acoustic cavity. The sensing strategy aims at global control and works with a fewer number of sensors. It is based on the established concept of radiation modes and hence does not add too many states to the order of the system. Acoustic potential energy is sensed using a combination of a Kalman filter and a frequency weighting filter with the structural response measurements as the inputs. The use of Kalman filter also makes the system robust against measurement noise. The formulation of the strategy is presented using finite element models of the system including that of sensors and actuators so that it can be easily applied to practical systems. The sensing strategy is numerically evaluated in the framework of Linear Quadratic Gaussian based feedback control of interior noise in a rectangular box cavity with a flexible plate with single and multiple pairs of piezoelectric sensor-actuator patches when broadband disturbances act on the plate. The performance is compared with an "acoustic filter" that models the complete transfer function from the structure to the acoustic domain. The sensing performance is also compared with a direct estimation strategy.

Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers.

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.

Nuclear F-actin Cytology in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

Oral cavity cancer has a low 5-y survival rate, but outcomes improve when the disease is detected early. Cytology is a less invasive method to assess oral potentially malignant disorders relative to the gold-standard scalpel biopsy and histopathology. In this report, we aimed to determine the utility of cytological signatures, including nuclear F-actin cell phenotypes, for classifying the entire spectrum of oral epithelial dysplasia and oral squamous cell carcinoma. We enrolled subjects with oral potentially malignant disorders, subjects with previously diagnosed malignant lesions, and healthy volunteers without lesions and obtained brush cytology specimens and matched scalpel biopsies from 486 subjects. Histopathological assessment of the scalpel biopsy specimens classified lesions into 6 categories. Brush cytology specimens were analyzed by machine learning classifiers trained to identify relevant cytological features. Multimodal diagnostic models were developed using cytology results, lesion characteristics, and risk factors. Squamous cells with nuclear F-actin staining were associated with early disease (i.e., lower proportions in benign lesions than in more severe lesions), whereas small round parabasal-like cells and leukocytes were associated with late disease (i.e., higher proportions in severe dysplasia and carcinoma than in less severe lesions). Lesions with the impression of oral lichen planus were unlikely to be either dysplastic or malignant. Cytological features substantially improved upon lesion appearance and risk factors in predicting squamous cell carcinoma. Diagnostic models accurately discriminated early and late disease with AUCs (95% CI) of 0.82 (0.77 to 0.87) and 0.93 (0.88 to 0.97), respectively. The cytological features identified here have the potential to improve screening and surveillance of the entire spectrum of oral potentially malignant disorders in multiple care settings.

Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

Age-associated changes in the DNA of mouse tissue.

The template activity of DNA with calf thymus DNA polymerase has been studied in sections of fixed brain, liver, and heart tissues from young and senescent mice. The enzyme catalyzed greater incorporation of deoxyribonucleotide monophosphates into nuclei of old mouse neurons, astrocytes, Kupffer cells, and heart muscle fibers. The results are interpreted as the accumulation of DNA strand breaks with aging.

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system.

We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, x 4 days; thiotepa 300 mg/m2/day, x 3 days; and carboplatin approximately 500 mg/m2/day, x 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, +/-oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.+/-8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.

In vivo efficacy of an alcohol-based surgical hand disinfectant containing a synergistic combination of ethylhexylglycerin and preservatives.

Alcohol-based surgical hand disinfectants are widely available in healthcare settings. Some currently marketed alcohol-based products use active concentrations of antimicrobials to achieve the required efficacy, raising the risk for exposure to potentially irritating levels of antimicrobials. This study compares the in vitro and in vivo efficacy of an alcohol-based surgical hand preparation containing 70% ethanol and preservative levels of chlorhexidine gluconate (CHG) and benzalkonium chloride (BZK) in synergistic combination with ethylhexylglycerin (Surgicept) with a surgical hand disinfectant containing 61% ethanol and 1% CHG (Avagard). The in vivo efficacy of Surgicept and Avagard was evaluated in volunteers using the Tentative Final Monograph method of the Food and Drug Administration (FDA), and their prolonged effect against transient pathogens was compared using a pig skin model. Surgicept exceeded the FDA requirements for surgical hand antiseptic with mean log(10) reductions of 2.36, 3.3 and 3.54 in resident flora 1 min after initial application, and showed a persistent effect with mean log(10) reductions of 2.23, 2.73 and 3.3, 6h post application on days 1, 2 and 5, respectively. Surgicept showed a superior prolonged effect against transient bacteria compared with Avagard. Surgicept (70% alcohol and preservative levels of CHG and BZK) may provide similar in vivo efficacy as Avagard (61% ethanol and 1% CHG).

Singlet oxygen: a primary effector in the ultraviolet A/near-visible light induction of the human heme oxygenase gene.

Both singlet oxygen and the hydroxyl radical are generated in mammalian cells by UVA (320-380 nm) and possibly near-visible (380-420 nm) radiation. We have modulated the cellular levels of these two reactive oxygen species in order to compare their involvement in the induction of the human heme oxygenase (HO) gene by broad spectrum UVA/near-visible light (UVA/NVL). Irradiation in deuterium oxide (in which singlet oxygen has a longer half-life) enhances the broad spectrum UVA/NVL induction of this gene. Sodium azide and L-histidine which are scavengers of both singlet oxygen and the hydroxyl radical reduce the fluence-dependent accumulation of HO mRNA, while compounds which are only hydroxyl radical scavengers, namely, mannitol and dimethyl sulfoxide do not. Rose Bengal, a known generator of singlet oxygen, also increases the HO mRNA levels, and this induction is enhanced in deuterium oxide. We conclude that the observed effects of deuterium oxide and singlet oxygen scavengers on HO mRNA levels are not due to a nonspecific effect on transcription but that singlet oxygen is a primary effector in the UVA/NVL induction of the human heme oxygenase gene.

Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors.

Tumor-restricted surface antigens may be targets for diagnosis and immune-based therapies. Monoclonal antibody 8H9 is a murine IgG1 hybridoma derived from the fusion of mouse myeloma SP2/0 cells and splenic lymphocytes from BALB/c mice immunized with human neuroblastoma. By immunohistochemistry, 8H9 was highly reactive with human brain tumors, childhood sarcomas, and neuroblastomas, and less so with adenocarcinomas. Among primary brain tumors, 15 of 17 glioblastomas, 3 of 4 mixed gliomas, 4 of 11 oligodendrogliomas, 6 of 8 astrocytomas, 2 of 2 meningiomas, 3 of 3 schwannomas, 2 of 2 medulloblastomas, 1 of 1 neurofibroma, 1 of 2 neuronoglial tumors, 2 of 3 ependymomas, and 1 of 1 pineoblastoma tested positive. Among sarcomas, 21 of 21 Ewing's/primitive neuroectodermal tumor, 28 of 29 rhabdomyosarcomas, 28 of 29 osteosarcomas, 35 of 37 desmoplastic small round cell tumors, 2 of 3 synovial sarcomas, 4 of 4 leiomyosarcomas, 1 of 1 malignant fibrous histiocytoma, and 2 of 2 undifferentiated sarcomas tested positive with 8H9. Eighty-seven of 90 neuroblastomas, 12 of 16 melanomas, 3 of 4 hepatoblastomas, 7 of 8 Wilms' tumors, 3 of 3 rhabdoid tumors, and 12 of 27 adenocarcinomas also tested positive. In contrast, 8H9 was nonreactive with normal human tissues including bone marrow, colon, stomach, heart, lung, muscle, thyroid, testes, pancreas, and human brain (frontal lobe, cerebellum, pons, and spinal cord). Reactivity with normal cynomolgus monkey tissue was restricted similarly. Indirect immunofluorescence localized the antigen recognized by 8H9 to the cell membrane. The antigen is proteinase sensitive and is not easily modulated off the cell surface. 8H9 immunoprecipitated a M(r) 58,000 band after N-glycanase treatment, most likely a protein with a heterogeneous degree of glycosylation. This novel antibody-antigen system may have potential for tumor targeting.

Regulation of Xenopus c-myc promoter activity in oocytes and embryos.

We have studied the regulation of transcription of the Xenopus c-myc I gene in oocytes and embryos. Various 5' and internal deletions of a 1310-bp-long c-myc I promoter fragment have been ligated upstream of the chloramphenicol acetyl transferase (CAT) reporter gene and microinjected into oocytes and fertilized eggs. Activity was determined by CAT assay and primer extension. The c-myc promoter drives transcription very efficiently, and a truncated promoter -158/+46 essentially retains full activity. This region contains an overlapping E2F/SP1 site and two tandem Sp1 sites homologous to those found in the c-myc gene of mouse. Internal deletions show that both elements are equally active in oocytes in driving the expression of CAT. A germinal vesicle extract contains a DNA-binding activity specific for an Sp1 consensus sequence but not the E2F site. The data suggest that the high transcription level of the endogenous c-myc gene in Xenopus oocytes is mediated by Sp1 or a related transcription factor. In embryos a different mechanism emerges and the functional role of the Sp1 binding sites appears to be less important.

An alcohol hand rub containing a synergistic combination of an emollient and preservatives: prolonged activity against transient pathogens.

A new alcohol-based hand antiseptic (Octoxy hand rub) containing a synergistic combination of an emollient (Octoxyglycerine) and preservatives was developed and evaluated for immediate and prolonged activity against transient bacteria. The in vitro and in vivo antimicrobial efficacy was compared with other alcohol hand rubs containing preservative/antimicrobial (Prevacare and Avagard). In vitro evaluation was carried out using a tube-dilution method and a pig-skin model. Rapid and prolonged efficacy in vivo was evaluated against Staphylococcus epidermidis on the hands of volunteers. Octoxy hand rub was 100% effective in rapidly killing pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium in vitro. In volunteers, all three hand rubs gave a significant reduction in microbial count within 15s. Octoxy hand rub showed significantly higher efficacy against S. aureus and Escherichia coli than Avagard and Prevacare 15 min after application to the pig-skin model, and against S. epidermidis in both the pig-skin model and in volunteers. Use of Octoxy hand rub with broad-spectrum immediate and prolonged antimicrobial activity may be a very effective way of improving hand hygiene without exposing the hands to higher concentrations of antimicrobials.

The neural inductive response of competent chick ectoblast decreases away from the host axis and correlates with an increased proliferative activity.

We have assessed the quality and quantity of the neural inductive response of the chick gastrula ectoblast located at increasing distancefrom the host axis. In a stage 4 gastrula, entire ectoblast exhibits neural competence. The quality of induced neural tissue shifts from deuterencephalic type in the area pellucida to archencephalic type in the area opaca and primitive medullary or palisade type atthe margin of overgrowth with a concomitant reduction in the number of induced neural cells. In contrast, the mitotic and 3H-TdR labelling frequencies in the competent ectoblast increase with increasing distance from the host axis and in a proportion inverse to the amount of induced neural tissue. It is suggested that the strong neural inductive response is correlated with low proliferative activity, or longer cell cycle time, of the competent ectoblast.

The neural inductive signal is transferred to ectoblast in 1-2 h but a continued contact with mesoblast for 2-3 h is essential for neuralization in the chick area pellucida.

In the area pellucida of the chick gastrula, the Hensen's node (HN) graft must contact the competent ectoblast for at least 4 h to promote neural induction. When we removed the grafted HN after 1 to 3 h and replaced it by a non-inducing post nodal (PN) fragment, a 1-2 h contact with HN was found to be sufficient to promote neural induction. When HN graft was removed after 3 or 4 h and replaced by PN, the neural inductive response was substantially improved towards formation of archencephalic structures. Thus, our results indicate that neural induction takes place in two steps. In the first step, a contact with HN for 1-2 h is sufficient to transferthe inductive signal which is stabilized through a second step involving continued cell-cell contact with even non-inducing PN mesoblast.

Caudalization by retinoic acid is correlated with inhibition of cell population growth and expansion of chick blastoderms cultured in vitro.

Full primitive streak stage chick embryos, cultured in vitro for 20 h in the presence of 10(-9) to 10(-7) moles of retinoic acid (retinol, all-trans), exhibit increasing extent of malformations. RA causes caudalization, suppression of telencephalon, formation of open and enlarged neural tube in the regions of midbrain, hindbrain and spinal cord, failure of fusion of heart tubes, and gives rise to winged or diffused, and even supernumerary somites. Extreme abnormalities include failure to form the head fold and foregut. Abnormal embryos were graded according to Rao and Chauhan (Teratology 4: 191-198, 1971), and we find that the larger the severity of malformation, the smaller the size of total cell population and blastoderm area. Concomitant to caudalization, retinoic acid suppresses the cell population growth.

Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding.

PPARs are members of the nuclear hormone receptor superfamily and are primarily involved in lipid metabolism. The expression patterns of all 3 PPAR isotypes in 22 adult rat organs were analyzed by a quantitative ribonuclease protection assay. The data obtained allowed comparison of the expression of each isotype to the others and provided new insight into the less studied PPAR beta (NR1C2) expression and function. This isotype shows a ubiquitous expression pattern and is the most abundant of the three PPARs in all analyzed tissues except adipose tissue. Its expression is especially high in the digestive tract, in addition to kidney, heart, diaphragm, and esophagus. After an overnight fast, PPAR beta mRNA levels are dramatically down-regulated in liver and kidney by up to 80% and are rapidly restored to control levels upon refeeding. This tight nutritional regulation is independent of the circulating glucocorticoid levels and the presence of PPAR alpha, whose activity is markedly up-regulated in the liver and small intestine during fasting. Finally, PPAR gamma 2 mRNA levels are decreased by 50% during fasting in both white and brown adipose tissue. In conclusion, fasting can strongly influence PPAR expression, but in only a few selected tissues.

Lipid metabolite involvement in the activation of the human heme oxygenase-1 gene.

Cellular effects of ultraviolet A (UVA) radiation include peroxidation of membrane lipids as well as a decrease in intracellular glutathione. We have investigated whether damage to membrane lipids is involved in the activation of the human heme oxygenase-1 gene by UVA. Irradiation of human skin fibroblasts in the presence of the lipophilic antioxidants, butylated hydroxytoluene and alpha-tocopherol, enhances the UVA-induced HO-1 mRNA accumulation, suggesting that peroxidation of plasma membrane lipids is not involved. Furthermore, sodium ascorbate, which induces lipid peroxidation mainly in the plasma membrane, induces HO-1 mRNA to low levels only. The decrease in GSH by UVA radiation is not affected by the presence of the lipophilic antioxidants while ascorbate treatment increases the intracellular GSH by twofold above controls. These results indicate that peroxidation of internal membrane lipids, a decrease in the intracellular GSH levels and the integrity of the plasma membrane are all important for the UVA-induction of heme oxygenase-1. Both nonenzymatic as well as enzymatic lipid peroxidation metabolites are inducers of heme oxygenase-1. The nonenzymatic lipid peroxidation product 4-hydroxynonenal induces heme oxygenase-1 mRNA up to 40-fold and the phospholipase metabolites diacylglycerol and arachidonic acid induce this mRNA by three-to sixfold above basal levels. We also demonstrate that the cyclooxygenase metabolites of arachidonic acid are important for the UVA-activation of the heme oxygenase-1 gene.

Cyclooxygenase dependent release of heme from microsomal hemeproteins correlates with induction of heme oxygenase 1 transcription in human fibroblasts.

Induction of heme oxygenase 1 transcription and enzymatic activity is a common response after exposure of cells to various forms of oxidative stress including ultraviolet A radiation (UVA) and hydrogen peroxide. We now show that UVA irradiation or hydrogen peroxide treatment of human skin fibroblasts leads to an immediate release of the heme oxygenase substrate, heme, from microsomal hemeproteins. The release of heme by UVA apparently involves cyclooxygenase activity because it is inhibited by the cyclooxygenase inhibitor indomethacin. We also demonstrate a high degree of correlation between the amount of heme released and the degree of subsequent induction of heme oxygenase 1 transcription following UVA and hydrogen peroxide treatment. We propose that release of heme from microsomal hemeproteins determines the degree of induction of heme oxygenase 1 transcription in human fibroblasts after oxidative stress.

Longevity, stability and DNA repair.

The functional capacity of a cell, tissue, organ, or organism is dependent upon its ability to maintain the stability of its unit components. The higher the differentiated state of the system, the greater the amount of stability required to maintain that state as a function of time. Stability can be achieved via either redundancy or repair. Redundancy while easily achievable in biological systems is both costly and limited by thermodynamic considerations. Repair, in its general sense, has no such limitations. Repair at the cellular and macromolecular level is multiple in its forms and varies as a function of species, tissue, and stage of the cell cycle. The repair of DNA damage is a dynamic process with many components and subcomponents, each interacting with one another in order to achieve a balance between individual stability and evolutionary diversity. Thus, between internal and external factors which damage DNA and the subsequent expression of alterations in the functional stability of DNA lie the multi-functional pathways which attempt to maintain DNA fidelity. A strong correlation between ulta-violet light induced excision or pre-replication repair, as measured by autoradiogrphy and maximum species lifespan has been reported within different strains of the same species, between related species (e.g. Mus musculus and Peromyscus leucopus), between five orders of mammals, and most recently within members of the primate family. As has been demonstrated by the authors and others, differences in excision repair between species and tissues may relate to the turning off of portions of the repair processes during embryogenesis. Regardless of why such correlations exist or the nature of their mechanisms, it is naive to either assert or deny a causal role for DNA repair in longevity assurance systems. For example, while species-related differences in DNA repair may reflect the turning off of such repair processes during fetal development this does not mean that rates of accumulation of DNA damage are not altered by such changes. Indeed, such a phenomena might well explain the rapid evolution of lifespan within the primates without a concurrent input of new genes.

Response of previously untreated metastatic rhabdomyosarcoma to combination chemotherapy with carboplatin, epirubicin and vincristine.

This study aimed to assess the response to a novel combination chemotherapy containing carboplatin plus epirubicin in previously untreated children with metastatic rhabdomyosarcoma. 81 children (< or = 18 years) were treated between 1989 and 1994 with a combination of carboplatin, epirubicin and vincristine, given as initial therapy as part of a multicentre European trial (SIOP Intergroup Study of Stage IV Malignant Mesenchymal Tumours in Children). The chemotherapy regimen (CEV) was: carboplatin 500 mg/m2 plus epirubicin 150 mg/m2 administered on day 1, and vincristine 1.5 mg/m2 administered on days 1 and 7. Response was evaluated at day 21. 2 patients achieved complete remission and 41 patients partial remission, with an overall response rate of 53% (95% confidence interval 45-76%). Three patients showed progressive disease (4%). Toxicity was mainly haematological, with 52% experiencing grade IV neutropenia and 34% grade IV thrombocytopenia. Mucositis and infections were not severe. There were no toxic deaths. The combination of carboplatin, epirubicin and vincristine is effective and well tolerated in patients with metastatic rhabdomyosarcoma.