Spatially-resolved individual particle spectroscopy using photothermal modulation of Mie scattering.

We report a photothermal modulation of Mie scattering (PMMS) method that enables concurrent spatial and spectral discrimination of individual micron-sized particles. This approach provides a direct measurement of the "fingerprint" infrared absorption spectrum with the spatial resolution of visible light. Trace quantities (tens of picograms) of material were deposited onto an infrared-transparent substrate and simultaneously illuminated by a wavelength-tunable intensity-modulated quantum cascade pump laser and a continuous-wave 532 nm probe laser. Absorption of the pump laser by the particles results in direct modulation of the scatter field of the probe laser. The probe light scattered from the interrogated region is imaged onto a visible camera, enabling simultaneous probing of spatially-separated individual particles. By tuning the wavelength of the pump laser, the IR absorption spectrum is obtained. Using this approach, we measured the infrared absorption spectra of individual 3 µm PMMA and silica spheres. Experimental PMMS signal amplitudes agree with modeling using an extended version of the Mie scattering theory for particles on substrates, enabling the prediction of the PMMS signal magnitude based on the material and substrate properties.

Coherent combining of a 4 kW, eight-element fiber amplifier array.

Commercial 0.5 kW Yb-doped fiber amplifiers have been characterized and found to be suitable for coherent beam combining. Eight such fiber amplifiers have been coherently combined in a tiled-aperture configuration with 78% combining efficiency and total output power of 4 kW. The power-in-the-bucket vertical beam quality of the combined output is 1.25 times diffraction limited at full power. The beam-combining performance is independent of output power.

Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls.

BACKGROUND AND AIMS: Many patients with irritable bowel syndrome (IBS) show intestinal hypersensitivity to distension and sensitisation after repeated intestinal distensions. Abnormalities in endogenous pain inhibitory mechanisms, such as diffuse noxious inhibitory controls (DNIC), may be implicated and were investigated during brain functional magnetic resonance imaging (fMRI). PATIENTS AND METHODS: fMRI was performed in 10 female patients with IBS (five constipated (IBS-C) and five with diarrhoea (IBS-D)) and 10 female healthy controls during rectal balloon distension alone or during activation of DNIC by painful heterotopic stimulation of the foot with ice water. Rectal pain was scored with and without heterotopic stimulation (0 = none, 10 = maximal). RESULTS: Heterotopic stimulation decreased median rectal pain scores significantly in healthy controls (-1.5 (interquartile range -2 to -1); p = 0.001) but not in IBS-C (-0.7 (-1 to 0.5)), IBS-D (-0.5 (-1.5 to 0.5)), or in all IBS patients (0 (-1.5 to 1.3)). Brain activation changes during heterotopic stimulation differed highly significantly between IBS-C, IBS-D, and controls. The main centres affected were the amygdala, anterior cingulate cortex, hippocampus, insula, periaqueductal gray, and prefrontal cortex, which form part of the matrix controlling emotional, autonomic, and descending modulatory responses to pain. CONCLUSIONS: IBS-C and IBS-D appear to have differing abnormal endogenous pain inhibitory mechanisms, involving DNIC and other supraspinal modulatory pathways.

Intrinsic chromatic switching of visible luminescence in Yb3+,Er3+:CsCdBr3.

Bistability is reported in sensitized Er3+ luminescence driven by an Yb3+ transition that previously revealed an Yb3+ luminescent instability. To our knowledge this is the first report of bistable energy transfer between different rare-earth ions.

Detection of irregular verb violations by children with and without SLI.

Fifty-seven children (ages in years;months: 5;7-8;8) with and without Specific Language Impairment (SLI) participated in judgment and elicitation tasks designed to evaluate their understanding of restrictions associated with irregular verb forms. The performance of the SLI group was similar to the performances of the control groups in that all children demonstrated high levels of sensitivity to violations involving verb-agreement errors (e.g., he am falling). The production and acceptance rates of past tense overregularizations (e.g., he falled) by the SLI and language-match groups were similar, and both were higher than the age-match group. Differences between affected and unaffected children were observed in their productions and relative levels of sensitivity to infinitive errors in finite positions (e.g., he fall off). As expected, children in the SLI group were more likely to produce and accept infinitive forms in finite positions. Children in the SLI group also accepted more finite form errors in VP complement positions (e.g., he made him fell) than the control groups, although the latter occurred rarely in children's productions. Implications for understanding morphophonological and morphosyntactic development in children with SLI are discussed.

Different ipsilateral representations for distal and proximal movements in the sensorimotor cortex: activation and deactivation patterns.

Each hemisphere is known to be also involved in controlling the ipsilateral arm, but with an asymmetry favoring the dominant hemisphere. However, the relative role of primary and secondary motor areas in ipsilateral control is not well defined. We used whole brain functional magnetic resonance imaging in healthy human subjects to differentiate between contributions from primary and secondary areas during discrete unilateral distal finger and proximal shoulder movements. It was found that ipsilateral distal movements activated secondary areas only, while sparing or even significantly deactivating the primary sensorimotor cortex. Ipsilateral proximal movements substantially activated both SM1 and secondary areas. A newly defined small territory within the precentral gyrus, extending from the premotor cortex and intruding toward SM1, showed an activation pattern corresponding to secondary motor areas. Finally, the effects of hemispheric dominance were confirmed, but attributed exclusively to secondary areas. These new imaging findings agree well with functional requirements as well as established anatomical and neurophysiological data.

Evaluating the morphological competence of children with severe speech and physical impairments.

Reports present mixed findings on the extent to which the development of receptive language skills in children with severe speech and physical impairments (SSPI) is compromised by their difficulty with speaking (V. W. Berninger & B. M. Gans, 1986; D. V. M. Bishop, B. Byers Brown, & J. Robson, 1990; O. Udwin & W. Yule, 1990). In this study, grammaticality judgments were used to measure the sensitivity of 4 school-age children with SSPI to different morphological errors. These errors included violations of agreement between the subject and auxiliary verbs (e.g., she are falling), the marking of aspect (e.g., she is play the horn), and the marking of past tense on regular and irregular verbs (e.g., he jump, he fall, he falled). Performance of the participants with SSPI was compared to groups of typically developing children and adults. Results indicated that children in the SSPI and control groups made similar judgments. All groups showed high levels of sensitivity to agreement violations, aspect-marking errors, and tense-marking errors involving irregular verbs. Participants with SSPI had greater difficulty detecting tense-marking errors involving regular verbs. Implications for improving clinical assessments within this population are discussed.

Grammaticality judgements of an extended optional infinitive grammar: evidence from English-speaking children with specific language impairment.

This study reports on the outcomes of an investigation designed to evaluate competing accounts of the nature of the grammatical limitations of children with specific language impairment (SLI) with a new comprehension measure involving well-formedness judgments. It is a follow-up to the longitudinal study of Rice, Wexler, and Hershberger (1998), which reported on the production of grammatical morphemes by young children with SLI and 2 control groups of children, one at equivalent levels of mean length of utterance at the outset of the study, the other of equivalent age. In this investigation, we report on grammaticality judgment measures collected from the same 3 groups of children over a period of 2 years for 5 times of measurement. It is the first longitudinal study of grammaticality judgments of children with SLI. The findings show that children's grammatical judgments parallel their productions: Children with SLI can make fine-tuned grammatical judgments to reject morphosyntactic errors they are unlikely to commit, whereas they accept morphosyntactic errors that they are likely to produce. The findings support the extended optional infinitive (EOI) account of morphosyntactic limitation based in underlying grammatical representations and do not support accounts of input processing deficits or production constraints.

The socioemotional behaviors of children with SLI: Social Adaptation or Social Deviance?

Two models of the relationship between socioemotional behavior and verbal abilities are compared: Social Adaptation and Social Deviance. The socioemotional integrity of 17 children with specific language impairment (SLI) and 20 unaffected children who were age-matched (AM) was examined using the Child Behavior Checklist (CBCL) and the Teacher's Report Form (TRF) at kindergarten and first grade. All CBCL and TRF syndrome scale means for both groups were within normal limits. Significant group x respondent interaction effects were observed; teachers, and not parents, rated the children with SLI as having more social and internalizing behavioral problems than their AM peers. Significant differences between groups were restricted to internalizing, social, and attention problems. Very little congruence or stability over time was observed in the clinical ratings. The outcomes support a Social Adaptation Model of socioemotional behavior and language impairment. Implications for the clinical management of children with SLI are discussed.

Cytostatic drug resistance: parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA-alkyltransferase and P-glycoprotein in adult patients with leukaemia.

The levels of several potential indicators of resistance to cytostatic drugs were measured in leukaemic cells of a total of 64 adult patients with acute or chronic leukaemias before and during treatment and at relapse or recurrence of disease and compared with those of mononuclear cells from the bone marrow of healthy donors. The resistance factors included glutathione (GSH) and its associated enzymes glutathione-S-transferase (GST) and glutathione peroxidase (GPx) as well as O6-alkyguanine-DNA-alkyltransferase (ATase) and P-glycoprotein. Median values for most parameters were significantly higher in leukaemic cells than in those of normal donors although wide interindividual variation in the values of the various parameters, particularly GST, were seen. P-glycoprotein was measurable in 12.5% of untreated leukaemias but in none of the normal donors. The values of the parameters in untreated leukaemic patients were not statistically different from those at relapse or during disease progression. However, the median values for GSH, GST and GPx but not ATase in samples from untreated patients were significantly higher than those in samples taken during drug treatment. Patient response, disease-free survival or duration of remission did not correlate with the values of any of the parameters studied.

Assessment of P-glycoprotein, glutathione-based detoxifying enzymes and O6-alkylguanine-DNA alkyltransferase as potential indicators of constitutive drug resistance in human colorectal tumors.

Drug resistance is a major problem in cancer chemotherapy. Treatment protocols generally include a number of different cytotoxic drugs given in combination. Therefore, drug resistance in the tumor is likely to result from the coexpression of several cellular activities able to prevent cell killing by any of the drugs used. In this study we have measured several potential drug resistance mechanisms consisting of the multidrug resistance gene product P-glycoprotein, glutathione, glutathione-transferase and -peroxidase, and the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase in samples of colon carcinoma and normal adjacent mucosa from 23 untreated patients. All of these, with the exception of P-glycoprotein, showed significant increases in tumor tissue levels when compared with normal tissue from the same patient. The significance was highest for glutathione peroxidase (P less than or equal to 0.0005). Individual patients, however, showed very different patterns, with none, several, or all monitored resistance mechanisms elevated in the tumor. The implications both in the choice of drugs and in the use of resistance modifying agents to improve therapy for the individual patient are discussed.

The transformation of primary and established mouse mammary epithelial cells by p21-ras is concentration dependent.

We constructed a retroviral vector (pZSR) which is capable of simultaneously expressing the neomycin resistance gene and the viral ras oncogene. Primary mammary gland epithelial cells were prepared from mid-pregnant mice and infected with this virus. Cell lines with epithelial cell characteristics could be established with a low frequency. High expression of p21 v-ras was observed in these cells. They are tumorigenic and form soft agar colonies dependent on the presence of EGF and insulin in the growth medium but progress to hormone independent growth at higher passage numbers. A cloned cell line of non-tumorigenic, established mammary epithelial cells (NOG8) was also infected with the v-ras expressing virus. Individual cell clones expressing increasing amounts of p21 v-ras were selected. The level of p21 v-ras expression directly influences the morphology of the epithelial cells in culture, determines their cloning efficiency in soft agar and their tumorigenicity.

v-myc alters the response of a cloned mouse mammary epithelial cell line to lactogenic hormones.

Several oncogenes have now been implicated in mammary carcinogenesis. We investigated the phenotypic effects of expressing three representative oncogenes in mammary epithelial cells. v-myc (coding for a nuclear protein), v-Ha-ras (a G-protein homologue) and v-fgr (a tyrosine kinase) genes were introduced into the nontumorigenic clone 14 of the mouse mammary epithelial cell line COMMA-1D. Their effects upon growth and differentiation were determined. Anchorage-independent growth was induced by all three oncogenes with low efficiency. v-Ha-ras and v-fgr induced tumorigenicity in nude mice. The effect of oncogenes upon parameters unique to mammary epithelial cells in vitro was assayed. Both v-myc and v-fgr abolished the ability of clone 14 to grow as three-dimensional branching structures in hydrated collagen gel. v-fgr completely and v-myc partially inhibited the expression of the epithelium specific cytokeratins. Clone 14 can be induced to produce the beta-casein milk protein by the combination of the lactogenic hormones, dexamethasone, insulin, and PRL. Introduction of v-myc into clone 14 cells resulted in an estimated 50-fold increased induction of beta-casein protein and at least a 60-fold increase in beta-casein mRNA. The number of cells stained with anti-beta casein antibodies also showed a 10-fold increase after v-myc introduction. This still required the synergistic action of all three lactogenic hormones. Thus v-myc can alter the normal response of mammary epithelial cells to lactogenic hormones.

Gamma interferon regulates long terminal repeat-controlled oncogene expression in transformed mouse fibroblasts at the level of mRNA transcription.

In transformed NIH 3T3 cells, murine gamma interferon reduces the expression of the long terminal repeat-controlled oncogenes v-mos, c-myc, and v-Ha-ras by a direct effect on the activity of retroviral promoters, as revealed by analyses of RNA half-life and transcriptional activity of retroviral genes as well as by analyses of chloramphenicol acetyltransferase activity in cells transformed with the cat gene under the control of long terminal repeats.

Activation of the receptor kinase domain of the trk oncogene by recombination with two different cellular sequences.

A new chimeric oncogene, trk-2h, has been generated by recombination of two segments of MDA-MB231 human breast carcinoma cell line DNA after transfection in NIH/3T3 cells. The rearranged DNA segments form a fused transcriptional unit. Sequences at the 3' end are homologous to the tyrosine kinase receptor moiety found in the trk oncogene which resembles a truncated growth factor receptor lacking part of its extracellular domain (Martin-Zanca et al., 1986). The 5' sequence of the trk-2h oncogene is contributed by a gene which is expressed in all human cells tested, and is not related to any known gene. Transfection of the receptor kinase domain DNA fragment into NIH/3T3 cells generated another oncogene, trk-3mh, which contains a mouse-specific sequence fused 5' to the receptor kinase. All three trk recombinants have the receptor kinase moiety fused to an activating amino terminus at the same nucleotide in their transcriptional product.

Sequence and expression of the mouse mammary tumour virus env gene.

We have determined the DNA sequence of the envelope gene region of the GR strain of mouse mammary tumour virus. The sequence extends for 3012 nucleotides from the single EcoRI site to beyond the PstI site in the 3' long terminal repeat (LTR) of the provirus. There is a major open reading frame from nucleotides 752 to 2818 which encompasses the entire env gene. This reading frame extends through a polypurine tract and into the LTR. There is another open reading frame from the first nucleotide to position 803, presumably corresponding to the end of the pol gene. The splice acceptor site which generates env mRNA has been mapped experimentally to nucleotide 750. The env gene products, gp52 and gp36, have been positioned on the sequence using the directly determined amino acid sequences of the amino terminus of gp52; and both the amino and carboxyl termini of gp36. The start of gp52 is preceded by a series of 19 uncharged amino acids which could function as a typical signal sequence, but this sequence is only part of a much longer leader peptide. The tetrad Arg-Ala-Lys-Arg is the presumed cleavage site in the gPr73env precursor, and occurs just before the gp36 amino terminus. There are five potential asparagine-linked glycosylation sites which agrees with previous experimental results. The gp36 has two long hydrophobic regions at its amino and carboxy termini, these are suggested to act as a fusion peptide and the trans-membrane anchor, respectively.